TLR2–TLR4/CD14 polymorphisms and predisposition to severe invasive infections by Neisseria meningitidis and Streptococcus pneumoniae

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Tellería-Orriols, A. García-Salido, D. Varillas, A. Serrano-González, J. Casado-Flores" "autores" => array:5 [ 0 => array:3 [ "nombre" => "J.J." "apellidos" => "Tellería-Orriols" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "b" "identificador" => "aff0010" ] ] ] 1 => array:4 [ "nombre" => "A." "apellidos" => "García-Salido" "email" => array:1 [ 0 => "citopensis@yahoo.es" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "*" "identificador" => "cor0005" ] ] ] 2 => array:3 [ "nombre" => "D." "apellidos" => "Varillas" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "b" "identificador" => "aff0010" ] ] ] 3 => array:3 [ "nombre" => "A." "apellidos" => "Serrano-González" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] ] ] 4 => array:3 [ "nombre" => "J." 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(D) The frequency of carriers of both risk alleles in patients and controls. Neis. Men: Neisseria meningitidis; Srt. pn: Streptococcus pneumoniae." ] ] ] "textoCompleto" => "IntroductionIt is known that Streptococcus pneumoniae and Neisseria menigitidis are causes of severe invasive bacterial infections in some individuals, producing high morbidity and mortality, leading to mild or banal infections in others. The asymptomatic nasopharyngeal colonization by these bacterias is common and is related with an invasive disease in only a short number of cases.<a class="elsevierStyleCrossRefs" href="#bib0005">1,2</a> It has been described that the rate of carriers of Neisseria meningitidis rise to 80% in severely crowded conditions.<a class="elsevierStyleCrossRefs" href="#bib0015">3,4</a> On one hand, the instauration of S. pneumoniae conjugate vaccine did not decrease as expected the rates of nasopharyngeal carriers for S. pneumoniae.<a class="elsevierStyleCrossRefs" href="#bib0025">5,6</a>There are multiple underlying immune defects that may predispose to invasive infections as inmunosuppression (primary or secondary), asplenia or immune factors deficiency (properdin, components of complement or MyD88<a class="elsevierStyleCrossRefs" href="#bib0035">7,8</a>). Individuals with these conditions have an increased risk but they are only a small proportion of all cases.In healthy patients the innate immune system looks crucial for the early containment of microbial infections by triggering inflammation and coordinating the acquired immune response. The family of Toll-like receptors (TLRs) is a central component of this system and its description has permitted a better understanding of the molecular mechanisms concerning to antimicrobial and inflammatory responses. The TLRs seem to play a key role in signaling molecules of pathogens and endogenous proteins related to immune activation given their ability to recognize evolutionary conserved pathogen-associated molecular patterns of microbial origin.<a class="elsevierStyleCrossRef" href="#bib0045">9</a>Several TLRs have been identified in humans, and each one recognizes different structures, also each bacterium could activate different sets of TLRs. The TLR2 is activated by bacterial lipoproteins,<a class="elsevierStyleCrossRef" href="#bib0050">10</a> peptidoglycan and lipoteichoic acid of the cell wall. It is well known that the ability of S. pneumoniae to activate TLR2 through this pathway.<a class="elsevierStyleCrossRefs" href="#bib0045">9,11,12</a> It has been also described that S. pneumoniae pneumolysin could also stimulate cells through TLR4, but this observation has not been confirmed by all studies.<a class="elsevierStyleCrossRef" href="#bib0065">13</a> Moreover, besides TLR2, and maybe TLR4, additional TLRs are probably involved in recognition of this Gram-positive bacteria, among them TLR9.<a class="elsevierStyleCrossRefs" href="#bib0045">9,14</a>Lipopolysacharide (LPS) is a major component of the outer cell wall of Gram-negative bacteria such as N. meningitidis. The immune cell recognition of LPS involves an LPS receptor complex; of which CD14 and TLR4 are important components<a class="elsevierStyleCrossRef" href="#bib0075">15</a> and its activation could depend from the bacterial dosage. At lower bacterial concentrations, LPS activation of macrophages is TLR4/CD14 dependent. This activation can be blocked by specific antibodies to CD14 and TLR4.<a class="elsevierStyleCrossRef" href="#bib0080">16</a> Higher bacterial concentrations activate the complement and non-LPS components initiate TLR2 and TLR4 activation independent of CD14.<a class="elsevierStyleCrossRef" href="#bib0085">17</a> Finally the porin, an outer membrane protein of N. meningitidis stimulates immune response also through TLR2.<a class="elsevierStyleCrossRefs" href="#bib0090">18,19</a>Genetic variation of immune response genes is associated with susceptibility to and severity of infectious diseases.<a class="elsevierStyleCrossRefs" href="#bib0100">20–22</a> Single nucleotide polymorphisms could be in the origin of this risk explaining the interindividual susceptibility to invasive bacterial infections. In the present study we analyze the presence of a set of polymorphisms (p.R753Q of TLR2, p.D299G of the TLR4 gene and c.-159C→T located in the CD14 promoter) in 157 children with severe invasive bacterial infection by S. pneumoniae and N. meningitidis. We hypothesize that severe invasive bacterial infections by these microorganism affect the susceptible healthy individuals. Their susceptibility could be determined by genetic factors based on the relationship between its variants and the susceptibility to these infections.Materials, patients and methodsControls and cases characteristicsThe study was approved by the ethics committee of the Hospital Infantil Universitario Niño Jesús of Madrid (Spain) according to local laws and regulations. The patients were recruited from January 1 (2008) to December 31 (2010) after signing the consent by the legal tutors or caregivers of each patient.Sixty-six Caucasian healthy children were enrolled as controls: the samples were collected from blood samples taken in the hospital blood-extractions department because of non-infectious or inflammatory causes.The cases were collected from the Pediatric Intensive Care Unit (PICU). One hundred and seventy three consecutive previously healthy Caucasian children were enrolled because an invasive bacterial infection by N. meningitidis (n=59) or S. pneumoniae (n=114).The criteria applied for invasive meningococcal infection were:<ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005">•Isolation of N. meningitidis in blood or cerebrospinal fluid.</li><li class="elsevierStyleListItem" id="lsti0010">•Presence of Gram-negative diplococcus in cerebrospinal fluid.</li><li class="elsevierStyleListItem" id="lsti0015">•Severe sepsis and extensive purpura without identification of causing agent.<a class="elsevierStyleCrossRefs" href="#bib0015">3,4,23</a></li></ul>The criteria for invasive S. pneumoniae infection were:<ul class="elsevierStyleList" id="lis0010"><li class="elsevierStyleListItem" id="lsti0020">•Isolation of Gram-positive diplococcus in culture or positive protein chain reaction (PCR) for S. pneumoniae in a sterile body fluid (blood, cerebrospinal fluid, pleural fluid or peritoneal fluid) or detection of S. pneumoniae antigen by immunochromatography in the same fluids (Binnax Now®).</li></ul>Genetic analysisBlood samples from cases were obtained at hospital blood extractions department. For the cases the blood samples were obtained at PICU admission and submitted for genotyping to the laboratory of genetics. The DNA was extracted and genotyped by staff blinded to clinical data.All polymorphisms were genotyped by restriction analysis after PCR amplification. PCR of 35 cycles was performed on a thermal cycler GeneAmp9700 (Perkin-Elmer Cetus, Norwalk, CT, USA). Primers were synthesized (VWR International Eurolab, Bcn, Spain). The PCR reaction consisted of 50ng DNA, 10pm of each primer, 10μl PCR master mix (Promega®, Madison, WI, USA) and water up to 20μl.<ul class="elsevierStyleList" id="lis0015"><li class="elsevierStyleListItem" id="lsti0025">1TLR2 p.R753Q (rs5743708) PCR primers were 5′-GAAGAGAACAATGATGCTGCCATTC-3′ and R: 5′-CTAGGACTTTATCGCAGCTCTC-3′. The cycle program consisted of 94°C for 30s, 49°C for 30s, and 72°C for 30s. SsiI (Fermentas, Burlington, Canada) digestion resulted in two fragments of 115bp and 58bp (R allele) or 173bp (Q allele).</li><li class="elsevierStyleListItem" id="lsti0030">2TLR4 p.D299G (rs4986790) PCR primers were 5′-ACTTAGACTACTACCTCGGTG-3′ and R:5′-GATTTGAGTTTCAATGTGGGAAAC-3′. The cycle program consisted of 94°C for 30s, 53°C for 30s, and 72°C for 30s. HphI (Fermentas, Burlington, Canada) digestion resulted in two fragments of 168bp and 15bp (G allele) or 183bp (D allele).</li><li class="elsevierStyleListItem" id="lsti0035">3CD14 c.-159C>T (rs2569190) PCR primers were: 5′-TCACCTCCCCACCTCTCTT-3′ and R: 5′-CCTGCAGAATCCTTCCTGTT-3′. The cycle program consisted of 94°C for 30s, 59°C for 30s, and 72°C for 30s. HaeIII (Roche® Mannheim Germany) digestion resulted in two fragments of 85bp and 22bp (C allele) or 107bp (T allele).</li></ul>Statistical analysisStatistical analysis was performed in a Hewlett–Packard computer with the statistical program SPSS® 19.0 (IBM®). A descriptive analysis was done with the epidemiological and clinical variables; the values are shown with mean and range. Genotype and allele frequencies between groups were compared using the chi-square test. Alternatively Fisher's exact test was used when frequencies were <5. The value reported is the Yates chi-square, corrected for continuity when applicable. Findings of p<0.05 were considered statistically significant.ResultsControls and cases characteristicsThe control group has a mean age of 50 months (range 3 months–14 years); 33 were males and 33 females. The mean age of the patients was 41 months (range 3 days–17 years); 92 of them were males and 81 females.The distribution of severe invasive bacterial infection by N. meningitidis was: meningitis n=8, sepsis n=41 and meningitis with sepsis n=10.The distribution for S. pneumoniae infections was: meningitis n=12, Sepsis n=102.GenotypingGenotypic distribution of the polymorphisms studied in patients and controls are shown in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>.<elsevierMultimedia ident="tbl0005"></elsevierMultimedia>TLR2The p.753Q allele of the p.R753Q polymorphism of the TLR2 gene was clearly overrepresented in patients compare to controls. Fifty nine percent of the patients with meningococcal infection (p=0.0003) and 59.3% of those with S. pneumoniae infection, (p<0.0001) carried at least one copy of this allele (see <a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a> and <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>).<elsevierMultimedia ident="fig0005"></elsevierMultimedia><elsevierMultimedia ident="tbl0010"></elsevierMultimedia>TLR4The frequency of carriers of the p.299G allele was higher (p=0.0472) in the case of meningococcal infection (23.7%) compared to controls (9.1%). The allelic frequency of the p.299G allele was also higher (p=0.0189) in this group of patients (16.1%) when compared to healthy children (6.1%) with (data not shown in tables). No differences were found between patients with S. pneumoniae infections and controls (see <a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a> and <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>).CD14The study of c.-159C>T polymorphism showed that the allele c.-159T was more frequent in both group of patients than the c.-159C allele which was the most frequent in controls. Nevertheless, the p value reached statistical significance only comparing the allelic frequencies in patients with meningococcal infections and controls (p=0.0084). The frequency of patients with one or two copies (carriers) of the allele c.-159T was higher in case of meningococcal (86.4%; p=0.0276) or S. pneumoniae (85.1%; p=0.0128) infections than in controls (68.2%; see <a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a> and <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>).TLR4 plus CD14Taking together the p.753Q of TLR2 and c.-159T of CD14 alleles, 50.8 ((30/59) and 50.0% (57/114) of the patients with meningococcal and S. pneumoniae infections carried at least one copy of both risk alleles (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>D) while this haplotype was found in 16.6% (11/66) controls (p<0.0001 in both cases)Hardy–Weinberg equilibriumThe distribution of genotypes in the control population was in H–W equilibrium in all the studied polymorphisms.DiscussionThe ability to sense pathogenic organisms and to respond adequately preserving the host biological identity is essential to survival. The innate immune system is the first defence line against invading pathogens. It plays a key role in acute host response.<a class="elsevierStyleCrossRef" href="#bib0120">24</a> The pathogens are recognized by a set of receptors which recognize conserved pathogen associated molecular patterns (PAMPs). The potential effect of the genetic variability on the individual susceptibility to disease is not completely known. Related to this, in our study, there are two main original findings: (1) patients with N. meningitidis or S. pneumoniae infections showed a higher prevalence of p.753Q TLR2 variant and c.-159T allele of the CD14 promoter polymorphism; (2) the ratio of carriers for the p.299G allele was slightly higher in meningococcal disease.TLR2TLR2 can recognize a wide spectrum of PAMPs including molecules shared by Gram-positive bacteria or specific molecules of Gram-negative bacteria (as the porins of meningococci or the LPS of Bordetella or Legionella species). Moreover, TLR2 is capable to recognize molecular patterns of viruses, parasites and mycobacteria.Association between TLR2 polimorphisms and leprosy, tuberculosis and staphylococcal infection has been previously reported. Moreover TLR2-knockout mice are more susceptible to septicemia and/or meningitis caused by a wide spectrum of bacteria including S. pneumoniae.<a class="elsevierStyleCrossRefs" href="#bib0125">25,26</a> Also TLR2-deficient mice show an increased susceptibility to infections, suggesting that polymorphisms that affect TLR expression or function may impair host response to a given spectrum of pathogens.TLR2 is probably the most important receptor for Gram-positive bacterial products. Moreover, TLR2 is capable to detect a wide variety of molecules from Gram-negative bacteria, between others the porin from meningococci. This ability to recognize such a variety of ligands probably arises from its potential to form TLR2 homodimers and heterodimers with TLR1 and TLR6.<a class="elsevierStyleCrossRef" href="#bib0135">27</a>In our study, the ratio of patients with N. meningitidis or S. pneumoniae infection that carried the allele p.753Q were close to 60%, much more than the expected 25% based on the frequency found in the control group (see <a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>A). These findings suggest that the p.753Q allele affects the ability of TLR2 to respond to molecules of S. pneumoniae. This finding agrees to the observation that transfected cells with p.753Q TLR2 variant show impaired cellular activation in response to lipoproteins.Our data suggest strongly that the p.753Q allele also affects the host response to N. meningitidis. This polymorphism is within the TIR domain of TLR2 which is critical to TLR signaling and dimerization with other TLR molecules<a class="elsevierStyleCrossRefs" href="#bib0120">24,28</a> and have been linked to decreased NF-κB activation and to increased risk of infection.<a class="elsevierStyleCrossRef" href="#bib0145">29</a> The impaired dimerization of TLR2 could be linked to a decreased response to meningococcal porin PorB which requires TLR1 for signaling.<a class="elsevierStyleCrossRef" href="#bib0150">30</a>TLR4The macrophages activation by meningococcal lipopolysaccharide (LPS) is TLR4 dependent. The p.D299G substitution is associated with functional changes as demonstrated by impaired airway responsiveness after LPS stimulation.<a class="elsevierStyleCrossRef" href="#bib0150">30</a>In this study we found that the ratio of carriers for the p.299G allele was slightly higher in the group of patients with meningococcal disease, as well as the allelic frequency of this transition (p=0.0189, data not shown). Our study did not show association between S. pneumoniae disease and this TLR4 polymorphism.While some previous studies have not found association between this polymorphism and meningococcal disease<a class="elsevierStyleCrossRefs" href="#bib0155">31–33</a> there is a previous study<a class="elsevierStyleCrossRef" href="#bib0170">34</a> that reports a significantly higher incidence of Gram-negative infections in a cohort of patients with systemic inflammatory response syndrome bearing the p.299G allele of TLR4.CD14The CD14 is the anchor protein of the TLR4 receptor complex and its soluble form binds to Gram-negative LPS and the antibodies to CD14 blocks meningococcal LPS activation of macrophages.<a class="elsevierStyleCrossRef" href="#bib0175">35</a> Moreover, CD14 is a high affinity receptor for bacterial endotoxins, constituents of bacterial cell-wall. Several studies confirmed that CD14 interacts not only with LP from Gram-negative bacteria, but also with other microbial ligands as lipoteichoic acid and peptidoglycan from Gram-positive bacteria.<a class="elsevierStyleCrossRef" href="#bib0080">16</a>The promoter polymorphisms c.-159C>T included in our study had been previously associated with shock and mortality rate in patients with sepsis; it causes a reduced circulating CD14 concentrations.<a class="elsevierStyleCrossRef" href="#bib0180">36</a> In our study, 86.4% (51/8) and 85.1% (97/114) of the patients with meningococcal and S. pneumoniae infections respectively carried the c.-159T allele of the CD14 promoter polymorphism. In the control group, the rate of carriers reaches 68.2% (45/66) which is significantly lower.The broad specificity of CD14 in ligand recognition suggests that a decreased CD14 response linked to the c.-159T allele of this promoter polymorphism could impair the recognition and binding of different microbial endotoxins (LPS to CD14). It could decrease the triggering of a signaling cascade-mediated by Toll-like receptors that promote the synthesis of multiple host-derived inflammatory mediators. Although the trend seems to be similar, the p values obtained are more significant for S. pneumoniae than meningococcal infections; this observation could be due to the shorter number of patients in the second group.Finally, the effect of the “risk” alleles of TLR2 and CD14 is additive: only 16% of the controls bore at least one copy of both alleles, while this haplotype was found in 50.0 and 50.8% of the patients respectively with a p=0.0001.This study has limitations; first the small numbers of controls and patients. Also the clinical evolution and cases outcome were not collected and analyzed; it should be done in future studies in order to consider the influence of these findings in the patients’ evolution. The statistical approaches to multiple hypothesis testing and lack of validation of findings in a second cohort owe to interpret the significance of the results with precaution.ConclusionCorrelation between functional polymorphisms within the TLR2, TLR4 and CD14 and children susceptibility to severe invasive bacterial infections is not completely defined. In our study the c.-159T allele of the CD14 gene and, especially, the p.753Q allele of TLR4 could be related to an increased risk of developing severe infections by S. pneumoniae and N. meningitidis. Our data suggest a key role of the innate immunity system in the protection against these bacterias that should be confirmed in future studies.Conflict of interestThis work has been supported by grant by the “Fondo de Investigaciones Sanitarias” from the Institute Carlos III.Abbreviations<ul class="elsevierStyleList" id="lis0020"><li class="elsevierStyleListItem" id="lsti0040">Lipopolysacharide: LPS.</li><li class="elsevierStyleListItem" id="lsti0045">Pediatric Intensive Care Unit: PICU.</li><li class="elsevierStyleListItem" id="lsti0050">Protein chain reaction: PCR.</li><li class="elsevierStyleListItem" id="lsti0055">Toll-like receptors: TLRs.</li></ul>" "textoCompletoSecciones" => array:1 [ "secciones" => array:13 [ 0 => array:2 [ "identificador" => "xres360697" "titulo" => array:5 [ 0 => "Abstract" 1 => "Purpose" 2 => "Material and methods" 3 => "Results" 4 => "Conclusions" ] ] 1 => array:2 [ "identificador" => "xpalclavsec340549" "titulo" => "Keywords" ] 2 => array:2 [ "identificador" => "xres360698" "titulo" => array:5 [ 0 => "Resumen" 1 => "Objetivo" 2 => "Material y métodos" 3 => "Resultados" 4 => "Conclusiones" ] ] 3 => array:2 [ "identificador" => "xpalclavsec340548" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:3 [ "identificador" => "sec0010" "titulo" => "Materials, patients and methods" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0015" "titulo" => "Controls and cases characteristics" ] 1 => array:2 [ "identificador" => "sec0020" "titulo" => "Genetic analysis" ] 2 => array:2 [ "identificador" => "sec0025" "titulo" => "Statistical analysis" ] ] ] 6 => array:3 [ "identificador" => "sec0030" "titulo" => "Results" "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0035" "titulo" => "Controls and cases characteristics" ] 1 => array:3 [ "identificador" => "sec0040" "titulo" => "Genotyping" "secciones" => array:5 [ 0 => array:2 [ "identificador" => "sec0045" "titulo" => "TLR2" ] 1 => array:2 [ "identificador" => "sec0050" "titulo" => "TLR4" ] 2 => array:2 [ "identificador" => "sec0055" "titulo" => "CD14" ] 3 => array:2 [ "identificador" => "sec0060" "titulo" => "TLR4 plus CD14" ] 4 => array:2 [ "identificador" => "sec0065" "titulo" => "Hardy–Weinberg equilibrium" ] ] ] ] ] 7 => array:3 [ "identificador" => "sec0070" "titulo" => "Discussion" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0075" "titulo" => "TLR2" ] 1 => array:2 [ "identificador" => "sec0080" "titulo" => "TLR4" ] 2 => array:2 [ "identificador" => "sec0085" "titulo" => "CD14" ] ] ] 8 => array:2 [ "identificador" => "sec0090" "titulo" => "Conclusion" ] 9 => array:2 [ "identificador" => "sec0095" "titulo" => "Conflict of interest" ] 10 => array:2 [ "identificador" => "sec0100" "titulo" => "Abbreviations" ] 11 => array:2 [ "identificador" => "xack89086" "titulo" => "Acknowledgments" ] 12 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2013-04-24" "fechaAceptado" => "2013-08-01" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec340549" "palabras" => array:4 [ 0 => "Polymorphisms" 1 => "Bacterial infections" 2 => "Streptococcus pneumoniae" 3 => "Neisseria meningitidis" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec340548" "palabras" => array:4 [ 0 => "Polimorfismos" 1 => "Infecciones bacterianas" 2 => "Streptococcus pneumoniae" 3 => "Neisseria meningitidis" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "PurposeStreptococcus pneumoniae and Neisseria meningitidis are major causes of severe invasive bacterial infections in some individuals. Apparently the genetic is a major susceptibility determinant to these infectious diseases. We study if the functional polymorphisms within genes of the innate immune system (TLR2–TLR4 and CD14) are related to the predisposition to severe invasive infections caused by S. pneumoniae and N. meningitidis. Material and methodsProspective descriptive study. Sixty-six Caucasian healthy children and 173 consecutive Caucasian children with invasive bacterial infections by N. meningitidis (n=59) and S. pneumoniae (n=114) were enrolled between January 1, 2008 and December 31, 2010. All blood samples were genotyped with description of the coding polymorphisms in p.R753Q of TLR2 gene and p.D299G of TLR4 gene as well as the promotor polymorphism c.-159C>T of the CD14 gene. ResultsCompared to the controls the p.753Q allele of TLR2 and the allele c.-159T of CD14 were more frequent in patients with S. pneumoniae (p<0.0001 and p=0.0167) and meningococcal infections (p=0.0003 and p=0.0276 respectively). ConclusionsGenetical variations in the innate immune system by polymorphisms in the TLR2 and CD14, could be related with an increases susceptibility to severe invasive infections by S. pneumoniae and N. meningitidis." ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "ObjetivoStreptococcus pneumoniae y Neisseria meningitides son causantes de infección bacteriana grave en algunos individuos. Cierta susceptibilidad genética puede ser determinante para este hecho. Nuestro objetivo es determinar si el polimorfismo de genes relacionados con el sistema inmune innato (Toll like receptor 2 y 4 junto con CD14) se relaciona con la predisposición a sufrir infecciones graves por los citados patógenos. Material y métodosEstudio prospectivo observacional (desde el 1 de enero de 2008 hasta el 31 de diciembre de 2010). Se incluye a 66 niños sanos y 173 niños con infección bacteriana grave (59 por Neisseria meningitidis y 114 por Streptococcus pneumoniae). Todas las muestras fueron genotipadas para los polimorfismos p.R753Q de TLR2, p.D299G de TLR4 y c.–159C>T del CD14. ResultadosComparados con los controles, los polimorfismos p.753Q de TLR2 y c.–159C>T de CD14 fueron más frecuentes en pacientes con infección neumocócica (p<0,0001 y p=0,0167) y meningocócica (p=0,0003 y p=0,0276). ConclusionesLas variaciones genéticas en el sistema inmune innato mediante polimorfismos en TLR2 y CD14 podrían estar relacionadas con la susceptibilidad a las infecciones graves por Streptococcus pneumoniae y Neisseria meningitides." ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "This work has been supported by grant by the “Fondo de Investigaciones Sanitarias” from the Institute Carlos III." ] ] "multimedia" => array:3 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 3450 "Ancho" => 1579 "Tamanyo" => 393286 ] ] "descripcion" => array:1 [ "en" => "(A–C) The genotypic frequencies in patients and controls of the studied polymorphisms. (D) The frequency of carriers of both risk alleles in patients and controls. Neis. Men: Neisseria meningitidis; Srt. pn: Streptococcus pneumoniae." ] ] 1 => array:7 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Gene \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">TLR2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">TLR4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">CD 14 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Polymorphism \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">p.R753Q \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">p.D299G \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">c.-159C>T \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Genotype \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">RR-RQ-QQ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">DD-DG-GG \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">CC-CT-CT \t\t\t\t\t\t\n \t\t\t\t</td></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="4" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">S. Pneumoniae</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Meningitis (n=12) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">4-7-1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">9-3-0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1-6-5 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Sepsis (n=10) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">5-3-2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">9-1-0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3-4-3 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Pneumonia and sepsis (n=92) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">37-46-9 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">76-13-3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">13-48-31 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Total (n=114) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">46-56-12 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">94-17-3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">17-58-39 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="4" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"></td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="4" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">N. Meningitidis</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Meningitis (n=8) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">5-1-2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">7-0-1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3-3-2 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Sepsis (n=41) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">15-19-7 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">29-9-3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">5-25-10 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Meningitis and sepsis (n=10) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">4-4-2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">9-0-1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1-8-2 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Total (n=59) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">24-24-11 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">45-9-5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">9-36-14 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="4" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"></td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Controls (n=66) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">49-15-2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">60-4-2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">21-31-14 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab539283.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Genotypic distribution of the studied polymorphsims in patients and controls. Patients have been sudivided depending on the phenotype." ] ] 2 => array:7 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">TLR2 p.R753Q \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">TLR4 p.D299G \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">CD14 c.-159C>T \t\t\t\t\t\t\n \t\t\t\t</td></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="4" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">N. meninigitidis vs. controls</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Codominance \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">p: 0.0003 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">n.s \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">n.s \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Dominance of the WT allele \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">n.a. \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">n.a. \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">n.s \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Recessivity of the WT allele \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">p: 0.0003 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">p: 0.0472 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">p: 0.0276 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="4" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"></td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="4" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">S. pneumoniae vs controls</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Codominance \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">p: <0.0001 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">n.s \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">p: 0.0167 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Dominance of the WT allele \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">n.s \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">n.s \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">n.s \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Recessivity of the WT allele \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">p: <0.0001 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">n.s \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">p: 0.0128 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="4" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"></td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="4" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">N. meninigitidis. vs. S. pneumoniae</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Codominance \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">n.s \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">n.s \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">n.s \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Dominance of the WT allele \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">n.s \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">n.s \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">n.s \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Recessivity of the WT allele \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">n.s \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">n.s \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">n.s \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab539282.png" ] ] ] ] "descripcion" => array:1 [ "en" => "p values of the comparison of genotypic frequencies of the polymorphisms studied between patients with severe invasive infections caused by Streptococcus pneumoniae and Neisseria meningitidis and controls under the hypothesis of codominance, dominance or recessivity of the wild-type allele." ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:36 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Meningococcal carriage in a population of normal families" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "S. 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TLR2–TLR4/CD14 polymorphisms and predisposition to severe invasive infections by Neisseria meningitidis and Streptococcus pneumoniae

Polimorfismos TLR2-TLR4/CD14 y predisposición a sufrir infecciones invasivas graves por Neisseria meningitidis y Streptoccocus pneumoniae

J.J. Tellería-Orriolsb, A. García-Salidoa,

Corresponding author

citopensis@yahoo.es

Corresponding author.

, D. Varillasb, A. Serrano-Gonzáleza, J. Casado-Floresa

a Pediatric Critical Care Unit, Hospital Infantil Universitario Niño Jesús, Madrid, Spain

b Medicine Faculty, University of Valladolid, Valladolid, Spain

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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">It is known that <span class="elsevierStyleItalic">Streptococcus pneumoniae</span> and <span class="elsevierStyleItalic">Neisseria menigitidis</span> are causes of severe invasive bacterial infections in some individuals&#44; producing high morbidity and mortality&#44; leading to mild or banal infections in others&#46; The asymptomatic nasopharyngeal colonization by these bacterias is common and is related with an invasive disease in only a short number of cases&#46;<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#44;2</span></a> It has been described that the rate of carriers of <span class="elsevierStyleItalic">Neisseria meningitidis</span> rise to 80&#37; in severely crowded conditions&#46;<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3&#44;4</span></a> On one hand&#44; the instauration of <span class="elsevierStyleItalic">S&#46; pneumoniae</span> conjugate vaccine did not decrease as expected the rates of nasopharyngeal carriers for <span class="elsevierStyleItalic">S&#46; pneumoniae</span>&#46;<a class="elsevierStyleCrossRefs" href="#bib0025"><span class="elsevierStyleSup">5&#44;6</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">There are multiple underlying immune defects that may predispose to invasive infections as inmunosuppression &#40;primary or secondary&#41;&#44; asplenia or immune factors deficiency &#40;properdin&#44; components of complement or MyD88<a class="elsevierStyleCrossRefs" href="#bib0035"><span class="elsevierStyleSup">7&#44;8</span></a>&#41;&#46; Individuals with these conditions have an increased risk but they are only a small proportion of all cases&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">In healthy patients the innate immune system looks crucial for the early containment of microbial infections by triggering inflammation and coordinating the acquired immune response&#46; The family of Toll-like receptors &#40;TLRs&#41; is a central component of this system and its description has permitted a better understanding of the molecular mechanisms concerning to antimicrobial and inflammatory responses&#46; The TLRs seem to play a key role in signaling molecules of pathogens and endogenous proteins related to immune activation given their ability to recognize evolutionary conserved pathogen-associated molecular patterns of microbial origin&#46;<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">Several TLRs have been identified in humans&#44; and each one recognizes different structures&#44; also each bacterium could activate different sets of TLRs&#46; The TLR2 is activated by bacterial lipoproteins&#44;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> peptidoglycan and lipoteichoic acid of the cell wall&#46; It is well known that the ability of <span class="elsevierStyleItalic">S&#46; pneumoniae</span> to activate TLR2 through this pathway&#46;<a class="elsevierStyleCrossRefs" href="#bib0045"><span class="elsevierStyleSup">9&#44;11&#44;12</span></a> It has been also described that <span class="elsevierStyleItalic">S&#46; pneumoniae</span> pneumolysin could also stimulate cells through TLR4&#44; but this observation has not been confirmed by all studies&#46;<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a> Moreover&#44; besides TLR2&#44; and maybe TLR4&#44; additional TLRs are probably involved in recognition of this Gram-positive bacteria&#44; among them TLR9&#46;<a class="elsevierStyleCrossRefs" href="#bib0045"><span class="elsevierStyleSup">9&#44;14</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">Lipopolysacharide &#40;LPS&#41; is a major component of the outer cell wall of Gram-negative bacteria such as <span class="elsevierStyleItalic">N&#46; meningitidis&#46;</span> The immune cell recognition of LPS involves an LPS receptor complex&#59; of which CD14 and TLR4 are important components<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a> and its activation could depend from the bacterial dosage&#46; At lower bacterial concentrations&#44; LPS activation of macrophages is TLR4&#47;CD14 dependent&#46; This activation can be blocked by specific antibodies to CD14 and TLR4&#46;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a> Higher bacterial concentrations activate the complement and non-LPS components initiate TLR2 and TLR4 activation independent of CD14&#46;<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a> Finally the porin&#44; an outer membrane protein of <span class="elsevierStyleItalic">N&#46; meningitidis</span> stimulates immune response also through TLR2&#46;<a class="elsevierStyleCrossRefs" href="#bib0090"><span class="elsevierStyleSup">18&#44;19</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">Genetic variation of immune response genes is associated with susceptibility to and severity of infectious diseases&#46;<a class="elsevierStyleCrossRefs" href="#bib0100"><span class="elsevierStyleSup">20&#8211;22</span></a> Single nucleotide polymorphisms could be in the origin of this risk explaining the interindividual susceptibility to invasive bacterial infections&#46; In the present study we analyze the presence of a set of polymorphisms &#40;p&#46;R753Q of TLR2&#44; p&#46;D299G of the TLR4 gene and c&#46;-159C&#8594;T located in the CD14 promoter&#41; in 157 children with severe invasive bacterial infection by <span class="elsevierStyleItalic">S&#46; pneumoniae</span> and <span class="elsevierStyleItalic">N&#46; meningitidis</span>&#46; We hypothesize that severe invasive bacterial infections by these microorganism affect the susceptible healthy individuals&#46; Their susceptibility could be determined by genetic factors based on the relationship between its variants and the susceptibility to these infections&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Materials&#44; patients and methods</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Controls and cases characteristics</span><p id="par0035" class="elsevierStylePara elsevierViewall">The study was approved by the ethics committee of the Hospital Infantil Universitario Ni&#241;o Jes&#250;s of Madrid &#40;Spain&#41; according to local laws and regulations&#46; The patients were recruited from January 1 &#40;2008&#41; to December 31 &#40;2010&#41; after signing the consent by the legal tutors or caregivers of each patient&#46;</p><p id="par0040" class="elsevierStylePara elsevierViewall">Sixty-six Caucasian healthy children were enrolled as controls&#58; the samples were collected from blood samples taken in the hospital blood-extractions department because of non-infectious or inflammatory causes&#46;</p><p id="par0045" class="elsevierStylePara elsevierViewall">The cases were collected from the Pediatric Intensive Care Unit &#40;PICU&#41;&#46; One hundred and seventy three consecutive previously healthy Caucasian children were enrolled because an invasive bacterial infection by <span class="elsevierStyleItalic">N&#46; meningitidis</span> &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>59&#41; or <span class="elsevierStyleItalic">S&#46; pneumoniae</span> &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>114&#41;&#46;</p><p id="par0050" class="elsevierStylePara elsevierViewall">The criteria applied for invasive meningococcal infection were&#58;<ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005"><span class="elsevierStyleLabel">&#8226;</span><p id="par0055" class="elsevierStylePara elsevierViewall">Isolation of <span class="elsevierStyleItalic">N&#46; meningitidis</span> in blood or cerebrospinal fluid&#46;</p></li><li class="elsevierStyleListItem" id="lsti0010"><span class="elsevierStyleLabel">&#8226;</span><p id="par0060" class="elsevierStylePara elsevierViewall">Presence of Gram-negative diplococcus in cerebrospinal fluid&#46;</p></li><li class="elsevierStyleListItem" id="lsti0015"><span class="elsevierStyleLabel">&#8226;</span><p id="par0065" class="elsevierStylePara elsevierViewall">Severe sepsis and extensive purpura without identification of causing agent&#46;<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3&#44;4&#44;23</span></a></p></li></ul></p><p id="par0070" class="elsevierStylePara elsevierViewall">The criteria for invasive <span class="elsevierStyleItalic">S&#46; pneumoniae</span> infection were&#58;<ul class="elsevierStyleList" id="lis0010"><li class="elsevierStyleListItem" id="lsti0020"><span class="elsevierStyleLabel">&#8226;</span><p id="par0075" class="elsevierStylePara elsevierViewall">Isolation of Gram-positive diplococcus in culture or positive protein chain reaction &#40;PCR&#41; for <span class="elsevierStyleItalic">S&#46; pneumoniae</span> in a sterile body fluid &#40;blood&#44; cerebrospinal fluid&#44; pleural fluid or peritoneal fluid&#41; or detection of <span class="elsevierStyleItalic">S&#46; pneumoniae</span> antigen by immunochromatography in the same fluids &#40;Binnax Now<span class="elsevierStyleSup">&#174;</span>&#41;&#46;</p></li></ul></p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Genetic analysis</span><p id="par0080" class="elsevierStylePara elsevierViewall">Blood samples from cases were obtained at hospital blood extractions department&#46; For the cases the blood samples were obtained at PICU admission and submitted for genotyping to the laboratory of genetics&#46; The DNA was extracted and genotyped by staff blinded to clinical data&#46;</p><p id="par0085" class="elsevierStylePara elsevierViewall">All polymorphisms were genotyped by restriction analysis after PCR amplification&#46; PCR of 35 cycles was performed on a thermal cycler GeneAmp9700 &#40;Perkin-Elmer Cetus&#44; Norwalk&#44; CT&#44; USA&#41;&#46; Primers were synthesized &#40;VWR International Eurolab&#44; Bcn&#44; Spain&#41;&#46; The PCR reaction consisted of 50<span class="elsevierStyleHsp" style=""></span>ng DNA&#44; 10pm of each primer&#44; 10<span class="elsevierStyleHsp" style=""></span>&#956;l PCR master mix &#40;Promega<span class="elsevierStyleSup">&#174;</span>&#44; Madison&#44; WI&#44; USA&#41; and water up to 20<span class="elsevierStyleHsp" style=""></span>&#956;l&#46;<ul class="elsevierStyleList" id="lis0015"><li class="elsevierStyleListItem" id="lsti0025"><span class="elsevierStyleLabel">1</span><p id="par0090" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">TLR2 p&#46;R753Q</span> &#40;rs5743708&#41; PCR primers were 5&#8242;-GAAGAGAACAATGATGCTGCCATTC-3&#8242; and R&#58; 5&#8242;-CTAGGACTTTATCGCAGCTCTC-3&#8242;&#46; The cycle program consisted of 94<span class="elsevierStyleHsp" style=""></span>&#176;C for 30<span class="elsevierStyleHsp" style=""></span>s&#44; 49<span class="elsevierStyleHsp" style=""></span>&#176;C for 30<span class="elsevierStyleHsp" style=""></span>s&#44; and 72<span class="elsevierStyleHsp" style=""></span>&#176;C for 30<span class="elsevierStyleHsp" style=""></span>s&#46; SsiI &#40;Fermentas&#44; Burlington&#44; Canada&#41; digestion resulted in two fragments of 115<span class="elsevierStyleHsp" style=""></span>bp and 58<span class="elsevierStyleHsp" style=""></span>bp &#40;R allele&#41; or 173<span class="elsevierStyleHsp" style=""></span>bp &#40;Q allele&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0030"><span class="elsevierStyleLabel">2</span><p id="par0095" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">TLR4 p&#46;D299G</span> &#40;rs4986790&#41; PCR primers were 5&#8242;-ACTTAGACTACTACCTCGGTG-3&#8242; and R&#58;5&#8242;-GATTTGAGTTTCAATGTGGGAAAC-3&#8242;&#46; The cycle program consisted of 94<span class="elsevierStyleHsp" style=""></span>&#176;C for 30<span class="elsevierStyleHsp" style=""></span>s&#44; 53<span class="elsevierStyleHsp" style=""></span>&#176;C for 30<span class="elsevierStyleHsp" style=""></span>s&#44; and 72<span class="elsevierStyleHsp" style=""></span>&#176;C for 30<span class="elsevierStyleHsp" style=""></span>s&#46; HphI &#40;Fermentas&#44; Burlington&#44; Canada&#41; digestion resulted in two fragments of 168<span class="elsevierStyleHsp" style=""></span>bp and 15<span class="elsevierStyleHsp" style=""></span>bp &#40;G allele&#41; or 183<span class="elsevierStyleHsp" style=""></span>bp &#40;D allele&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0035"><span class="elsevierStyleLabel">3</span><p id="par0100" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">CD14 c&#46;-159C&#62;T</span> &#40;rs2569190&#41; PCR primers were&#58; 5&#8242;-TCACCTCCCCACCTCTCTT-3&#8242; and R&#58; 5&#8242;-CCTGCAGAATCCTTCCTGTT-3&#8242;&#46; The cycle program consisted of 94<span class="elsevierStyleHsp" style=""></span>&#176;C for 30<span class="elsevierStyleHsp" style=""></span>s&#44; 59<span class="elsevierStyleHsp" style=""></span>&#176;C for 30<span class="elsevierStyleHsp" style=""></span>s&#44; and 72<span class="elsevierStyleHsp" style=""></span>&#176;C for 30<span class="elsevierStyleHsp" style=""></span>s&#46; HaeIII &#40;Roche<span class="elsevierStyleSup">&#174;</span> Mannheim Germany&#41; digestion resulted in two fragments of 85<span class="elsevierStyleHsp" style=""></span>bp and 22<span class="elsevierStyleHsp" style=""></span>bp &#40;C allele&#41; or 107<span class="elsevierStyleHsp" style=""></span>bp &#40;T allele&#41;&#46;</p></li></ul></p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Statistical analysis</span><p id="par0105" class="elsevierStylePara elsevierViewall">Statistical analysis was performed in a Hewlett&#8211;Packard computer with the statistical program SPSS<span class="elsevierStyleSup">&#174;</span> 19&#46;0 &#40;IBM<span class="elsevierStyleSup">&#174;</span>&#41;&#46; A descriptive analysis was done with the epidemiological and clinical variables&#59; the values are shown with mean and range&#46; Genotype and allele frequencies between groups were compared using the chi-square test&#46; Alternatively Fisher&#39;s exact test was used when frequencies were &#60;5&#46; The value reported is the Yates chi-square&#44; corrected for continuity when applicable&#46; Findings of <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05 were considered statistically significant&#46;</p></span></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Results</span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Controls and cases characteristics</span><p id="par0110" class="elsevierStylePara elsevierViewall">The control group has a mean age of 50 months &#40;range 3 months&#8211;14 years&#41;&#59; 33 were males and 33 females&#46; The mean age of the patients was 41 months &#40;range 3 days&#8211;17 years&#41;&#59; 92 of them were males and 81 females&#46;</p><p id="par0115" class="elsevierStylePara elsevierViewall">The distribution of severe invasive bacterial infection by <span class="elsevierStyleItalic">N&#46; meningitidis</span> was&#58; meningitis <span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>8&#44; sepsis <span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>41 and meningitis with sepsis <span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>10&#46;</p><p id="par0120" class="elsevierStylePara elsevierViewall">The distribution for <span class="elsevierStyleItalic">S&#46; pneumoniae</span> infections was&#58; meningitis <span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>12&#44; Sepsis <span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>102&#46;</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Genotyping</span><p id="par0125" class="elsevierStylePara elsevierViewall">Genotypic distribution of the polymorphisms studied in patients and controls are shown in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">TLR2</span><p id="par0130" class="elsevierStylePara elsevierViewall">The p&#46;753Q allele of the p&#46;R753Q polymorphism of the TLR2 gene was clearly overrepresented in patients compare to controls&#46; Fifty nine percent of the patients with meningococcal infection &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;0003&#41; and 59&#46;3&#37; of those with <span class="elsevierStyleItalic">S&#46; pneumoniae</span> infection&#44; &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;0001&#41; carried at least one copy of this allele &#40;see <a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a> and <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><elsevierMultimedia ident="tbl0010"></elsevierMultimedia></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">TLR4</span><p id="par0135" class="elsevierStylePara elsevierViewall">The frequency of carriers of the p&#46;299G allele was higher &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;0472&#41; in the case of meningococcal infection &#40;23&#46;7&#37;&#41; compared to controls &#40;9&#46;1&#37;&#41;&#46; The allelic frequency of the p&#46;299G allele was also higher &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;0189&#41; in this group of patients &#40;16&#46;1&#37;&#41; when compared to healthy children &#40;6&#46;1&#37;&#41; with &#40;data not shown in tables&#41;&#46; No differences were found between patients with <span class="elsevierStyleItalic">S&#46; pneumoniae</span> infections and controls &#40;see <a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a> and <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46;</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">CD14</span><p id="par0140" class="elsevierStylePara elsevierViewall">The study of c&#46;-159C&#62;T polymorphism showed that the allele c&#46;-159T was more frequent in both group of patients than the c&#46;-159C allele which was the most frequent in controls&#46; Nevertheless&#44; the <span class="elsevierStyleItalic">p</span> value reached statistical significance only comparing the allelic frequencies in patients with meningococcal infections and controls &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;0084&#41;&#46; The frequency of patients with one or two copies &#40;carriers&#41; of the allele c&#46;-159T was higher in case of meningococcal &#40;86&#46;4&#37;&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;0276&#41; or <span class="elsevierStyleItalic">S&#46; pneumoniae</span> &#40;85&#46;1&#37;&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;0128&#41; infections than in controls &#40;68&#46;2&#37;&#59; see <a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a> and <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46;</p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">TLR4 plus CD14</span><p id="par0145" class="elsevierStylePara elsevierViewall">Taking together the p&#46;753Q of TLR2 and c&#46;-159T of CD14 alleles&#44; 50&#46;8 &#40;&#40;30&#47;59&#41; and 50&#46;0&#37; &#40;57&#47;114&#41; of the patients with meningococcal and <span class="elsevierStyleItalic">S&#46; pneumoniae</span> infections carried at least one copy of both risk alleles &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>D&#41; while this haplotype was found in 16&#46;6&#37; &#40;11&#47;66&#41; controls &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;0001 in both cases&#41;</p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Hardy&#8211;Weinberg equilibrium</span><p id="par0150" class="elsevierStylePara elsevierViewall">The distribution of genotypes in the control population was in H&#8211;W equilibrium in all the studied polymorphisms&#46;</p></span></span></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0130">Discussion</span><p id="par0155" class="elsevierStylePara elsevierViewall">The ability to sense pathogenic organisms and to respond adequately preserving the host biological identity is essential to survival&#46; The innate immune system is the first defence line against invading pathogens&#46; It plays a key role in acute host response&#46;<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">24</span></a> The pathogens are recognized by a set of receptors which recognize conserved pathogen associated molecular patterns &#40;PAMPs&#41;&#46; The potential effect of the genetic variability on the individual susceptibility to disease is not completely known&#46; Related to this&#44; in our study&#44; there are two main original findings&#58; &#40;1&#41; patients with <span class="elsevierStyleItalic">N&#46; meningitidis</span> or <span class="elsevierStyleItalic">S&#46; pneumoniae</span> infections showed a higher prevalence of p&#46;753Q TLR2 variant and c&#46;-159T allele of the CD14 promoter polymorphism&#59; &#40;2&#41; the ratio of carriers for the p&#46;299G allele was slightly higher in meningococcal disease&#46;</p><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0135">TLR2</span><p id="par0160" class="elsevierStylePara elsevierViewall">TLR2 can recognize a wide spectrum of PAMPs including molecules shared by Gram-positive bacteria or specific molecules of Gram-negative bacteria &#40;as the porins of meningococci or the LPS of <span class="elsevierStyleItalic">Bordetella</span> or <span class="elsevierStyleItalic">Legionella</span> species&#41;&#46; Moreover&#44; TLR2 is capable to recognize molecular patterns of viruses&#44; parasites and mycobacteria&#46;</p><p id="par0165" class="elsevierStylePara elsevierViewall">Association between TLR2 polimorphisms and leprosy&#44; tuberculosis and staphylococcal infection has been previously reported&#46; Moreover TLR2-knockout mice are more susceptible to septicemia and&#47;or meningitis caused by a wide spectrum of bacteria including <span class="elsevierStyleItalic">S&#46; pneumoniae</span>&#46;<a class="elsevierStyleCrossRefs" href="#bib0125"><span class="elsevierStyleSup">25&#44;26</span></a> Also TLR2-deficient mice show an increased susceptibility to infections&#44; suggesting that polymorphisms that affect TLR expression or function may impair host response to a given spectrum of pathogens&#46;</p><p id="par0170" class="elsevierStylePara elsevierViewall">TLR2 is probably the most important receptor for Gram-positive bacterial products&#46; Moreover&#44; TLR2 is capable to detect a wide variety of molecules from Gram-negative bacteria&#44; between others the porin from meningococci&#46; This ability to recognize such a variety of ligands probably arises from its potential to form TLR2 homodimers and heterodimers with TLR1 and TLR6&#46;<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">27</span></a></p><p id="par0175" class="elsevierStylePara elsevierViewall">In our study&#44; the ratio of patients with <span class="elsevierStyleItalic">N&#46; meningitidis</span> or <span class="elsevierStyleItalic">S&#46; pneumoniae</span> infection that carried the allele p&#46;753Q were close to 60&#37;&#44; much more than the expected 25&#37; based on the frequency found in the control group &#40;see <a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>A&#41;&#46; These findings suggest that the p&#46;753Q allele affects the ability of TLR2 to respond to molecules of <span class="elsevierStyleItalic">S&#46; pneumoniae</span>&#46; This finding agrees to the observation that transfected cells with p&#46;753Q TLR2 variant show impaired cellular activation in response to lipoproteins&#46;</p><p id="par0180" class="elsevierStylePara elsevierViewall">Our data suggest strongly that the p&#46;753Q allele also affects the host response to <span class="elsevierStyleItalic">N&#46; meningitidis</span>&#46; This polymorphism is within the TIR domain of TLR2 which is critical to TLR signaling and dimerization with other TLR molecules<a class="elsevierStyleCrossRefs" href="#bib0120"><span class="elsevierStyleSup">24&#44;28</span></a> and have been linked to decreased NF-&#954;B activation and to increased risk of infection&#46;<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">29</span></a> The impaired dimerization of TLR2 could be linked to a decreased response to meningococcal porin PorB which requires TLR1 for signaling&#46;<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">30</span></a></p></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0140">TLR4</span><p id="par0185" class="elsevierStylePara elsevierViewall">The macrophages activation by meningococcal lipopolysaccharide &#40;LPS&#41; is TLR4 dependent&#46; The p&#46;D299G substitution is associated with functional changes as demonstrated by impaired airway responsiveness after LPS stimulation&#46;<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">30</span></a></p><p id="par0190" class="elsevierStylePara elsevierViewall">In this study we found that the ratio of carriers for the p&#46;299G allele was slightly higher in the group of patients with meningococcal disease&#44; as well as the allelic frequency of this transition &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;0189&#44; data not shown&#41;&#46; Our study did not show association between <span class="elsevierStyleItalic">S&#46; pneumoniae</span> disease and this TLR4 polymorphism&#46;</p><p id="par0195" class="elsevierStylePara elsevierViewall">While some previous studies have not found association between this polymorphism and meningococcal disease<a class="elsevierStyleCrossRefs" href="#bib0155"><span class="elsevierStyleSup">31&#8211;33</span></a> there is a previous study<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">34</span></a> that reports a significantly higher incidence of Gram-negative infections in a cohort of patients with systemic inflammatory response syndrome bearing the p&#46;299G allele of TLR4&#46;</p></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0145">CD14</span><p id="par0200" class="elsevierStylePara elsevierViewall">The CD14 is the anchor protein of the TLR4 receptor complex and its soluble form binds to Gram-negative LPS and the antibodies to CD14 blocks meningococcal LPS activation of macrophages&#46;<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">35</span></a> Moreover&#44; CD14 is a high affinity receptor for bacterial endotoxins&#44; constituents of bacterial cell-wall&#46; Several studies confirmed that CD14 interacts not only with LP from Gram-negative bacteria&#44; but also with other microbial ligands as lipoteichoic acid and peptidoglycan from Gram-positive bacteria&#46;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a></p><p id="par0205" class="elsevierStylePara elsevierViewall">The promoter polymorphisms c&#46;-159C&#62;T included in our study had been previously associated with shock and mortality rate in patients with sepsis&#59; it causes a reduced circulating CD14 concentrations&#46;<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">36</span></a> In our study&#44; 86&#46;4&#37; &#40;51&#47;8&#41; and 85&#46;1&#37; &#40;97&#47;114&#41; of the patients with meningococcal and <span class="elsevierStyleItalic">S&#46; pneumoniae</span> infections respectively carried the c&#46;-159T allele of the CD14 promoter polymorphism&#46; In the control group&#44; the rate of carriers reaches 68&#46;2&#37; &#40;45&#47;66&#41; which is significantly lower&#46;</p><p id="par0210" class="elsevierStylePara elsevierViewall">The broad specificity of CD14 in ligand recognition suggests that a decreased CD14 response linked to the c&#46;-159T allele of this promoter polymorphism could impair the recognition and binding of different microbial endotoxins &#40;LPS to CD14&#41;&#46; It could decrease the triggering of a signaling cascade-mediated by Toll-like receptors that promote the synthesis of multiple host-derived inflammatory mediators&#46; Although the trend seems to be similar&#44; the <span class="elsevierStyleItalic">p</span> values obtained are more significant for <span class="elsevierStyleItalic">S&#46; pneumoniae</span> than meningococcal infections&#59; this observation could be due to the shorter number of patients in the second group&#46;</p><p id="par0215" class="elsevierStylePara elsevierViewall">Finally&#44; the effect of the &#8220;risk&#8221; alleles of TLR2 and CD14 is additive&#58; only 16&#37; of the controls bore at least one copy of both alleles&#44; while this haplotype was found in 50&#46;0 and 50&#46;8&#37; of the patients respectively with a <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;0001&#46;</p><p id="par0220" class="elsevierStylePara elsevierViewall">This study has limitations&#59; first the small numbers of controls and patients&#46; Also the clinical evolution and cases outcome were not collected and analyzed&#59; it should be done in future studies in order to consider the influence of these findings in the patients&#8217; evolution&#46; The statistical approaches to multiple hypothesis testing and lack of validation of findings in a second cohort owe to interpret the significance of the results with precaution&#46;</p></span></span><span id="sec0090" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0150">Conclusion</span><p id="par0225" class="elsevierStylePara elsevierViewall">Correlation between functional polymorphisms within the TLR2&#44; TLR4 and CD14 and children susceptibility to severe invasive bacterial infections is not completely defined&#46; In our study the c&#46;-159T allele of the CD14 gene and&#44; especially&#44; the p&#46;753Q allele of TLR4 could be related to an increased risk of developing severe infections by <span class="elsevierStyleItalic">S&#46; pneumoniae</span> and <span class="elsevierStyleItalic">N&#46; meningitidis</span>&#46; Our data suggest a key role of the innate immunity system in the protection against these bacterias that should be confirmed in future studies&#46;</p></span><span id="sec0095" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0155">Conflict of interest</span><p id="par0230" class="elsevierStylePara elsevierViewall">This work has been supported by grant by the &#8220;Fondo de Investigaciones Sanitarias&#8221; from the Institute Carlos III&#46;</p></span><span id="sec0100" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0160">Abbreviations</span><p id="par0235" class="elsevierStylePara elsevierViewall"><ul class="elsevierStyleList" id="lis0020"><li class="elsevierStyleListItem" id="lsti0040"><p id="par0240" class="elsevierStylePara elsevierViewall">Lipopolysacharide&#58; LPS&#46;</p></li><li class="elsevierStyleListItem" id="lsti0045"><p id="par0245" class="elsevierStylePara elsevierViewall">Pediatric Intensive Care Unit&#58; PICU&#46;</p></li><li class="elsevierStyleListItem" id="lsti0050"><p id="par0250" class="elsevierStylePara elsevierViewall">Protein chain reaction&#58; PCR&#46;</p></li><li class="elsevierStyleListItem" id="lsti0055"><p id="par0255" class="elsevierStylePara elsevierViewall">Toll-like receptors&#58; TLRs&#46;</p></li></ul></p></span></span>"
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          "titulo" => "Introduction"
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          "titulo" => "Materials&#44; patients and methods"
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              "titulo" => "Controls and cases characteristics"
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              "titulo" => "Genotyping"
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                0 => array:2 [
                  "identificador" => "sec0045"
                  "titulo" => "TLR2"
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                1 => array:2 [
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                  "titulo" => "TLR4"
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                  "identificador" => "sec0055"
                  "titulo" => "CD14"
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                  "identificador" => "sec0060"
                  "titulo" => "TLR4 plus CD14"
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                  "titulo" => "Hardy&#8211;Weinberg equilibrium"
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          "titulo" => "Discussion"
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              "identificador" => "sec0075"
              "titulo" => "TLR2"
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              "titulo" => "CD14"
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          "identificador" => "sec0090"
          "titulo" => "Conclusion"
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          "titulo" => "Conflict of interest"
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          "identificador" => "sec0100"
          "titulo" => "Abbreviations"
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          "identificador" => "xack89086"
          "titulo" => "Acknowledgments"
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          "titulo" => "References"
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    "pdfFichero" => "main.pdf"
    "tienePdf" => true
    "fechaRecibido" => "2013-04-24"
    "fechaAceptado" => "2013-08-01"
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        0 => array:4 [
          "clase" => "keyword"
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          "identificador" => "xpalclavsec340549"
          "palabras" => array:4 [
            0 => "Polymorphisms"
            1 => "Bacterial infections"
            2 => "<span class="elsevierStyleItalic">Streptococcus pneumoniae</span>"
            3 => "<span class="elsevierStyleItalic">Neisseria meningitidis</span>"
          ]
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          "palabras" => array:4 [
            0 => "Polimorfismos"
            1 => "Infecciones bacterianas"
            2 => "<span class="elsevierStyleItalic">Streptococcus pneumoniae</span>"
            3 => "<span class="elsevierStyleItalic">Neisseria meningitidis</span>"
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    "resumen" => array:2 [
      "en" => array:2 [
        "titulo" => "Abstract"
        "resumen" => "<span class="elsevierStyleSectionTitle" id="sect0010">Purpose</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">Streptococcus pneumoniae</span> and <span class="elsevierStyleItalic">Neisseria meningitidis</span> are major causes of severe invasive bacterial infections in some individuals&#46; Apparently the genetic is a major susceptibility determinant to these infectious diseases&#46; We study if the functional polymorphisms within genes of the innate immune system &#40;TLR2&#8211;TLR4 and CD14&#41; are related to the predisposition to severe invasive infections caused by <span class="elsevierStyleItalic">S&#46; pneumoniae</span> and <span class="elsevierStyleItalic">N&#46; meningitidis</span>&#46;</p> <span class="elsevierStyleSectionTitle" id="sect0015">Material and methods</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Prospective descriptive study&#46; Sixty-six Caucasian healthy children and 173 consecutive Caucasian children with invasive bacterial infections by <span class="elsevierStyleItalic">N&#46; meningitidis</span> &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>59&#41; and <span class="elsevierStyleItalic">S&#46; pneumoniae</span> &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>114&#41; were enrolled between January 1&#44; 2008 and December 31&#44; 2010&#46; All blood samples were genotyped with description of the coding polymorphisms in p&#46;R753Q of TLR2 gene and p&#46;D299G of TLR4 gene as well as the promotor polymorphism c&#46;-159C&#62;T of the CD14 gene&#46;</p> <span class="elsevierStyleSectionTitle" id="sect0020">Results</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Compared to the controls the p&#46;753Q allele of TLR2 and the allele c&#46;-159T of CD14 were more frequent in patients with <span class="elsevierStyleItalic">S&#46; pneumoniae</span> &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;0001 and <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;0167&#41; and meningococcal infections &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;0003 and <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;0276 respectively&#41;&#46;</p> <span class="elsevierStyleSectionTitle" id="sect0025">Conclusions</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Genetical variations in the innate immune system by polymorphisms in the TLR2 and CD14&#44; could be related with an increases susceptibility to severe invasive infections by <span class="elsevierStyleItalic">S&#46; pneumoniae</span> and <span class="elsevierStyleItalic">N&#46; meningitidis</span>&#46;</p>"
      ]
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        "titulo" => "Resumen"
        "resumen" => "<span class="elsevierStyleSectionTitle" id="sect0035">Objetivo</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">Streptococcus pneumoniae</span> y <span class="elsevierStyleItalic">Neisseria meningitides</span> son causantes de infecci&#243;n bacteriana grave en algunos individuos&#46; Cierta susceptibilidad gen&#233;tica puede ser determinante para este hecho&#46; Nuestro objetivo es determinar si el polimorfismo de genes relacionados con el sistema inmune innato &#40;Toll like receptor 2 y 4 junto con CD14&#41; se relaciona con la predisposici&#243;n a sufrir infecciones graves por los citados pat&#243;genos&#46;</p> <span class="elsevierStyleSectionTitle" id="sect0040">Material y m&#233;todos</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Estudio prospectivo observacional &#40;desde el 1 de enero de 2008 hasta el 31 de diciembre de 2010&#41;&#46; Se incluye a 66 ni&#241;os sanos y 173 ni&#241;os con infecci&#243;n bacteriana grave &#40;59 por <span class="elsevierStyleItalic">Neisseria meningitidis</span> y 114 por <span class="elsevierStyleItalic">Streptococcus pneumoniae</span>&#41;&#46; Todas las muestras fueron genotipadas para los polimorfismos p&#46;R753Q de TLR2&#44; p&#46;D299G de TLR4 y c&#46;&#8211;159C<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>T del CD14&#46;</p> <span class="elsevierStyleSectionTitle" id="sect0045">Resultados</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Comparados con los controles&#44; los polimorfismos p&#46;753Q de TLR2 y c&#46;&#8211;159C<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>T de CD14 fueron m&#225;s frecuentes en pacientes con infecci&#243;n neumoc&#243;cica &#40;p<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#44;0001 y p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;0167&#41; y meningoc&#243;cica &#40;p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;0003 y p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;0276&#41;&#46;</p> <span class="elsevierStyleSectionTitle" id="sect0050">Conclusiones</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Las variaciones gen&#233;ticas en el sistema inmune innato mediante polimorfismos en TLR2 y CD14 podr&#237;an estar relacionadas con la susceptibilidad a las infecciones graves por <span class="elsevierStyleItalic">Streptococcus pneumoniae</span> y <span class="elsevierStyleItalic">Neisseria meningitides</span>&#46;</p>"
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        "nota" => "<p class="elsevierStyleNotepara" id="npar0005">This work has been supported by grant by the &#8220;<span class="elsevierStyleGrantSponsor" id="gs0005">Fondo de Investigaciones Sanitarias</span>&#8221; from the Institute Carlos III&#46;</p>"
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          "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">&#40;A&#8211;C&#41; The genotypic frequencies in patients and controls of the studied polymorphisms&#46; &#40;D&#41; The frequency of carriers of both risk alleles in patients and controls&#46; Neis&#46; Men&#58; <span class="elsevierStyleItalic">Neisseria meningitidis</span>&#59; Srt&#46; pn&#58; <span class="elsevierStyleItalic">Streptococcus pneumoniae</span>&#46;</p>"
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                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Gene&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">TLR2&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">TLR4&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">CD 14&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">Polymorphism&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">p&#46;R753Q&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">p&#46;D299G&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">c&#46;-159C&#62;T&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">Genotype&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">RR-RQ-QQ&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">DD-DG-GG&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Meningitis &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>12&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">4-7-1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">9-3-0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Sepsis &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>10&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Pneumonia and sepsis &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>92&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
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                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">46-56-12&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t  " colspan="4" align="left" valign="\n
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                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t">3-3-2&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Sepsis &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>41&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">5-25-10&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Meningitis and sepsis &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>10&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">9-0-1&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">1-8-2&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Total &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>59&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">Controls &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>66&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">49-15-2&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">60-4-2&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">n&#46;s&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleItalic">p</span>&#58; 0&#46;0167&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Dominance of the WT allele&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">n&#46;s&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">n&#46;s&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">n&#46;s&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Recessivity of the WT allele&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleItalic">p</span>&#58; &#60;0&#46;0001&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">n&#46;s&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleItalic">p</span>&#58; 0&#46;0128&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Codominance&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">n&#46;s&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">n&#46;s&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Dominance of the WT allele&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">n&#46;s&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">n&#46;s&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Recessivity of the WT allele&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t">n&#46;s&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">n&#46;s&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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          "en" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">p</span> values of the comparison of genotypic frequencies of the polymorphisms studied between patients with severe invasive infections caused by <span class="elsevierStyleItalic">Streptococcus pneumoniae</span> and <span class="elsevierStyleItalic">Neisseria meningitidis</span> and controls under the hypothesis of codominance&#44; dominance or recessivity of the wild-type allele&#46;</p>"
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Article information

ISSN: 21735727
Original language: English

DOI:10.1016/j.medine.2013.08.002

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Year/Month	Html	Pdf	Total

2024 November	5	11	16
2024 October	47	48	95
2024 September	59	32	91
2024 August	53	40	93
2024 July	35	24	59
2024 June	46	46	92
2024 May	35	29	64
2024 April	33	35	68
2024 March	27	22	49
2024 February	25	41	66
2024 January	28	31	59
2023 December	26	36	62
2023 November	38	39	77
2023 October	32	32	64
2023 September	30	40	70
2023 August	22	15	37
2023 July	29	27	56
2023 June	30	31	61
2023 May	43	28	71
2023 April	27	22	49
2023 March	51	31	82
2023 February	46	15	61
2023 January	25	18	43
2022 December	55	30	85
2022 November	41	37	78
2022 October	44	38	82
2022 September	37	38	75
2022 August	47	43	90
2022 July	28	33	61
2022 June	65	22	87
2022 May	48	45	93
2022 April	22	34	56
2022 March	33	36	69
2022 February	32	34	66
2022 January	26	28	54
2021 December	49	45	94
2021 November	33	46	79
2021 October	78	56	134
2021 September	59	37	96
2021 August	63	28	91
2021 July	41	28	69
2021 June	28	24	52
2021 May	45	57	102
2021 April	60	91	151
2021 March	45	29	74
2021 February	59	17	76
2021 January	39	29	68
2020 December	44	15	59
2020 November	19	18	37
2020 October	36	25	61
2020 September	17	16	33
2020 August	41	14	55
2020 July	44	13	57
2020 June	14	12	26
2020 May	29	17	46
2020 April	32	12	44
2020 March	16	13	29
2020 February	60	34	94
2020 January	29	23	52
2019 December	34	22	56
2019 November	25	29	54
2019 October	26	15	41
2019 September	19	17	36
2019 August	30	17	47
2019 July	21	22	43
2019 June	17	15	32
2019 May	37	24	61
2019 April	25	12	37
2019 March	18	12	30
2019 February	24	31	55
2019 January	33	30	63
2018 December	30	69	99
2018 November	56	33	89
2018 October	59	23	82
2018 September	36	6	42
2018 August	13	4	17
2018 July	14	6	20
2018 June	13	7	20
2018 May	11	3	14
2018 April	14	4	18
2018 March	12	2	14
2018 February	16	6	22
2018 January	20	5	25
2017 December	17	3	20
2017 November	19	10	29
2017 October	16	4	20
2017 September	9	6	15
2017 August	9	4	13
2017 July	14	4	18
2017 June	26	7	33
2017 May	12	5	17
2017 April	22	8	30
2017 March	11	10	21
2017 February	9	1	10
2017 January	7	3	10
2016 December	22	4	26
2016 November	18	10	28
2016 October	36	7	43
2016 September	27	9	36
2016 August	20	7	27
2016 July	11	8	19
2016 February	1	0	1
2015 December	2	0	2
2015 September	1	7	8
2014 December	1	0	1

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