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      TLR4 genetic variation is associated with inflammatory responses in Gram-positive sepsis

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          Abstract

          <div class="section"> <a class="named-anchor" id="S1"> <!-- named anchor --> </a> <h5 class="section-title" id="d525228e356">Objectives</h5> <p id="P1">Gram-positive infection is a common cause of sepsis worldwide. Our objective was to identify important pathogen recognition receptor (PRR) pathways regulating innate immune responses and outcome in <i>Staphylococcus aureus</i> sepsis. </p> </div><div class="section"> <a class="named-anchor" id="S2"> <!-- named anchor --> </a> <h5 class="section-title" id="d525228e364">Methods</h5> <p id="P2">We analyzed whether candidate PRR pathway genetic variants were associated with killed <i>S. aureus</i>-induced cytokine responses ex vivo and performed follow up in vitro studies. We tested the association of our top ranked variant with cytokine responses and clinical outcomes in a prospective multi-center cohort of patients with staphylococcal sepsis. </p> </div><div class="section"> <a class="named-anchor" id="S3"> <!-- named anchor --> </a> <h5 class="section-title" id="d525228e372">Results</h5> <p id="P3">An intronic <i>TLR4</i> polymorphism and expression quantitative trait locus, rs1927907, was highly associated with cytokine release induced by stimulation of blood from healthy Thai subjects with <i>S. aureus</i> ex vivo. <i>S. aureus</i> did not induce TLR4-dependent NF-κB activation in transfected HEK293 cells. In monocytes TNF-α release induced by <i>S. aureus</i> was not blunted by a TLR4/MD-2 neutralizing antibody but in a monocyte cell line TNF-α was reduced by knockdown of <i>TLR4</i>. In Thai patients with staphylococcal sepsis, rs1927907 was associated with higher IL-6 and IL-8 levels, and with respiratory failure. <i>S. aureus</i>-induced responses in blood were most highly correlated with responses to Gram-negative stimulants. </p> </div><div class="section"> <a class="named-anchor" id="S4"> <!-- named anchor --> </a> <h5 class="section-title" id="d525228e396">Conclusions</h5> <p id="P4">A genetic variant in <i>TLR4</i> is associated with cytokine responses to <i>S. aureus</i> ex vivo, and with cytokine levels and respiratory failure in staphylococcal sepsis. While <i>S. aureus</i> does not express lipopolysaccharide or activate TLR4 directly, the innate immune response to <i>S. aureus</i> does appear to be modulated by TLR4 and shares significant commonality with that induced by Gram-negative pathogens and lipopolysaccharide. </p> </div>

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          Author and article information

          Journal
          Clinical Microbiology and Infection
          Clinical Microbiology and Infection
          Elsevier BV
          1198743X
          January 2017
          January 2017
          : 23
          : 1
          : 47.e1-47.e10
          Article
          10.1016/j.cmi.2016.08.028
          5218870
          27615723
          f9bfc34f-0505-4288-9563-d12cdb6632b3
          © 2017

          https://www.elsevier.com/tdm/userlicense/1.0/

          http://creativecommons.org/licenses/by-nc-nd/4.0/


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