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

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          Abstract

          Objectives

          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 Staphylococcus aureus sepsis.

          Methods

          We analyzed whether candidate PRR pathway genetic variants were associated with killed S. aureus-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.

          Results

          An intronic TLR4 polymorphism and expression quantitative trait locus, rs1927907, was highly associated with cytokine release induced by stimulation of blood from healthy Thai subjects with S. aureus ex vivo. S. aureus did not induce TLR4-dependent NF-κB activation in transfected HEK293 cells. In monocytes TNF-α release induced by S. aureus was not blunted by a TLR4/MD-2 neutralizing antibody but in a monocyte cell line TNF-α was reduced by knockdown of TLR4. In Thai patients with staphylococcal sepsis, rs1927907 was associated with higher IL-6 and IL-8 levels, and with respiratory failure. S. aureus-induced responses in blood were most highly correlated with responses to Gram-negative stimulants.

          Conclusions

          A genetic variant in TLR4 is associated with cytokine responses to S. aureus ex vivo, and with cytokine levels and respiratory failure in staphylococcal sepsis. While S. aureus does not express lipopolysaccharide or activate TLR4 directly, the innate immune response to S. aureus does appear to be modulated by TLR4 and shares significant commonality with that induced by Gram-negative pathogens and lipopolysaccharide.

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          Author and article information

          Journal
          9516420
          21005
          Clin Microbiol Infect
          Clin. Microbiol. Infect.
          Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases
          1198-743X
          1469-0691
          20 October 2016
          08 September 2016
          January 2017
          01 January 2018
          : 23
          : 1
          : 47.e1-47.e10
          Affiliations
          [1 ]Department of Microbiology and Immunology, Faculty of Tropical Medicine, Mahidol University, Bangkok, 10400, Thailand
          [2 ]Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, 10400, Thailand
          [3 ]Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Washington, Seattle, WA, 98104-2499, USA
          [4 ]Department of Clinical Pathology, Sunpasitthiprasong Hospital, Ubon Ratchathani, 34000, Thailand
          [5 ]Department of Clinical Pathology, Udon Thani Regional Hospital, Udon Thani, 41000, Thailand
          [6 ]Department of Clinical Pathology, Khon Kaen Regional Hospital, Khon Kaen, 40000, Thailand
          [7 ]Srinagarind Hospital, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand
          [8 ]Department of Medicine, Sunpasitthiprasong Hospital, Ubon Ratchathani, 34000, Thailand
          [9 ]Department of Pediatrics, Sunpasitthiprasong Hospital, Ubon Ratchathani, 34000, Thailand
          [10 ]Department of Medicine, Udon Thani Regional Hospital, Udon Thani, 41000, Thailand
          [11 ]Department of Medicine, Khon Kaen Regional Hospital, Khon Kaen, 40000, Thailand
          [12 ]Department of Microbiology and Melioidosis Research Center, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand
          [13 ]Department of Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand
          [14 ]Department of Biostatistics, University of Washington, Seattle, WA, 98195-7232, USA
          [15 ]London School of Hygiene and Tropical Medicine, London, WC1E 7HT, United Kingdom
          [16 ]International Respiratory and Severe Illness Center, University of Washington, Seattle, WA, 98104, USA
          Author notes
          Corresponding author: Narisara Chantratita, Department of Microbiology and Immunology, Faculty of Tropical Medicine, Mahidol University, 420/6 Rajvithi Road, Bangkok 10400, Thailand, Tel: +662 306-9172, Fax: +662 643-5583, narisara@ 123456tropmedres.ac
          Article
          PMC5218870 PMC5218870 5218870 nihpa823905
          10.1016/j.cmi.2016.08.028
          5218870
          27615723
          f9bfc34f-0505-4288-9563-d12cdb6632b3
          History
          Categories
          Article

          humans,immunity,innate,polymorphism,genetic
          humans, immunity, innate, polymorphism, genetic

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