Abstract
BackgroundMelioidosis, caused by the flagellated bacterium Burkholderia pseudomallei, is a life-threatening and increasingly recognized emerging disease. Toll-like receptor (TLR) 5 is a germline-encoded pattern recognition receptor to bacterial flagellin. We evaluated the association of a nonsense TLR5 genetic variant that truncates the receptor with clinical outcomes and with immune responses in melioidosis.Methodology/Principal findingsWe genotyped TLR5 c.1174C>T in 194 acute melioidosis patients in Thailand. Twenty-six (13%) were genotype CT or TT. In univariable analysis, carriage of the c.1174C>T variant was associated with lower 28-day mortality (odds ratio (OR) 0.21, 95% confidence interval (CI) 0.05–0.94, P = 0.04) and with lower 90-day mortality (OR 0.25, 95% CI 0.07–086, P = 0.03). In multivariable analysis adjusting for age, sex, diabetes and renal disease, the adjusted OR for 28-day mortality in carriers of the variant was 0.24 (95% CI 0.05–1.08, P = 0.06); and the adjusted OR for 90-day mortality was 0.27 (95% CI 0.08–0.97, P = 0.04). c.1174C>T was associated with a lower rate of bacteremia (P = 0.04) and reduced plasma levels of IL-10 (P = 0.049) and TNF-α (P < 0.0001). We did not find an association between c.1174C>T and IFN-γ ELISPOT (T-cell) responses (P = 0.49), indirect haemagglutination titers or IgG antibodies to bacterial flagellin during acute melioidosis (P = 0.30 and 0.1, respectively).Conclusions/SignificanceThis study independently confirms the association of TLR5 c.1174C>T with protection against death in melioidosis, identifies lower bacteremia, IL-10 and TNF-α production in carriers of the variant with melioidosis, but does not demonstrate an association of the variant with acute T-cell IFN-γ response, indirect haemagglutination antibody titer, or anti-flagellin IgG antibodies.
Highlights
Melioidosis is caused by the Gram-negative, flagellated bacillus and environmental saprophyte, Burkholderia pseudomallei, which the US Centers for Disease Control and Prevention (CDC) have identified as a Tier 1 bioterrorism agent
Melioidosis is a high-mortality infectious disease in Southeast Asia and northern Australia caused by Burkholderia pseudomallei, which is a flagellated, rod-shaped Gram-negative bacterium
A previous study demonstrated a strong relationship between a TLR5 stop codon polymorphism that encodes a truncated receptor for bacterial flagellin and protection against death from melioidosis
Summary
Melioidosis is caused by the Gram-negative, flagellated bacillus and environmental saprophyte, Burkholderia pseudomallei, which the US Centers for Disease Control and Prevention (CDC) have identified as a Tier 1 bioterrorism agent. Further expansion of endemic boundaries of melioidosis [4,5,6,7], increasing prevalence of diabetes [8], and population ageing [9] lead to an urgent demand for a vaccine against melioidosis, especially in at-risk populations. Emerging evidence suggests the importance of membrane-bound Toll-like receptors (TLRs) in defense against B. pseudomallei infection in vitro and in vivo [10,11,12], and the TLR5 ligand flagellin has potential as a vaccine adjuvant [13]. Melioidosis, caused by the flagellated bacterium Burkholderia pseudomallei, is a life-threatening and increasingly recognized emerging disease. We evaluated the association of a nonsense TLR5 genetic variant that truncates the receptor with clinical outcomes and with immune responses in melioidosis
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