A nonsense mutation in TLR5 is associated with survival and reduced IL-10 and TNF-α levels in human melioidosis

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.

Diabetes alters immune response patterns to acute melioidosis in humans

“…However, the TNF‐α /IL‐10 ratio remained unchanged in the DM group. In general, IL‐10 levels were significantly higher in DM compared to non‐DM survivors ( p = 0.02), which was corroborated in plasma using a larger patient cohort . In line with this, HLA‐DR expression on pDC was significantly lower in DM compared to non‐DM survivors ( p = 0.01) and in contrast to non‐DM patients no further decrease of HLA‐DR expression was observed in DM patients, who died (Supporting Information Table ).…”

Immune response to recombinant Burkholderia pseudomallei FliC

“…Prior to determining antibody responses to rFliC in patient serum, the optimal conditions for the ELISA were determined using pooled serum from healthy individuals and melioidosis patients as described in previous studies [ 8 , 16 , 18 ]. The optimal concentration of rFliC for coating was 15 μg/ml and the optimal serum dilution was 1:300.…”

“…In a murine model of respiratory melioidosis, TLR5 plays an important role in host survival [ 7 ]. In humans, we previously demonstrated that genetic polymorphism of TLR5 is associated with organ failure and death [ 8 , 9 ].…”

“…pseudomallei FliC are limited. We previously determined the antibody to rFliC in clinical collections in Thailand and reported that plasma IgG anti-rFliC antibody levels were not significantly different between TLR5 1174C>T in melioidosis cases [ 8 ]. During this study, however, we did not determine the association of anti-FliC antibody levels and diabetes or clinical conditions of melioidosis.…”

Role of Toll-Like Receptor 5 (TLR5) in Experimental Melioidosis

“…First, caution is needed when extrapolating these data derived from mouse experiments to human disease. Human carriers of a hyporesponsive TLR5 polymorphism are in part protected against death from melioidosis (21,49). In this respect, it is of interest that TLR5 hyporesponsiveness in humans leads to higher susceptibility to invasive aspergillosis (50), recurrent urinary tract infections (51), and Legionnaires' disease (52).…”