Screen of whole blood responses to flagellin identifies TLR5 variation associated with outcome in melioidosis

Melioidosis is a severe infection caused by the flagellated bacterium Burkholderia pseudomallei. The nonsense polymorphism TLR5(1174C>T) is associated with improved outcome in Thais with melioidosis. We hypothesized that other TLR5 variants may modulate the host response and determine outcome in melioidosis. We genotyped 12 TLR5 variants selected de novo from the HapMap database and examined the association of each with cytokines induced by flagellin stimulation of whole blood from healthy Thai subjects. We found a blunted cytokine response for three related markers that were in linkage disequilibrium with a non-synonymous variant, TLR5(1846T>C). Carriers of TLR5(1846T>C) had broadly impaired cytokine responses induced by flagellin. TLR5(1846T>C) was associated with protection against death in melioidosis patients (OR 0.62, 95% CI: 0.42-0.93, p=0.021). We observed no impairment in TLR5(1846C)-dependent NF-κB activation, however, suggesting an alternative mechanism for the effect. We found that TLR5(1846T>C) was in strong linkage disequilibrium with TLR5(1174C>T). Many of the blunted cytokine responses observed and the association of TLR5(1846T>C) with survival in melioidosis patients may be attributable to TLR5(1174C>T), but we could not exclude an independent effect of TLR5(1846T>C). These data identify novel associations for TLR5(1846T>C), enhance our understanding of TLR5 genetic architecture in Thais, and provide future directions of study.