Melioidosis, Susceptibility To

Watchlist

(log in to enable)

Retrieved

2019-09-22

Source

Omim

Trials

—

Genes

TLR5, PRMT1, CYCSP51, PDE7A, TNF, SLC46A1, TLR4, IL1B, IL10, IL18, TLR1, IFNG, NLRC4, TLR2, CASP1, NLRP3, HSPD1, HSD17B6, TNFSF4, TXNRD1, VWF, ABCA4, ABCG2, SELL, IL24, ADAMTS13, PYCARD, IL23A, TREM1, RHOF, NOD2, NBEAL1, GSDMD, RNF34, RBM45, SLC11A1, KITLG, PTPN6, POMC, ARG1, STS, CALR, CASP6, CD14, CPOX, CRP, CSF2, CX3CR1, DECR1, EMP1, HLA-DQA1, HLA-DRB1, HMGB1, HRC, IFNA1, IFNA13, IL1A, IL4, IL6, CXCL8, IL17A, LTA, AMBP, NM, BIRC6-AS1

Drugs

—

Interested in hearing about new therapies?

A number sign (#) is used with this entry because resistance to melioidosis is associated with a nonsense polymorphism in the gene encoding Toll-like receptor-5 (TLR5; 603031) on chromosome 1q41.

Description

Melioidosis is infection caused by the gram-negative, flagellated soil saprophyte Burkholderia pseudomallei, which is endemic in parts of southeast Asia and northern Australia. Sepsis is a common clinical presentation of disease, and lung is the organ most commonly involved. In northern Thailand, where B. pseudomallei is the most common bloodstream isolate, the overall melioidosis mortality rate exceeds 40%, and pneumonia confers more than 2-fold increased risk of death (summary by West et al., 2013).

Molecular Genetics

West et al. (2013) found that B. pseudomallei induced NFKB (see 164011) signaling in human embryonic kidney cells transfected with full-length TLR5 (603031), but not those transfected with TLR5 containing a nonsense polymorphism, arg392 to ter (R392X; 603031.0001). By studying 600 Thai patients with melioidosis, they found that, in a dominant model, TLR5 with R392X was associated with protection against in-hospital death (adjusted odds ratio (OR) = 0.20; 95% confidence interval (CI) = 0.08-0.50; p = 0.001) and organ failure (adjusted OR = 0.37; 95% CI = 0.19-0.71; p = 0.003). Stimulation of whole blood cells with flagellin or heat-killed B. pseudomallei and normalizing for monocyte count showed that there were lower levels of proinflammatory cytokines, notably IL10 (124092), and chemokines in healthy individuals with full-length TLR5 compared with R392X. West et al. (2013) concluded that the hypofunctional TLR5 variant R392X is associated with reduced organ failure and improved survival in melioidosis, possibly due to the absence of immunoregulatory effects mediated by IL10.