Role of type VI secretion in Burkholderia pseudomallei virulence and host interaction
Final Report Abstract
Burkholderia pseudomallei is a soilborne pathogen that causes melioidosis, a severe invasive disease of humans and animals in the tropics and subtropics. A common presentation is rapidly fatal bacteremic pneumonia, which carries a 90% mortality rate if untreated. Considering the public health burden of melioidosis, surprisingly little is known about the factors employed by B. pseudomallei to establish an infection and to combat host defense responses. The aim of this study was to delineate the role of type VI secretion (T6S) in the pathogenesis of B. pseudomallei infection. To this end, we used the closely related but non-select agent Burkholderia thailandensis for our analyses. Both B. pseudomallei and B. thailandensis harbor multiple T6SSs that are orthologous between the species. By systematically analysing the role of each of the secretion systems in virulence, we showed that one of them, T6SS-5, is a major virulence determinant in a murine model of pneumonic melioidosis. The inactivation of T6SS-5 resulted in a loss of virulence of B. thailandensis and clearance of infection, while a lack of activity of the other secretion systems did not affect virulence. Importantly, the capability of a T6SS-5 mutant to cause rapid fatality in MyD88-/- mice indicates a specific role of the secretion system in evasion or manipulation of MyD88-dependent immune responses. We also probed the Burkholderia T6SSs for their role in interbacterial interactions utilizing a growth competition screen against a panel of 31 Gramnegative and -positive bacteria. This analysis revealed that the activity of T6SS-1 is required to prevent B. thailandensis from being outgrown by three other bacterial species in a cell contact dependent manner. In summary, this study provided an initial systematic evaluation of the role of Burkholderia T6SSs. Our work conclusively demonstrated that T6SS-5 is essential for survival in mice by specifically interacting with the host. Thus, components or substrates of this secretion system constitute promising targets for anti-infective drugs. On the other hand, T6SS-1 provides a fitness advantage for B. thailandensis in direct contact with other bacteria. This finding defined a novel role for T6S in the interaction between different bacterial species, which is likely of relevance in the environment and in polymicrobial infections.
Publications
- (2009) TagR promotes PpkA catalysed type VI secretion activation in Pseudomonas aeruginosa. Mol Microbiol 72(5): 1111-25
Hsu F, Schwarz S, and Mougous JD
- (2010) Burkholderia type VI secretion systems have distinct roles in eukaryotic and bacterial cell interactions. PLoS Pathog 6(8): e1001068
Schwarz S, West TE, Boyer F, Chiang WC, Carl MA, Hood RD, Rohmer L, Tolker-Nielsen T, Skerrett SJ, Mougous JD
- (2010) What is type VI secretion doing in all those bugs? Trends Microbiol. 2010 Dec;18(12):531-7
Schwarz S, Hood RD, Mougous JD
