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Published on: March 20, 2013
Regulation of type VI secretion system during Burkholderia pseudomallei infection
Yahua Chen1, Jocelyn Wong, Guang Wen Sun
1Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597.
Abstract:
Type III and type VI secretion systems (T3SSs and T6SSs, respectively) are critical virulence determinants in several Gram-negative pathogens. In Burkholderia pseudomallei, the T3SS-3 and T6SS-1 clusters have been implicated in bacterial virulence in mammalian hosts. We recently discovered a regulatory cascade that coordinately controls the expression of T3SS-3 and T6SS-1. BsaN is a central regulator located within T3SS-3 for the expression of T3SS-3 effectors and regulators for T6SS-1 such as VirA-VirG (VirAG) and BprC. Whereas T6SS-1 gene expression was completely dependent on BprC when bacteria were grown in medium, the expression inside host cells was dependent on the two-component sensor-regulator VirAG, with the exception of the tssAB operon, which was dependent primarily on BprC. VirAG and BprC initiate different transcriptional start sites within T6SS-1, and VirAG is able to activate the hcp1 promoter directly. We also provided novel evidence that virAG, bprC, and tssAB are critical for T6SS-1 function in macrophages. Furthermore, virAG and bprC regulator mutants were avirulent in mice, demonstrating the absolute dependence of T6SS-1 expression on these regulators in vivo.
Insights
The study reveals how Burkholderia pseudomallei controls its secretion systems. VirAG and BprC are essential regulators for the type VI secretion system (T6SS-1) in both lab conditions and host infections.
Area of Science:
- Microbiology
- Bacterial Pathogenesis
- Molecular Biology
Background:
- Type III and type VI secretion systems (T3SSs and T6SSs) are key virulence factors in Gram-negative bacteria.
- In Burkholderia pseudomallei, T3SS-3 and T6SS-1 contribute significantly to virulence in mammalian hosts.
Purpose of the Study:
- To elucidate the regulatory cascade controlling T3SS-3 and T6SS-1 expression in Burkholderia pseudomallei.
- To investigate the roles of BsaN, VirAG, and BprC in regulating T6SS-1.
Main Methods:
- Analysis of gene expression under different growth conditions (in vitro vs. host cells).
- Identification of transcriptional start sites regulated by VirAG and BprC.
- Assessment of bacterial virulence in macrophages and mouse models using regulator mutants.
Main Results:
- BsaN regulates T3SS-3 effectors and T6SS-1 regulators (VirAG, BprC).
- T6SS-1 expression is BprC-dependent in vitro, but VirAG-dependent in host cells (except for tssAB operon, which is BprC-dependent).
- VirAG and BprC directly control T6SS-1 gene expression and are critical for virulence in macrophages and mice.
Conclusions:
- VirAG and BprC are indispensable regulators for T6SS-1 function and Burkholderia pseudomallei virulence.
- The regulatory mechanism differs between in vitro and host cell environments, highlighting adaptive virulence strategies.
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