TYPE VI SECRETION SYSTEM IN BURKHOLDERIA PSEUDOMALLEI

Abstract

The Type VI Secretion System cluster 1 (T6SS-1) is a critical virulence determinant in Burkholderia pseudomallei, the causative agent of melioidosis. We found that T6SS-1 expression is upregulated inside the mammalian host by VirAG, a two component sensor-regulator system. T6SS-1 is upregulated when bacteria enter the cytosol from the phagosomes. We identify thiol compounds such as cysteine and glutathione, present mainly in the host cytosol, to significantly upregulate T6SS-1 expression through VirA, the sensor kinase. Site directed mutagenesis in VirA shows that mutation of cysteine 62 led to constitutive hcp1 expression. Thiol compounds likely reduce the disulfide bonds formed in VirA, causing a conformational change that leads to T6SS-1 activation. We are elucidating the chemical modification of VirA by thiol compounds. These results aid in our understanding of how B. pseudomallei adapts to the mammalian host environment and exerts virulence through sensing of host cytosolic signals to facilitate bacterial spreading.