Epithelial Invasion by Salmonella Typhi using STIV-Met Interaction.

Typhoid is a life-threatening febrile illness, which affects ~24.2 million people worldwide and is caused by the intracellular bacteria, Salmonella Typhi (S. Typhi). Intestinal epithelial invasion by S. Typhi is essential for the establishment of successful infection and is traditionally believed to depend on Salmonella Pathogenicity Island (SPI1) encoded Type 3 Secretion System (T3SS-1). We had previously reported that bacterial outer membrane protein T2942/STIV functions as a standalone invasin and contributes to pathogenesis of S. Typhi by promoting epithelial invasion independent of T3SS-1 (Cell Microbiol, 2015). Here, we show that STIV, using its 20-amino acid extracellular loop, interacts with receptor tyrosine kinase, Met, of host intestinal epithelial cells. This interaction leads to Met phosphorylation and activation of a downstream signaling cascade, involving Src, PI3-K/Akt and Rac1, which culminates into localized actin polymerization and bacterial engulfment by the cell. Inhibition of Met tyrosine kinase activity severely limited intestinal invasion and systemic infection by S. Typhi in vivo, highlighting the importance of this invasion pathway in disease progression. This is the first report elucidating the mechanism of T3SS-1-independent epithelial invasion of S. Typhi and this crucial host-pathogen interaction may be targeted therapeutically to restrict pathogenesis.