RESTRAINT IS STRENGTH - DIFFERENCES IN HOST CELL INVASION AND SPI-1 EXPRESSION BETWEEN SALMONELLA ENTERICA SEROVAR PARATYPHI A AND THE NON-TYPHOIDAL SEROVAR TYPHIMURIUM

Active invasion into non-phagocytic host cells is central to Salmonella enterica pathogenicity and dependent on multiple genes encoded within the Salmonella Pathogenicity Island-1 (SPI-1). Here we explored the invasion phenotype and the expression of SPI-1 in the typhoidal serovar S. Paratyphi A in comparison to the non-typhoidal serovar S. Typhimurium. We demonstrate that while S. Typhimurium is equally invasive under both aerobic and microaerobic conditions, S. Paratyphi A invades only following growth under microaerobic conditions. RNA-Seq, RT-PCR, western blot and secretome analyses established that S. Paratyphi A expresses much lower levels of SPI-1 genes and secretes lesser amounts of SPI-1 effector proteins compared to S. Typhimurium, especially under aerobic growth. Bypassing the native SPI-1 regulation by inducible expression of the SPI-1 activator, HilA, considerably elevated SPI-1 genes expression, host cell invasion, disruption of epithelial integrity, and induction of pro-inflammatory cytokine secretion by S. Paratyphi A, but not by S. Typhimurium, suggesting that SPI-1 expression is naturally down-regulated in S. Paratyphi A. Using streptomycin-treated mice, we were able to establish substantial intestinal colonization by S. Paratyphi A and showed moderately higher pathology and intestinal inflammation in mice infected with S. Paratyphi A, overexpressing hilA. Collectively, our results reveal unexpected differences in SPI-1 expression between S. Paratyphi A and S. Typhimurium, indicate that S. Paratyphi A host cell invasion is suppressed under aerobic conditions, and suggest that lower invasion and expression of immunogenic SPI-1 components in aerobic sites may contribute to the restrained-inflammatory infection elicited by S. Paratyphi A.