Abstract
Salmonella hijack host machinery in order to invade cells and establish infection. While considerable work has described the role of host proteins in invasion, much less is known regarding how natural variation in these invasion-associated host proteins affects Salmonella pathogenesis. Here we leveraged a candidate cellular GWAS screen to identify natural genetic variation in the ARHGEF26 (Rho Guanine Nucleotide Exchange Factor 26) gene that renders lymphoblastoid cells susceptible to Salmonella Typhi and Typhimurium invasion. Experimental follow-up redefined ARHGEF26's role in Salmonella epithelial cell infection. Specifically, we identified complex serovar-by-host interactions whereby ARHGEF26 stimulation of S. Typhi and S. Typhimurium invasion into host cells varied in magnitude and effector-dependence based on host cell type. While ARHGEF26 regulated SopB- and SopE-mediated S. Typhi (but not S. Typhimurium) infection of HeLa cells, the largest effect of ARHGEF26 was observed with S. Typhimurium in polarized MDCK cells through a SopB- and SopE2-independent mechanism. In both cell types, knockdown of the ARHGEF26-associated protein DLG1 resulted in a similar phenotype and serovar specificity. Importantly, we show that ARHGEF26 plays a critical role in S. Typhimurium pathogenesis by contributing to bacterial burden in the enteric fever murine model, as well as inflammation in the colitis infection model. In the enteric fever model, SopB and SopE2 are required for the effects of Arhgef26 deletion on bacterial burden, and the impact of sopB and sopE2 deletion in turn required ARHGEF26. In contrast, SopB and SopE2 were not required for the impacts of Arhgef26 deletion on colitis. A role for ARHGEF26 on inflammation was also seen in cells, as knockdown reduced IL-8 production in HeLa cells. Together, these data reveal pleiotropic roles for ARHGEF26 during infection and highlight that many of the interactions that occur during infection that are thought to be well understood likely have underappreciated complexity.
Highlights
The ability for bacteria to invade non-phagocytic host cells has long been recognized as a crucial trait of many pathogenic bacteria
We leveraged a candidate genetic screen to identify natural genetic variation in the human ARHGEF26 gene that correlates with Salmonella invasion
Building on how ARHGEF26 functions in other contexts, we implicated two ARHGEF26-interacting host proteins as contributors to Salmonella pathobiology. These results identify a potential source of interperson diversity in susceptibility to Salmonella disease and expand our molecular understanding of Salmonella infection to include a multifaceted role for ARHGEF26
Summary
The ability for bacteria to invade non-phagocytic host cells has long been recognized as a crucial trait of many pathogenic bacteria. Observations of this phenomena in Salmonella stretch back to at least 1920 when Margaret Reed Lewis observed that Salmonella enterica serovar Typhi Typhi) induces vacuole formation during invasion of chick embryo tissues [1]. Additional work demonstrated that the Salmonella effector proteins SopB, SopE, and SopE2 drive uptake of Salmonella in cultured cells by macropinocytosis through their ability to hijack or mimic host proteins to cause membrane ruffling [4,5,6,7,8,9]. The importance of Salmonella invasion has been affirmed through several in vivo studies, as strains defective for the invasion apparatus are severely attenuated in their ability to colonize and disseminate [3] and/ or drive inflammation [10,11] in mouse models
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