Vibrio cholerae ensures function of host proteins required for virulence through consumption of luminal methionine sulfoxide

Abstract

Vibrio cholerae is a diarrheal pathogen that induces accumulation of lipid droplets in enterocytes, leading to lethal infection of the model host Drosophila melanogaster. Through untargeted lipidomics, we provide evidence that this process is the product of a host phospholipid degradation cascade that induces lipid droplet coalescence in enterocytes. This infection-induced cascade is inhibited by mutation of the V. cholerae glycine cleavage system due to intestinal accumulation of methionine sulfoxide (MetO), and both dietary supplementation with MetO and enterocyte knock-down of host methionine sulfoxide reductase A (MsrA) yield increased resistance to infection. MsrA converts both free and protein-associated MetO to methionine. These findings support a model in which dietary MetO competitively inhibits repair of host proteins by MsrA. Bacterial virulence strategies depend on functional host proteins. We propose a novel virulence paradigm in which an intestinal pathogen ensures the repair of host proteins essential for pathogenesis through consumption of dietary MetO.

Vibrio cholerae-Symbiont Interactions Inhibit Intestinal Repair in Drosophila

“…For example, the gut is sensitive to growth cues received or generated through host-microbe interactions (Broderick et al, 2014;Buchon et al, 2009b;Jones et al, 2013;Shin et al, 2011), raising the possibility that V. cholerae prevents IPC proliferation by modifying microbiota-derived pro-growth cues. Consistent with this hypothesis, other studies have documented the effects of V. cholerae on the availability of microbial metabolites with downstream effects on epithelial renewal (Kamareddine et al, 2018;Vanhove et al, 2017). It will be interesting to determine whether the T6SS affects the bioavailability of microbiota-derived metabolites.…”

“…IMD pathway mutants have extended viability after infection with V. cholerae, implicating host immune activity in the pathogenesis of the bacteria (Berkey et al, 2009). At the same time, infections with V. cholerae affect intestinal levels of acetate (Hang et al, 2014), succinate (Kamareddine et al, 2018), and methionine sulfoxide (Vanhove et al, 2017), with consequences for host insulin signaling, lipid homeostasis, and epithelial renewal in the host. The ability of V. cholerae to suppress epithelial renewal is reversed by the mutational inactivation of IMD (Wang et al, 2013), suggesting functional links between immune activity and IPC growth in infected flies.…”

Modulation of CrbS-Dependent Activation of the Acetate Switch in Vibrio cholerae

“…Acetate consumption is either unaffected or slightly reduced in the Δcrp strain ( Fig. 6G), indicating both that (i) a reduction in acs transcription is not sufficient to prevent the removal of acetate from media and (ii) CRP may control levels of another metabolite, in addition to acetate, to affect virulence in Drosophila (11,12). Altogether, these findings collectively suggest that CRP regulates acs transcriptional activation.…”

“…arthropod (Drosophila melanogaster) model of infection revealed unexpected roles for bacterial metabolites, including short-chain fatty acids (SCFAs), in modulating the pathogenicity of these interactions (10)(11)(12). SCFAs produced by colonizing bacteria can alter the physiology of a variety of host organisms, affecting the development of the immune system, appetite, and overall body size (13)(14)(15)(16)(17)(18).…”

Removal of a Membrane Anchor Reveals the Opposing Regulatory Functions of Vibrio cholerae Glucose-Specific Enzyme IIA in Biofilms and the Mammalian Intestine

“…Furthermore, during infection, V. cholerae consumption of acetate and methionine sulfoxide, through the actions of pathogen acetyl coenzyme A (acetyl-CoA) synthase and the glycine cleavage system, respectively, results in host metabolic demise (42, 43). Here, we provide evidence that metabolites that alter the intestinal milieu and epithelial regeneration accumulate in cecal fluid during V.…”