RESEARCH HIGHLIGHTS

Nature Reviews Microbiology | AOP, published online 1 December 2015; doi:10.1038/nrmicro3409

BACTERIAL PATHOGENESIS Food for cholera

Infection of the by CrbS, a histidine kinase sensor, and these findings suggest that acetate cholerae causes the severe CrbR, its cognate response regula- consumption by V. cholerae disrupts the V. cholerae diarrhoeal disease cholera. The tor. The authors found that CrbRS insulin signalling, leading to intestinal two-component contributions of two controls the acetate switch, a process steatosis, which results in increased factors, the and the by which stop producing host lethality. Notably, removal of system CrbRS toxin coregulated pilus, to intestinal acetate and initiate acetate consump- lipids from the D. melanogaster diet regulates the colonization and pathology have tion. In , this switch is during prevented intestinal consumption been well characterized, but other solely dependent on transcriptional steatosis and resulted in increased of acetate mechanisms are also thought to be induction of acs1, the encod- survival, which indicates that lipid involved in disease pathogenesis. ing acetyl-CoA synthase, which is accumulation in enterocytes con- Now, Hang et al. show that the involved in acetate consumption. tributes to the lethality of V. cholerae V. cholerae two-component system Consistent with this, the transcrip- infection. CrbRS regulates the consumption tion of acs1 was reduced more than As the commensal microbiota of acetate by this , which 1,000‑fold in a V. cholerae produces most of the short chain alters insulin signalling and lipid lacking CrbRS, and the deletion of fatty acids in the gut, the authors metabolism in the host, resulting in asc1 reduced V. cholerae virulence. reasoned that depletion of the host death. Interestingly, deletion of CrbRS or microbiota should result in decreased V. cholerae causes a lethal infec- ACS1 had only minor effects on levels of acetate and dysregulation of tion in Drosophila melanogaster, V. cholerae colonization of the fly lipid metabolism, even in uninfected which established the fly as a model intestine, which suggests that acetate flies. Indeed, germ-free flies dis- in which to study host–pathogen consumption by V. cholerae in the played decreased insulin signalling, interactions. To identify novel intestine contributes to virulence decreased lipid accumulation in required for virulence, the authors primarily by affecting the host rather adipocytes and increased intestinal constructed a library of transposon than by promoting bacterial survival. steatosis, all of which were reversed mutants in a V. cholerae strain To understand how acetate con- by supplementing their diet with lacking the cholera toxin gene. By sumption by V. cholerae contributes acetate. screening this library of mutants for to pathogenesis, the authors com- Together, this study highlights virulence defects, they pared the transcriptional response of the CrbRS two-component system identified a novel D. melanogaster following infection as a major of two-component with wild-type and mutant bacteria V. cholerae in D. melanogaster that system comprised of lacking ACS1 or CrbRS. They perturbs insulin signalling and lipid observed that wild-type V. cholerae metabolism, leading to host death. inhibits the insulin signalling path- Interestingly, transcription of the way, whereas the mutant strains do gene encoding CrbS has previously not. Furthermore, infection with been shown to be activated during wild-type bacteria, but not with the V. cholerae infection in mice and mutant strains, was associated humans. Therefore, it is possible that with changes in lipid a similar process occurs in patients metabolism in the intes- with cholera and future studies tine; lipids accumulated are needed to understand whether in enterocytes (termed acetate supplementation can be used intestinal steatosis), rather as a treatment for cholera infection. than being transported Cláudio Nunes-Alves

to and stored in adipose ORIGINAL RESEARCH PAPER Hang, S. et al. NPG tissue. As insulin signalling The acetate switch of an intestinal pathogen is known to regulate lipid disrupts host insulin signaling and lipid metabolism. Cell Host Microbe 16, 592–604 (2014) storage in D. melanogaster,

NATURE REVIEWS | MICROBIOLOGY VOLUME 13 | JANUARY 2015

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