The Acetate Switch of an Intestinal Pathogen Disrupts Host Insulin Signaling and Lipid Metabolism

被引:84
|
作者
Hang, Saiyu [1 ]
Purdy, Alexandra E. [1 ]
Robins, William P. [2 ]
Wang, Zhipeng [1 ]
Mandal, Manabendra [1 ,3 ]
Chang, Sarah [1 ]
Mekalanos, John J. [2 ]
Watnick, Paula I. [1 ,2 ]
机构
[1] Harvard Univ, Sch Med, Boston Childrens Hosp, Div Infect Dis, Boston, MA 02115 USA
[2] Harvard Univ, Sch Med, Dept Microbiol & Immunol, Boston, MA 02115 USA
[3] Tezpur Univ, Dept Mol Biol & Biotechnol, Sonitpur 784028, Assam, India
基金
美国国家卫生研究院;
关键词
VIVO EXPRESSION TECHNOLOGY; CHAIN FATTY-ACIDS; VIBRIO-CHOLERAE; MOLECULAR-MECHANISMS; IMMUNE-RESPONSE; HOMEOSTASIS; COLONIZATION; GUT; ACTIVATION; INFECTION;
D O I
10.1016/j.chom.2014.10.006
中图分类号
Q93 [微生物学];
学科分类号
071005 ; 100705 ;
摘要
Vibrio cholerae is lethal to the model host Drosophila melanogaster through mechanisms not solely attributable to cholera toxin. To examine additional virulence determinants, we performed a genetic screen in V. cholerae-infected Drosophila and identified the two-component system CrbRS. CrbRS controls transcriptional activation of acetyl-CoA synthase-1 (ACS-1) and thus regulates the acetate switch, in which bacteria transition from excretion to assimilation of environmental acetate. The resultant loss of intestinal acetate leads to deactivation of host insulin signaling and lipid accumulation in enterocytes, resulting in host lethality. These metabolic effects are not observed upon infection with Delta crbS or Delta acs1 V. cholerae mutants. Additionally, uninfected flies lacking intestinal commensals, which supply short chain fatty acids (SCFAs) such as acetate, also exhibit altered insulin signaling and intestinal steatosis, which is reversed upon acetate supplementation. Thus, acetate consumption by V. cholerae alters host metabolism, and dietary acetate supplementation may ameliorate some sequelae of cholera.
引用
收藏
页码:592 / 604
页数:13
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