title: Activation of AMPK restricts coxsackievirus B3 replication by inhibiting lipid accumulation.
abstract: Coxsackievirus B3 (CVB3) is the major pathogen of human viral myocarditis. CVB3 has been found to manipulate and modify the cellular lipid metabolism for viral replication. The cellular AMP-activated protein kinase (AMPK) is a key regulator of multiple metabolic pathways, including lipid metabolism. Here we explore the potential roles AMPK plays in CVB3 infection. We found that AMPK is activated by the viral replication during CVB3 infection in Hela cells and primary myocardial cells. RNA interference mediated inhibition of AMPK could increase the CVB3 replication in cells, indicating that AMPK contributed to restricting the viral replication. Next, we showed that CVB3 replication could be inhibited by several different pharmacological AMPK activators including metformin, A769662 and AICAR. And the constitutively active AMPK mutant (CA-AMPK) could also inhibit the CVB3 replication. Furthermore, we found that CVB3 infection increased the cellular lipid levels and showed that the AMPK agonist AICAR both restricted CVB3 replication and reduced lipid accumulation through inhibiting the lipid synthesis associated gene expression. We further found that CVB3 infection would also induce AMPK activated in vivo. The AMPK agonist metformin, which has been widely used in diabetes therapy, could decrease the viral replication and further protect the mice from myocardial histological and functional changes in CVB3 induced myocarditis, and improve the survival rate of infected mice. Lastly, it was demonstrated that the AICAR-mediated restriction of viral replication could be rescued partially by exogenous palmitate, the first product of fatty acid biosynthesis, demonstrating that AMPK activation restricted CVB3 infection through its inhibition of lipid synthesis. Taken together, these data in the present study suggest a model in which AMPK is activated by CVB3 infection and restricts viral replication by inhibiting the cellular lipid accumulation, and inform a potential novel therapeutic strategy for CVB3-associated diseases.
authors.affiliation: Central Laboratory, Xinqiao Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Xie
authors.affiliation: Central Laboratory, Xinqiao Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Wang
authors.affiliation: Central Laboratory, Xinqiao Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Dai
authors.affiliation: Central Laboratory, Xinqiao Hospital, Third Military Medical University, Chongqing, China; Department of Microbiology, College of Basic Medical Sciences, Third Military Medical University, Chongqing, China.
authors.forename: Hua
authors.initials: H
authors.lastname: Yu
authors.affiliation: Central Laboratory, Xinqiao Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Xiaomei
authors.initials: X
authors.lastname: He
authors.affiliation: Central Laboratory, Xinqiao Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Junzhi
authors.initials: J
authors.lastname: Xiong
authors.affiliation: Central Laboratory, Xinqiao Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Halei
authors.initials: H
authors.lastname: Sheng
authors.affiliation: Central Laboratory, Xinqiao Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Di
authors.initials: D
authors.lastname: Zhang
authors.affiliation: Central Laboratory, Xinqiao Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Rong
authors.initials: R
authors.lastname: Xin
authors.affiliation: Division of Molecular Cardiology, Department of Medicine, College of Medicine, Texas A&M University Health Science Center, Temple, TX, USA.
authors.forename: Yajuan
authors.initials: Y
authors.lastname: Qi
authors.affiliation: Department of Microbiology, College of Basic Medical Sciences, Third Military Medical University, Chongqing, China.
authors.forename: Fuquan
authors.initials: F
authors.lastname: Hu
authors.affiliation: Division of Molecular Cardiology, Department of Medicine, College of Medicine, Texas A&M University Health Science Center, Temple, TX, USA. Electronic address: sguo@medicine.tamhsc.edu.
authors.forename: Shaodong
authors.initials: S
authors.lastname: Guo
authors.affiliation: Central Laboratory, Xinqiao Hospital, Third Military Medical University, Chongqing, China. Electronic address: zhangkebin12@163.com.
authors.forename: Kebin
authors.initials: K
authors.lastname: Zhang
mesh_terms: D000263:Adenylate Kinase / Q000378:metabolism*; D000818:Animals; D029822:Enterovirus B, Human / Q000502:physiology*; D004789:Enzyme Activation; D006367:HeLa Cells; D006801:Humans; D050356:Lipid Metabolism; D008297:Male; D008807:Mice, Inbred BALB C; D008820:Mice, Obese; D014779:Virus Replication
chemical_list: D000263:Adenylate Kinase
keywords: AMPK; Coxsackievirus B3; Lipid accumulation; Myocarditis; Viral replication