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Obesity Exacerbates Coxsackievirus Infection via Lipid-Induced Mitochondrial Reactive Oxygen Species Generation

  • Seong-Ryeol Kim (Department of Pharmacy, Kangwon National University) ;
  • Jae-Hyoung Song (Department of Pharmacy, Kangwon National University) ;
  • Jae-Hee Ahn (Department of Pharmacy, Kangwon National University) ;
  • Myeong Seon Jeong (Chuncheon Center, Korea Basic Science Institute (KBSI)) ;
  • Yoon Mee Yang (Department of Pharmacy, Kangwon National University) ;
  • Jaewon Cho (Department of Pharmacy, Kangwon National University) ;
  • Jae-Hyeon Jeong (Department of Pharmacy, Kangwon National University) ;
  • Younggil Cha (Department of Pharmacy, Kangwon National University) ;
  • Kil-Nam Kim (Chuncheon Center, Korea Basic Science Institute (KBSI)) ;
  • Hong Pyo Kim (College of Pharmacy, Ajou University) ;
  • Sun-Young Chang (College of Pharmacy, Ajou University) ;
  • Hyun-Jeong Ko (Department of Pharmacy, Kangwon National University)
  • Received : 2021.11.01
  • Accepted : 2022.03.27
  • Published : 2022.04.30
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Abstract

Coxsackievirus B3 (CVB3) infection causes acute pancreatitis and myocarditis. However, its pathophysiological mechanism is unclear. Here, we investigated how lipid metabolism is associated with exacerbation of CVB3 pathology using high-fat diet (HFD)-induced obese mice. Mice were intraperitoneally inoculated with 1×106 pfu/mouse of CVB3 after being fed a control or HFD to induce obesity. Mice were treated with mitoquinone (MitoQ) to reduce the level of mitochondrial ROS (mtROS). In obese mice, lipotoxicity of white adipose tissue-induced inflammation caused increased replication of CVB3 and mortality. The coxsackievirus adenovirus receptor increased under obese conditions, facilitating CVB3 replication in vitro. However, lipid-treated cells with receptor-specific inhibitors did not reduce CVB3 replication. In addition, lipid treatment increased mitochondria-derived vesicle formation and the number of multivesicular bodies. Alternatively, we found that inhibition of lipid-induced mtROS decreased viral replication. Notably, HFD-fed mice were more susceptible to CVB3-induced mortality in association with increased levels of CVB3 replication in adipose tissue, which was ameliorated by administration of the mtROS inhibitor, MitoQ. These results suggest that mtROS inhibitors can be used as potential treatments for CVB3 infection.

Keywords

Acknowledgement

This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIT) (grant No. NRF-2020R1A2B5B02001552, NRF-2020R1A5A8019180 and NRF-2019R1I1A1A01060238) and the Korea Basic Science Institute, Republic of Korea (grant No. C140360). This research was supported by Korea Basic Science Institute (National research Facilities and Equipment Center) grant funded by the Ministry of Education (grant No. 2020R1A6C101A195).

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