IMMUNE NETWORK

The Korean Association of Immunobiologists (대한면역학회)
권호 표지
DOI QR코드

DOI QR Code

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
Download PDF
⟨ Previous Next ⟩

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).

References

  1. Stefan N, Birkenfeld AL, Schulze MB, Ludwig DS. Obesity and impaired metabolic health in patients with COVID-19. Nat Rev Endocrinol 2020;16:341-342. https://doi.org/10.1038/s41574-020-0364-6
  2. Karjala Z, Neal D, Rohrer J. Association between HSV1 seropositivity and obesity: data from the National Health and Nutritional Examination Survey, 2007-2008. PLoS One 2011;6:e19092.
  3. Honce R, Schultz-Cherry S. Impact of obesity on influenza a virus pathogenesis, immune response, and evolution. Front Immunol 2019;10:1071.
  4. Fairweather D, Stafford KA, Sung YK. Update on coxsackievirus B3 myocarditis. Curr Opin Rheumatol 2012;24:401-407. https://doi.org/10.1097/BOR.0b013e328353372d
  5. Huber S, Ramsingh AI. Coxsackievirus-induced pancreatitis. Viral Immunol 2004;17:358-369. https://doi.org/10.1089/vim.2004.17.358
  6. Pedersen KW, van der Meer Y, Roos N, Snijder EJ. Open reading frame 1a-encoded subunits of the arterivirus replicase induce endoplasmic reticulum-derived double-membrane vesicles which carry the viral replication complex. J Virol 1999;73:2016-2026. https://doi.org/10.1128/JVI.73.3.2016-2026.1999
  7. Limpens RW, van der Schaar HM, Kumar D, Koster AJ, Snijder EJ, van Kuppeveld FJ, Barcena M. The transformation of enterovirus replication structures: a three-dimensional study of single- and double-membrane compartments. MBio 2011;2:e00166-11.
  8. Knoops K, Kikkert M, Worm SH, Zevenhoven-Dobbe JC, van der Meer Y, Koster AJ, Mommaas AM, Snijder EJ. SARS-coronavirus replication is supported by a reticulovesicular network of modified endoplasmic reticulum. PLoS Biol 2008;6:e226.
  9. Liu Z, Ren Z, Zhang J, Chuang CC, Kandaswamy E, Zhou T, Zuo L. Role of ros and nutritional antioxidants in human diseases. Front Physiol 2018;9:477. 
  10. Guillin OM, Vindry C, Ohlmann T, Chavatte L. Selenium, selenoproteins and viral infection. Nutrients 2019;11:2101.
  11. Chi J, Yu S, Liu C, Zhao X, Zhong J, Liang Y, Ta N, Yin X, Zhao D. Nox4-dependent ROS production is involved in CVB3-induced myocardial apoptosis. Biochem Biophys Res Commun 2018;503:1641-1644. https://doi.org/10.1016/j.bbrc.2018.07.093
  12. Wang Y, Gao B, Xiong S. Involvement of NLRP3 inflammasome in CVB3-induced viral myocarditis. Am J Physiol Heart Circ Physiol 2014;307:H1438-H1447. https://doi.org/10.1152/ajpheart.00441.2014
  13. To EE, Erlich JR, Liong F, Luong R, Liong S, Esaq F, Oseghale O, Anthony D, McQualter J, Bozinovski S, et al. Mitochondrial reactive oxygen species contribute to pathological inflammation during influenza a virus infection in mice. Antioxid Redox Signal 2020;32:929-942. https://doi.org/10.1089/ars.2019.7727
  14. Li J, Ma C, Long F, Yang D, Liu X, Hu Y, Wu C, Wang B, Wang M, Chen Y, et al. Parkin impairs antiviral immunity by suppressing the mitochondrial reactive oxygen species-nlrp3 axis and antiviral inflammation. iScience 2019;16:468-484. https://doi.org/10.1016/j.isci.2019.06.008
  15. Sreekanth GP, Panaampon J, Suttitheptumrong A, Chuncharunee A, Bootkunha J, Yenchitsomanus PT, Limjindaporn T. Drug repurposing of N-acetyl cysteine as antiviral against dengue virus infection. Antiviral Res 2019;166:42-55. https://doi.org/10.1016/j.antiviral.2019.03.011
  16. Hu M, Bogoyevitch MA, Jans DA. Subversion of host cell mitochondria by RSV to favor virus production is dependent on inhibition of mitochondrial complex I and ROS generation. Cells 2019;8:1417.
  17. Hong EH, Song JH, Kim SR, Cho J, Jeong B, Yang H, Jeong JH, Ahn JH, Jeong H, Kim SE, et al. Morin hydrate inhibits influenza virus entry into host cells and has anti-inflammatory effect in influenza-infected mice. Immune Netw 2020;20:e32.
  18. Kim SR, Song JH, Ahn JH, Lee GS, Ahn H, Yoon SI, Kang SG, Kim PH, Jeon SM, Choi EJ, et al. Antiviral and anti-inflammatory activity of budesonide against human rhinovirus infection mediated via autophagy activation. Antiviral Res 2018;151:87-96. https://doi.org/10.1016/j.antiviral.2018.01.012
  19. Shi H, Bartness TJ. White adipose tissue sensory nerve denervation mimics lipectomy-induced compensatory increases in adiposity. Am J Physiol Regul Integr Comp Physiol 2005;289:R514-R520. https://doi.org/10.1152/ajpregu.00036.2005
  20. Henke A, Launhardt H, Klement K, Stelzner A, Zell R, Munder T. Apoptosis in coxsackievirus B3-caused diseases: interaction between the capsid protein VP2 and the proapoptotic protein siva. J Virol 2000;74:4284-4290. https://doi.org/10.1128/JVI.74.9.4284-4290.2000
  21. Limsuwat N, Boonarkart C, Phakaratsakul S, Suptawiwat O, Auewarakul P. Influence of cellular lipid content on influenza A virus replication. Arch Virol 2020;165:1151-1161. https://doi.org/10.1007/s00705-020-04596-5
  22. Dias SSG, Soares VC, Ferreira AC, Sacramento CQ, Fintelman-Rodrigues N, Temerozo JR, Teixeira L, Nunes da Silva MA, Barreto E, Mattos M, et al. Lipid droplets fuel SARS-CoV-2 replication and production of inflammatory mediators. PLoS Pathog 2020;16:e1009127.
  23. Burckhardt CJ, Suomalainen M, Schoenenberger P, Boucke K, Hemmi S, Greber UF. Drifting motions of the adenovirus receptor CAR and immobile integrins initiate virus uncoating and membrane lytic protein exposure. Cell Host Microbe 2011;10:105-117. https://doi.org/10.1016/j.chom.2011.07.006
  24. Serrano M, Moreno M, Bassols J, Moreno-Navarrete JM, Ortega F, Ricart W, Fernandez-Real JM. Coxsackie and adenovirus receptor is increased in adipose tissue of obese subjects: a role for adenovirus infection? J Clin Endocrinol Metab 2015;100:1156-1163. https://doi.org/10.1210/jc.2014-3791
  25. Funke C, Farr M, Werner B, Dittmann S, uberla K, Piper C, Niehaus K, Horstkotte D. Antiviral effect of Bosentan and Valsartan during coxsackievirus B3 infection of human endothelial cells. J Gen Virol 2010;91:1959-1970. https://doi.org/10.1099/vir.0.020065-0
  26. Soto-Heredero G, Baixauli F, Mittelbrunn M. Interorganelle communication between mitochondria and the endolysosomal system. Front Cell Dev Biol 2017;5:95.
  27. Sugiura A, McLelland GL, Fon EA, McBride HM. A new pathway for mitochondrial quality control: mitochondrial-derived vesicles. EMBO J 2014;33:2142-2156. https://doi.org/10.15252/embj.201488104
  28. Picca A, Guerra F, Calvani R, Coelho-Junior HJ, Bossola M, Landi F, Bernabei R, Bucci C, Marzetti E. Generation and release of mitochondrial-derived vesicles in health, aging and disease. J Clin Med 2020;9:1440.
  29. Burgyan J, Rubino L, Russo M. The 5'-terminal region of a tombusvirus genome determines the origin of multivesicular bodies. J Gen Virol 1996;77:1967-1974. https://doi.org/10.1099/0022-1317-77-8-1967
  30. Bass VL, Soukup JM, Ghio AJ, Madden MC. Oleic acid and derivatives affect human endothelial cell mitochondrial function and vasoactive mediator production. Lipids Health Dis 2020;19:128.
  31. Bozi LH, Bechara LR, Dos Santos AF, Campos JC. Mitochondrial-derived vesicles: a new player in cardiac mitochondrial quality control. J Physiol 2016;594:6077-6078. https://doi.org/10.1113/JP273124
  32. Neuspiel M, Schauss AC, Braschi E, Zunino R, Rippstein P, Rachubinski RA, Andrade-Navarro MA, McBride HM. Cargo-selected transport from the mitochondria to peroxisomes is mediated by vesicular carriers. Curr Biol 2008;18:102-108. https://doi.org/10.1016/j.cub.2007.12.038
  33. Cadete VJ, Deschenes S, Cuillerier A, Brisebois F, Sugiura A, Vincent A, Turnbull D, Picard M, McBride HM, Burelle Y. Formation of mitochondrial-derived vesicles is an active and physiologically relevant mitochondrial quality control process in the cardiac system. J Physiol 2016;594:5343-5362. https://doi.org/10.1113/JP272703
  34. Li B, Zhao H, Wu Y, Zhu Y, Zhang J, Yang G, Yan Q, Li J, Li T, Liu L. Mitochondrial-derived vesicles protect cardiomyocytes against hypoxic damage. Front Cell Dev Biol 2020;8:214.
  35. Gremmels H, Bevers LM, Fledderus JO, Braam B, van Zonneveld AJ, Verhaar MC, Joles JA. Oleic acid increases mitochondrial reactive oxygen species production and decreases endothelial nitric oxide synthase activity in cultured endothelial cells. Eur J Pharmacol 2015;751:67-72. https://doi.org/10.1016/j.ejphar.2015.01.005
  36. Cheng ML, Weng SF, Kuo CH, Ho HY. Enterovirus 71 induces mitochondrial reactive oxygen species generation that is required for efficient replication. PLoS One 2014;9:e113234.
  37. Bond ST, Kim J, Calkin AC, Drew BG. The antioxidant moiety of mitoq imparts minimal metabolic effects in adipose tissue of high fat fed mice. Front Physiol 2019;10:543.
  38. Ghilotti F, Bellocco R, Ye W, Adami HO, Trolle Lagerros Y. Obesity and risk of infections: results from men and women in the Swedish National March Cohort. Int J Epidemiol 2019;48:1783-1794.
  39. Falagas ME, Kompoti M. Obesity and infection. Lancet Infect Dis 2006;6:438-446. https://doi.org/10.1016/S1473-3099(06)70523-0
  40. Kwok S, Adam S, Ho JH, Iqbal Z, Turkington P, Razvi S, Le Roux CW, Soran H, Syed AA. Obesity: a critical risk factor in the COVID-19 pandemic. Clin Obes 2020;10:e12403.
  41. Torres L, Martins VD, Faria AMC, Maioli TU. The intriguing relationship between obesity and infection. J Infect (Grand Rapids) 2018;1:6-10.
  42. Namkoong H, Ishii M, Fujii H, Asami T, Yagi K, Suzuki S, Azekawa S, Tasaka S, Hasegawa N, Betsuyaku T. Obesity worsens the outcome of influenza virus infection associated with impaired type I interferon induction in mice. Biochem Biophys Res Commun 2019;513:405-411. https://doi.org/10.1016/j.bbrc.2019.03.211
  43. Gebhard JR, Perry CM, Harkins S, Lane T, Mena I, Asensio VC, Campbell IL, Whitton JL. Coxsackievirus B3-induced myocarditis: perforin exacerbates disease, but plays no detectable role in virus clearance. Am J Pathol 1998;153:417-428. https://doi.org/10.1016/S0002-9440(10)65585-X
  44. Daley AJ, Isaacs D, Dwyer DE, Gilbert GL. A cluster of cases of neonatal coxsackievirus B meningitis and myocarditis. J Paediatr Child Health 1998;34:196-198.  https://doi.org/10.1046/j.1440-1754.1998.00176.x
  45. Wolff G, Melia CE, Snijder EJ, Barcena M. Double-membrane vesicles as platforms for viral replication. Trends Microbiol 2020;28:1022-1033. https://doi.org/10.1016/j.tim.2020.05.009
  46. Cook GW, Benton MG, Akerley W, Mayhew GF, Moehlenkamp C, Raterman D, Burgess DL, Rowell WJ, Lambert C, Eng K, et al. Structural variation and its potential impact on genome instability: novel discoveries in the EGFR landscape by long-read sequencing. PLoS One 2020;15:e0226340.
  47. Peters CE, Carette JE. Return of the neurotropic enteroviruses: co-opting cellular pathways for infection. Viruses 2021;13:166.
  48. Ormseth MJ, Swift LL, Fazio S, Linton MF, Raggi P, Solus JF, Oeser A, Bian A, Gebretsadik T, Shintani A, et al. Free fatty acids are associated with metabolic syndrome and insulin resistance but not inflammation in systemic lupus erythematosus. Lupus 2013;22:26-33. https://doi.org/10.1177/0961203312462756
  49. Muro E, Atilla-Gokcumen GE, Eggert US. Lipids in cell biology: how can we understand them better? Mol Biol Cell 2014;25:1819-1823. https://doi.org/10.1091/mbc.e13-09-0516
  50. Molteni CG, Principi N, Esposito S. Reactive oxygen and nitrogen species during viral infections. Free Radic Res 2014;48:1163-1169. https://doi.org/10.3109/10715762.2014.945443
  51. Camini FC, da Silva TF, da Silva Caetano CC, Almeida LT, Ferraz AC, Alves Vitoreti VM, de Mello Silva B, de Queiroz Silva S, de Magalhaes JC, de Brito Magalhaes CL. Antiviral activity of silymarin against Mayaro virus and protective effect in virus-induced oxidative stress. Antiviral Res 2018;158:8-12. https://doi.org/10.1016/j.antiviral.2018.07.023
  52. Paul D, Hoppe S, Saher G, Krijnse-Locker J, Bartenschlager R. Morphological and biochemical characterization of the membranous hepatitis C virus replication compartment. J Virol 2013;87:10612-10627. https://doi.org/10.1128/JVI.01370-13
  53. Melia CE, van der Schaar HM, Lyoo H, Limpens RW, Feng Q, Wahedi M, Overheul GJ, van Rij RP, Snijder EJ, Koster AJ, et al. Escaping host factor pi4kb inhibition: Enterovirus genomic RNA replication in the absence of replication organelles. Cell Reports 2017;21:587-599. https://doi.org/10.1016/j.celrep.2017.09.068
  54. Soubannier V, McLelland GL, Zunino R, Braschi E, Rippstein P, Fon EA, McBride HM. A vesicular transport pathway shuttles cargo from mitochondria to lysosomes. Curr Biol 2012;22:135-141. https://doi.org/10.1016/j.cub.2011.11.057
  55. Abuaita BH, Schultz TL, O'Riordan MX. Mitochondria-derived vesicles deliver antimicrobial reactive oxygen species to control phagosome-localized staphylococcus aureus. Cell Host Microbe 2018;24:625-636.e5. https://doi.org/10.1016/j.chom.2018.10.005
  56. Uchil P, Mothes W. Viral entry: a detour through multivesicular bodies. Nat Cell Biol 2005;7:641-642. https://doi.org/10.1038/ncb0705-641
  57. Chu H, Wang JJ, Spearman P. Human immunodeficiency virus type-1 gag and host vesicular trafficking pathways. Curr Top Microbiol Immunol 2009;339:67-84.
  58. Kelso GF, Porteous CM, Coulter CV, Hughes G, Porteous WK, Ledgerwood EC, Smith RA, Murphy MP. Selective targeting of a redox-active ubiquinone to mitochondria within cells: antioxidant and antiapoptotic properties. J Biol Chem 2001;276:4588-4596. https://doi.org/10.1074/jbc.M009093200
  59. Kelso GF, Porteous CM, Hughes G, Ledgerwood EC, Gane AM, Smith RA, Murphy MP. Prevention of mitochondrial oxidative damage using targeted antioxidants. Ann N Y Acad Sci 2002;959:263-274. https://doi.org/10.1111/j.1749-6632.2002.tb02098.x
  60. Smith RA, Porteous CM, Gane AM, Murphy MP. Delivery of bioactive molecules to mitochondria in vivo. Proc Natl Acad Sci U S A 2003;100:5407-5412. https://doi.org/10.1073/pnas.0931245100
  61. Weiss L, Hildt E, Hofschneider PH. Anti-hepatitis B virus activity of N-acetyl-L-cysteine (NAC): new aspects of a well-established drug. Antiviral Res 1996;32:43-53. https://doi.org/10.1016/0166-3542(95)00977-9
  62. Gaudernak E, Seipelt J, Triendl A, Grassauer A, Kuechler E. Antiviral effects of pyrrolidine dithiocarbamate on human rhinoviruses. J Virol 2002;76:6004-6015. https://doi.org/10.1128/JVI.76.12.6004-6015.2002
  63. Schweizer M, Peterhans E. Oxidative stress in cells infected with bovine viral diarrhoea virus: a crucial step in the induction of apoptosis. J Gen Virol 1999;80:1147-1155. https://doi.org/10.1099/0022-1317-80-5-1147
  64. Si X, McManus BM, Zhang J, Yuan J, Cheung C, Esfandiarei M, Suarez A, Morgan A, Luo H. Pyrrolidine dithiocarbamate reduces coxsackievirus B3 replication through inhibition of the ubiquitin-proteasome pathway. J Virol 2005;79:8014-8023. https://doi.org/10.1128/JVI.79.13.8014-8023.2005
  65. Wang Z, Cai F, Chen X, Luo M, Hu L, Lu Y. The role of mitochondria-derived reactive oxygen species in hyperthermia-induced platelet apoptosis. PLoS One 2013;8:e75044.
  66. Marchant D, Si X, Luo H, McManus B, Yang D. The impact of CVB3 infection on host cell biology. Curr Top Microbiol Immunol 2008;323:177-198.
  67. Perna AF, Violetti E, Lanza D, Sepe I, Bellinghieri G, Savica V, Santoro D, Satta E, Cirillo G, Lupo A, et al. Therapy of hyperhomocysteinemia in hemodialysis patients: effects of folates and N-acetylcysteine. J Ren Nutr 2012;22:507-514.e1. https://doi.org/10.1053/j.jrn.2011.10.007