Mitochondrial Injury and Complement Dysregulation Are Drivers of Pathological Inflammation in Viral Myocarditis

Overview

Journal J Virol

Publisher American Society for Microbiology

Date 2025 Jan 23

PMID 39846741

Authors

Yasir Mohamud

Amirhossein Bahreyni

Sinwoo Wendy Hwang

Jingfei Carly Lin

Zhihan Claire Wang

Jingchun Zhang

Honglin Luo

Affiliations

Soon will be listed here.

Abstract

Importance: This study sheds light on how enteroviruses, specifically coxsackievirus B3, may contribute to heart failure by triggering harmful immune responses in the heart. We discovered that viral infections in heart cells cause mitochondrial damage, which in turn activates a destructive immune response involving the complement system. This immune activation is one of the significant contributors that lead to further injury of heart tissues, worsening the damage caused by the virus. Additionally, we identified key protective molecules that are targeted and disrupted by the virus, allowing the immune system to attack the heart even more aggressively. Understanding these mechanisms may provide additional insights into how viral infections can lead to chronic heart conditions and suggests potential therapeutic targets to prevent or reduce heart damage in patients affected by viral myocarditis.

References

Martens P, Cooper L, Tang W . Diagnostic Approach for Suspected Acute Myocarditis: Considerations for Standardization and Broadening Clinical Spectrum. J Am Heart Assoc. 2023; 12(17):e031454. PMC: 10547314. DOI: 10.1161/JAHA.123.031454. View

Gavriilaki E, Tsiftsoglou S, Touloumenidou T, Farmaki E, Panagopoulou P, Michailidou E . Targeted Genotyping of MIS-C Patients Reveals a Potential Alternative Pathway Mediated Complement Dysregulation during COVID-19 Infection. Curr Issues Mol Biol. 2022; 44(7):2811-2824. PMC: 9325260. DOI: 10.3390/cimb44070193. View

Fernandes-Alnemri T, Yu J, Datta P, Wu J, Alnemri E . AIM2 activates the inflammasome and cell death in response to cytoplasmic DNA. Nature. 2009; 458(7237):509-13. PMC: 2862225. DOI: 10.1038/nature07710. View

Dalakas M, Semino-Mora C . Mitochondrial alterations with mitochondrial DNA depletion in the nerves of AIDS patients with peripheral neuropathy induced by 2'3'-dideoxycytidine (ddC). Lab Invest. 2001; 81(11):1537-44. DOI: 10.1038/labinvest.3780367. View

Aukrust P, Gullestad L, Lappegard K, Ueland T, Aass H, Wikeby L . Complement activation in patients with congestive heart failure: effect of high-dose intravenous immunoglobulin treatment. Circulation. 2001; 104(13):1494-500. DOI: 10.1161/hc3801.096353. View

. The Genotype-Tissue Expression (GTEx) project. Nat Genet. 2013; 45(6):580-5. PMC: 4010069. DOI: 10.1038/ng.2653. View

Bottermann M, Foss S, Caddy S, Clift D, van Tienen L, Vaysburd M . Complement C4 Prevents Viral Infection through Capsid Inactivation. Cell Host Microbe. 2019; 25(4):617-629.e7. PMC: 6461443. DOI: 10.1016/j.chom.2019.02.016. View

Chen Q, Sun L, Chen Z . Regulation and function of the cGAS-STING pathway of cytosolic DNA sensing. Nat Immunol. 2016; 17(10):1142-9. DOI: 10.1038/ni.3558. View

Mohamud Y, Shi J, Qu J, Poon T, Xue Y, Deng H . Enteroviral Infection Inhibits Autophagic Flux via Disruption of the SNARE Complex to Enhance Viral Replication. Cell Rep. 2018; 22(12):3292-3303. DOI: 10.1016/j.celrep.2018.02.090. View

10.

Zipfel P, Skerka C . Complement regulators and inhibitory proteins. Nat Rev Immunol. 2009; 9(10):729-40. DOI: 10.1038/nri2620. View

11.

Quispe-Tintaya W, White R, Popov V, Vijg J, Maslov A . Fast mitochondrial DNA isolation from mammalian cells for next-generation sequencing. Biotechniques. 2013; 55(3):133-6. PMC: 4353588. DOI: 10.2144/000114077. View

12.

Cooper Jr L . Myocarditis. N Engl J Med. 2009; 360(15):1526-38. PMC: 5814110. DOI: 10.1056/NEJMra0800028. View

13.

Peitsch M, Tschopp J, Kress A, ISLIKER H . Antibody-independent activation of the complement system by mitochondria is mediated by cardiolipin. Biochem J. 1988; 249(2):495-500. PMC: 1148730. DOI: 10.1042/bj2490495. View

14.

Hanson P, Liu-Fei F, Minato T, Hossain A, Rai H, Chen V . Advanced detection strategies for cardiotropic virus infection in a cohort study of heart failure patients. Lab Invest. 2021; 102(1):14-24. PMC: 8488924. DOI: 10.1038/s41374-021-00669-4. View

15.

Clark D, Cleman M, Pfau S, Rollins S, Ramahi T, Mayer C . Serum complement activation in congestive heart failure. Am Heart J. 2001; 141(4):684-90. DOI: 10.1067/mhj.2001.113758. View

16.

Sin J, McIntyre L, Stotland A, Feuer R, Gottlieb R . Coxsackievirus B Escapes the Infected Cell in Ejected Mitophagosomes. J Virol. 2017; 91(24). PMC: 5709598. DOI: 10.1128/JVI.01347-17. View

17.

Mohamud Y, Shi J, Tang H, Xiang P, Xue Y, Liu H . Coxsackievirus infection induces a non-canonical autophagy independent of the ULK and PI3K complexes. Sci Rep. 2020; 10(1):19068. PMC: 7642411. DOI: 10.1038/s41598-020-76227-7. View

18.

Siasos G, Tsigkou V, Kosmopoulos M, Theodosiadis D, Simantiris S, Tagkou N . Mitochondria and cardiovascular diseases-from pathophysiology to treatment. Ann Transl Med. 2018; 6(12):256. PMC: 6046286. DOI: 10.21037/atm.2018.06.21. View

19.

Rahman J, Singh P, Merle N, Niyonzima N, Kemper C . Complement's favourite organelle-Mitochondria?. Br J Pharmacol. 2020; 178(14):2771-2785. PMC: 8359399. DOI: 10.1111/bph.15238. View

20.

Kaya Z, Afanasyeva M, Wang Y, Dohmen K, Schlichting J, Tretter T . Contribution of the innate immune system to autoimmune myocarditis: a role for complement. Nat Immunol. 2001; 2(8):739-45. DOI: 10.1038/90686. View