Gammaherpesvirus Latency Accentuates EAE Pathogenesis: Relevance to Epstein-Barr Virus and Multiple Sclerosis

Overview

Journal PLoS Pathog

Specialty Microbiology

Date 2012 May 23

PMID 22615572

Citations 45

Authors

Costanza Casiraghi

Iryna Shanina

Sehyun Cho

Michael L Freeman

Marcia A Blackman

Marc S Horwitz

Affiliations

Soon will be listed here.

Abstract

Epstein-Barr virus (EBV) has been identified as a putative environmental trigger of multiple sclerosis (MS), yet EBV's role in MS remains elusive. We utilized murine gamma herpesvirus 68 (γHV-68), the murine homolog to EBV, to examine how infection by a virus like EBV could enhance CNS autoimmunity. Mice latently infected with γHV-68 developed more severe EAE including heightened paralysis and mortality. Similar to MS, γHV-68EAE mice developed lesions composed of CD4 and CD8 T cells, macrophages and loss of myelin in the brain and spinal cord. Further, T cells from the CNS of γHV-68 EAE mice were primarily Th1, producing heightened levels of IFN-γ and T-bet accompanied by IL-17 suppression, whereas a Th17 response was observed in uninfected EAE mice. Clearly, γHV-68 latency polarizes the adaptive immune response, directs a heightened CNS pathology following EAE induction reminiscent of human MS and portrays a novel mechanism by which EBV likely influences MS and other autoimmune diseases.

Citing Articles

Epstein-Barr virus infection promotes T cell dysregulation in a humanized mouse model of multiple sclerosis.

Allanach J, Fettig N, Hardman B, Rosen A, Fan V, Chung C Sci Adv. 2025; 11(10):eadu5110.

PMID: 40043135 PMC: 11881922. DOI: 10.1126/sciadv.adu5110.

Repurposing Licensed Drugs with Activity Against Epstein-Barr Virus for Treatment of Multiple Sclerosis: A Systematic Approach.

Li V, McKay F, Tscharke D, Smith C, Khanna R, Lechner-Scott J CNS Drugs. 2025; 39(3):305-320.

PMID: 39792343 DOI: 10.1007/s40263-024-01153-5.

The EBV-MS connection: the enigma remains.

van de Waterweg Berends A, Broux B, Machiels B, Gillet L, Hellings N Front Immunol. 2024; 15:1466339.

PMID: 39267757 PMC: 11390381. DOI: 10.3389/fimmu.2024.1466339.

Memory inflation: Beyond the acute phase of viral infection.

Li Y, Xiao J, Li C, Yang M Cell Prolif. 2024; 57(12):e13705.

PMID: 38992867 PMC: 11628752. DOI: 10.1111/cpr.13705.

Host Genetic Variation Has a Profound Impact on Immune Responses Mediating Control of Viral Load in Chronic Gammaherpesvirus Infection.

Holt E, Waytashek C, Sessions K, Asarian L, Lahue K, Usherwood E J Immunol. 2023; 211(10):1526-1539.

PMID: 37819784 PMC: 10841120. DOI: 10.4049/jimmunol.2300294.

References

Matullo C, ORegan K, Curtis M, Rall G . CNS recruitment of CD8+ T lymphocytes specific for a peripheral virus infection triggers neuropathogenesis during polymicrobial challenge. PLoS Pathog. 2012; 7(12):e1002462. PMC: 3245314. DOI: 10.1371/journal.ppat.1002462. View

Lunemann J, Tintore M, Messmer B, Strowig T, Rovira A, Perkal H . Elevated Epstein-Barr virus-encoded nuclear antigen-1 immune responses predict conversion to multiple sclerosis. Ann Neurol. 2010; 67(2):159-69. PMC: 2848293. DOI: 10.1002/ana.21886. View

Romero C, Herzig D, Etogo A, Nunez J, Mahmoudizad R, Fang G . The role of interferon-γ in the pathogenesis of acute intra-abdominal sepsis. J Leukoc Biol. 2010; 88(4):725-35. PMC: 2974432. DOI: 10.1189/jlb.0509307. View

Barton E, White D, Cathelyn J, Brett-McClellan K, Engle M, Diamond M . Herpesvirus latency confers symbiotic protection from bacterial infection. Nature. 2007; 447(7142):326-9. DOI: 10.1038/nature05762. View

Pender M, Csurhes P, Lenarczyk A, Pfluger C, Burrows S . Decreased T cell reactivity to Epstein-Barr virus infected lymphoblastoid cell lines in multiple sclerosis. J Neurol Neurosurg Psychiatry. 2008; 80(5):498-505. PMC: 2663364. DOI: 10.1136/jnnp.2008.161018. View

Ascherio A, Munger K . Environmental risk factors for multiple sclerosis. Part I: the role of infection. Ann Neurol. 2007; 61(4):288-99. DOI: 10.1002/ana.21117. View

Yang Y, Weiner J, Liu Y, Smith A, Huss D, Winger R . T-bet is essential for encephalitogenicity of both Th1 and Th17 cells. J Exp Med. 2009; 206(7):1549-64. PMC: 2715092. DOI: 10.1084/jem.20082584. View

Saxena A, Bauer J, Scheikl T, Zappulla J, Audebert M, Desbois S . Cutting edge: Multiple sclerosis-like lesions induced by effector CD8 T cells recognizing a sequestered antigen on oligodendrocytes. J Immunol. 2008; 181(3):1617-21. DOI: 10.4049/jimmunol.181.3.1617. View

Klein E, Kis L, Klein G . Epstein-Barr virus infection in humans: from harmless to life endangering virus-lymphocyte interactions. Oncogene. 2007; 26(9):1297-305. DOI: 10.1038/sj.onc.1210240. View

10.

Schleicher U, Hesse A, Bogdan C . Minute numbers of contaminant CD8+ T cells or CD11b+CD11c+ NK cells are the source of IFN-gamma in IL-12/IL-18-stimulated mouse macrophage populations. Blood. 2004; 105(3):1319-28. DOI: 10.1182/blood-2004-05-1749. View

11.

Kaplan C, Valdez J, Chandrasekaran R, Eibel H, Mikecz K, Glant T . Th1 and Th2 cytokines regulate proteoglycan-specific autoantibody isotypes and arthritis. Arthritis Res. 2002; 4(1):54-8. PMC: 64852. DOI: 10.1186/ar383. View

12.

Lunemann J, Jelcic I, Roberts S, Lutterotti A, Tackenberg B, Martin R . EBNA1-specific T cells from patients with multiple sclerosis cross react with myelin antigens and co-produce IFN-gamma and IL-2. J Exp Med. 2008; 205(8):1763-73. PMC: 2525578. DOI: 10.1084/jem.20072397. View

13.

Johnson T, Jirik F, Fournier S . Exploring the roles of CD8(+) T lymphocytes in the pathogenesis of autoimmune demyelination. Semin Immunopathol. 2010; 32(2):197-209. DOI: 10.1007/s00281-010-0199-7. View

14.

Sargsyan S, Shearer A, Ritchie A, Burgoon M, Anderson S, Hemmer B . Absence of Epstein-Barr virus in the brain and CSF of patients with multiple sclerosis. Neurology. 2010; 74(14):1127-35. PMC: 2865779. DOI: 10.1212/WNL.0b013e3181d865a1. View

15.

Serafini B, Rosicarelli B, Franciotta D, Magliozzi R, Reynolds R, Cinque P . Dysregulated Epstein-Barr virus infection in the multiple sclerosis brain. J Exp Med. 2007; 204(12):2899-912. PMC: 2118531. DOI: 10.1084/jem.20071030. View

16.

Gargano L, Forrest J, Speck S . Signaling through Toll-like receptors induces murine gammaherpesvirus 68 reactivation in vivo. J Virol. 2008; 83(3):1474-82. PMC: 2620905. DOI: 10.1128/JVI.01717-08. View

17.

Willis S, Stadelmann C, Rodig S, Caron T, Gattenloehner S, Mallozzi S . Epstein-Barr virus infection is not a characteristic feature of multiple sclerosis brain. Brain. 2009; 132(Pt 12):3318-28. PMC: 2792367. DOI: 10.1093/brain/awp200. View

18.

Schreiner B, Heppner F, Becher B . Modeling multiple sclerosis in laboratory animals. Semin Immunopathol. 2009; 31(4):479-95. DOI: 10.1007/s00281-009-0181-4. View

19.

Ascherio A, Munch M . Epstein-Barr virus and multiple sclerosis. Epidemiology. 2000; 11(2):220-4. DOI: 10.1097/00001648-200003000-00023. View

20.

Geissmann F, Manz M, Jung S, Sieweke M, Merad M, Ley K . Development of monocytes, macrophages, and dendritic cells. Science. 2010; 327(5966):656-61. PMC: 2887389. DOI: 10.1126/science.1178331. View