Theiler's murine encephalomyelitis virus (TMEV) is a highly cytolytic RNA virus that produces persistent central nervous system (CNS) infection and immune-mediated demyelination in susceptible strains of mice. TMEV infection provides a relevant experimental animal model for multiple sclerosis. In contrast to persistence of non-cytolytic RNA viruses in which the host cell survives, persistence of lytic RNA viruses in which an infected cell dies requires continuous cell- to-cell spread in order to maintain the infection. In this circumstance, the target cell in which the virus persists ideally should be renewable. The infection should not be highly productive;however, virus-specific host immune responses may control a more productive infection anyway. Macrophages are the principal virus reservoir and provide an in vitro model for TMEV persistence in the mouse CNS. TMEV infected macrophages undergo apoptosis and restrict virus production (<10 pfu/cell), in contrast to infection in other rodent cells, including neurons and oligodendrocytes, where necrotic cell death is associated with high virus yields (200-500 pfu/cell). TMEV infection is required to induce apoptosis in murine macrophages since UV- inactivated virus adsorbed to the cell surface to initiate infection does not induce apoptosis. We have shown that TMEV infection induces apoptosis through the intrinsic pathway that is Bax- mediated and severely restricts infectious virus production in murine macrophages. Our working hypothesis is that TMEV-induced apoptosis is a host cell-specific mechanism providing a means of spreading virus to uninfected macrophages that phagocytose apoptotic remnants containing infectious virus. To understand how TMEV infection triggers apoptosis in murine macrophages and restricts infectious virus production, four specific aims are proposed: 1) finish the identification of upstream signals (apical to the mitochondrion) involved in the intrinsic apoptotic pathway during TMEV virus infection in M1-D macrophages and determine potential differences in apoptosis in primary macrophages from resistant and susceptible strains of mice;2) inhibit apoptosis in infected mice to assess the effect on TMEV CNS persistence, virus-specific CD4+ T cell responses and demyelinating disease, and examine the effect in transgenic mice deficient in p53 and Noxa on CNS persistence and demyelinating disease;3) identify potential virus """"""""triggers"""""""" of apoptosis by expressing TMEV nonstructural proteins L and 3CD in mammalian cells, and determine whether TMEV replicons in which the capsid proteins are deleted can induce apoptosis;and 4) investigate the mechanism of loss of infectious virus in murine macrophages that is associated with onset of apoptosis.

Public Health Relevance

The notion that multiple sclerosis (MS) is an autoimmune disease is widely accepted as fact. While MS is undoubtedly immune-mediated, an autoimmune mechanism remains unproven. Circumstantial evidence points to a persistent virus infection in MS. Moreover, immune- mediated damage can result from a virus infection in which the host immune response is directed to virus proteins rather than self proteins (autoimmunity). Theiler's murine encephalomyelitis virus (TMEV) produces a persistent central nervous system infection and immune-mediated demyelination in susceptible strains of mice, providing a relevant experimental animal model for MS. TMEV persistence is needed to drive the demyelinating disease process, but just how this virus that rapidly kills infected cells is able to perpetuate the infection is not known. This proposal addresses a mechanism of TMEV persistence, programmed cell death also termed apoptosis, which decreases virus production (may be required for persistence of virulent virus) and also fosters cell-to-cell virus spread (required for persistence in the presence of host immunity).

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Clinical Neuroimmunology and Brain Tumors Study Section (CNBT)
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Wong, May
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University of Illinois at Chicago
Schools of Medicine
United States
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Moyano, Ana Lis; Steplowski, Jeffrey; Wang, Haibo et al. (2018) microRNA-219 Reduces Viral Load and Pathologic Changes in Theiler's Virus-Induced Demyelinating Disease. Mol Ther 26:730-743
Arslan, Sevim Yildiz; Son, Kyung-No; Lipton, Howard L (2016) During Infection, Theiler's Virions Are Cleaved by Caspases and Disassembled into Pentamers. J Virol 90:3573-83
Son, Kyung-No; Lipton, Howard L (2015) Inhibition of Theiler's virus-induced apoptosis in infected murine macrophages results in necroptosis. Virus Res 195:177-82
Smith, Phillip D; Shimamura, Masako; Musgrove, Lois C et al. (2014) Cytomegalovirus enhances macrophage TLR expression and MyD88-mediated signal transduction to potentiate inducible inflammatory responses. J Immunol 193:5604-12
Zhang, Jingshan; Lipton, Howard L; Perelson, Alan S et al. (2013) Modeling the acute and chronic phases of Theiler murine encephalomyelitis virus infection. J Virol 87:4052-9
Son, Kyung-No; Liang, Zhiguo; Lipton, Howard L (2013) Mutation of the Theiler's virus leader protein zinc-finger domain impairs apoptotic activity in murine macrophages. Virus Res 177:222-5
Arslan, Sevim Yildiz; Son, Kyung-No; Lipton, Howard L (2012) The antiapoptotic protein Mcl-1 controls the type of cell death in Theiler's virus-infected BHK-21 cells. J Virol 86:1922-9