The long term goals of this new program are an understanding of persistent viral infection and central nervous system (CNS) demyelinating disease. To this end, this program represents a multidisciplinary approach to defining mechanisms of viral persistence and myelin loss using a well defined murine model of demyelination induced by the neurotropic JHM strain (MHV-4) of mouse hepatitis virus (JHMV). This model provides a means to understand the interactions between a pathogen and its natural host that result in demyelination during acute and persistent CNS infection. The host response is competent to control infectious virus. However, a persistent CNS infection without detectable infectious virus is associated with chronic ongoing myelin loss. The pathological alterations within the CNS during viral persistence have numerous similarities to multiple sclerosis, the most prevalent human demyelinating disease. This program is unique, comprising a core of investigators addressing fundamental questions of viral persistence and immune responses, both as protective mechanisms and as inducers of demyelination. Project 1 focuses on the pro-inflammatory and anti-inflammatory effects of innate immunity. New data suggest that the limited capacity of oligodendroglia to respond to innate signals protect from oligodendroglial dysfunction and myelin loss. This project uses newly developed techniques and novel transgenic mice to demonstrate the unique response of oligodendroglia during both acute viral encephalomyelitis and viral persistence. Project 2 explores the unknown area of T cell retention and homeostasis within the CNS. The role of CNS resident and infiltrating cells in presenting viral antigen as well as the potential for cross priming are defined using a variety of transgenic and bone marrow chimeric mice. Project 3 analyzes the role of regulatory T cells and the anti-inflammatory cytokine IL-10 in CNS viral persistence and demyelination. This project uses a novel transgenic mouse which allows definition of the role of regulatory T cells during viral persistence and ongoing demyelination. Data obtained from these projects will provide novel insights into the mechanisms regulating viral persistence and demyelination as well as the CNS as a target for viral persistence. Importantly, it will provide valuable information on the interactions of specific CNS cells involved in viral persistence and demyelination and the cellular and soluble mediators of the host immune response.
. Using no more than two or three sentences, describe the relevance of this research to public health. In this section, be succinct and use plain language that can be understood by a general, lay audience. DO NOT EXCEED THE SPACE PROVIDED. The central nervous system is a target of many stealth viral infections. Although in the majority of individuals there is no evidence of disease associated with these infections, they can also have devastating consequences. This project uses a mouse model to explore the ways the immune system keeps infection of the central nervous system in check, preventing both the destructive effects of active virus infection and activation of immune cells that attack the central nervous system itself.
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|Hwang, Mihyun; Phares, Timothy W; Hinton, David R et al. (2014) Distinct CD4 T cell effects on primary versus recall CD8 T cell responses during viral encephalomyelitis. Immunology :|
|Kapil, Parul; Stohlman, Stephen A; Hinton, David R et al. (2014) PKR mediated regulation of inflammation and IL-10 during viral encephalomyelitis. J Neuroimmunol 270:1-12|
|Savarin, Carine; Bergmann, Cornelia C; Hinton, David R et al. (2013) MMP-independent role of TIMP-1 at the blood brain barrier during viral encephalomyelitis. ASN Neuro 5:e00127|
|Phares, Timothy W; DiSano, Krista D; Hinton, David R et al. (2013) IL-21 optimizes T cell and humoral responses in the central nervous system during viral encephalitis. J Neuroimmunol 263:43-54|
|de Aquino, Maria Teresa P; Puntambekar, Shweta S; Savarin, Carine et al. (2013) Role of CD25(+) CD4(+) T cells in acute and persistent coronavirus infection of the central nervous system. Virology 447:112-20|
|Phares, Timothy W; Stohlman, Stephen A; Hinton, David R et al. (2013) Astrocyte-derived CXCL10 drives accumulation of antibody-secreting cells in the central nervous system during viral encephalomyelitis. J Virol 87:3382-92|
|Phares, Timothy W; Stohlman, Stephen A; Hwang, Mihyun et al. (2012) CD4 T cells promote CD8 T cell immunity at the priming and effector site during viral encephalitis. J Virol 86:2416-27|
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