The central nervous system (CNS) is a preferential target for persistent viral infection. The mechanisnris maintaining viral persistence and limiting tissue damage related to persistent infection are poorly understood. This project focuses on viral persistence limited to the CNS and chronic demyelination established via infection with the JHMV strain of mouse hepatitis virus (MHV). The experiments define the contributions of regulatory T cells (Treg) and the anti-inflammatory cytokine IL-10 to viral persistence and demyelination within the CNS. In addition, regulation of potentially autoimmune self reactive T cells following an infection associated with significant myelin destruction will be defined. ? Treg not only contribute to the failure to adequately control infectious virus within the CNS, facilitating viral persistence but also limit collateral damage caused by the vigorous host response to infection. This project has three inter-related Specific Aims.
Aim 1 will demonstrate that Treg control the acute immune response facilitating viral persistence. Treg recruitment and location within the CNS will be defined using a Foxp3-GFP mouse. Treg mediated limitation of adaptive immune effector function, role in facilitating viral persistence and inhibition of demyelination will be directly tested in Treg deficient mice.
Aim 2 takes advantage of a mouse expressing the diphtheria toxin (DT) receptor under control of the Foxp3 promoter to examine the role of Treg during a persistent viral infection associated with chronic ongoing demyelination. The hypothesis tested is that during persistence Treg both prevent elimination of virus and limit demyelination. Treatment with DT during viral persistence will eliminate all CNS retained Treg without altering the parameters of acute disease. This will directly test the role of Treg during viral persistence.
Aim 3 will define the role of IL-10 during both acute and persistent infection using an IL-10-GFP reporter mouse.
This Aim directly tests our novel hypothesis that induction of IL-10 secreting T cells is facilitated by an IFN-y which interacts with astrocytes to induce secretion of IL 27.
This proposal will define the role of Treg cells and IL-10 within the CNS during an acute non-lethal viral induced encephalomyelitis. These data will reveal their roles in the transition to viral persistence, in maintaining persistence and in regulating the chronic ongoing demyelination which is a hallmark of this clinically relevant model of persistent viral infection.
|Butchi, Niranjan; Kapil, Parul; Puntambekar, Shweta et al. (2015) Myd88 Initiates Early Innate Immune Responses and Promotes CD4 T Cells during Coronavirus Encephalomyelitis. J Virol 89:9299-312|
|Butchi, Niranjan B; Hinton, David R; Stohlman, Stephen A et al. (2014) Ifit2 deficiency results in uncontrolled neurotropic coronavirus replication and enhanced encephalitis via impaired alpha/beta interferon induction in macrophages. J Virol 88:1051-64|
|de Aquino, Maria Teresa P; Kapil, Parul; Hinton, David R et al. (2014) IL-27 limits central nervous system viral clearance by promoting IL-10 and enhances demyelination. J Immunol 193:285-94|
|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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