C57BL/6 mice infected with the neurotropic JHM strain of mouse hepatitis virus (JHMV) develop acute and chronic demyelinating encephalomyelitis and thereby serve as a useful model for the human disease multiple sclerosis. Demyelination is largely immune-mediated and reflects a balance between pro-inflammatory factors necessary for virus clearance and anti-inflammatory factors critical for limiting bystander tissue damage. Virus clearance requires robust virus-specific CD8 and CD4 T cell responses. In the previous funding period, we showed that optimization of the CD8 T cell response, by mutating a subdominant CD8 T cell epitope, enhanced virus clearance. However, disease course was not changed. We showed that this was due to a pathogenic CD4 T cell response directed at the immunodominant M133 epitope. Only naive M133-specific CD4 T cells were pathogenic because we also showed that memory virus-specific CD4 T cells were protective. We also identified a potent regulatory T cell (Treg, Foxp3+) response directed against the M133 epitope, adding another layer of complexity to the balance between pro and anti-inflammatory factors. To probe these interactions in more detail, we developed mice that were retrogenic or transgenic for expression of an M133-specific T cell receptor. The central objective of this proposal is to investigate in more detail the balance of these immune factors, as delineated in the following specific aims.
In Aim 1, factors in M133-specific CD4 T cells that result in pathogenicity (naive T cells) or protection (memory T cells) will be investigated, using our newly developed M133-specific retrogenic and transgenic TCR mice. Adoptive transfer experiments and targeted and genome-wide gene expression approaches will be used in this aim.
In Aim 2, the role of M133-specific Tregs in pathogenesis in JHMV-infected mice will be investigated, also taking advantage of the M133- specific TCR transgenic mice. As part of this aim, we will assess whether virus-specific Tregs are more suppressive than bulk Treg populations and whether Tregs enter the memory T cell pool. We will also determine whether pathogen-specific Tregs require expression of a second TCR ? chain, recognizing a self epitope, for suppressive function.
Demyelination, which occurs after many viral infections of the central nervous system, is largely mediated by the host immune response during virus clearance. This application is directed at understanding aspects of the anti-virus immune response that are protective or pathogenic, with focus on the anti-inflammatory component of the immune response.
|Fehr, Anthony R; Perlman, Stanley (2015) Coronaviruses: an overview of their replication and pathogenesis. Methods Mol Biol 1282:1-23|
|Fehr, Anthony R; Athmer, Jeremiah; Channappanavar, Rudragouda et al. (2015) The nsp3 macrodomain promotes virulence in mice with coronavirus-induced encephalitis. J Virol 89:1523-36|
|Mielech, Anna M; Deng, Xufang; Chen, Yafang et al. (2015) Murine coronavirus ubiquitin-like domain is important for papain-like protease stability and viral pathogenesis. J Virol 89:4907-17|
|Channappanavar, Rudragouda; Zhao, Jincun; Perlman, Stanley (2014) T cell-mediated immune response to respiratory coronaviruses. Immunol Res 59:118-28|
|Zhao, Jingxian; Zhao, Jincun; Perlman, Stanley (2014) Virus-specific regulatory T cells ameliorate encephalitis by repressing effector T cell functions from priming to effector stages. PLoS Pathog 10:e1004279|
|Lin, Shing-Yen; Liu, Chia-Ling; Chang, Yu-Ming et al. (2014) Structural basis for the identification of the N-terminal domain of coronavirus nucleocapsid protein as an antiviral target. J Med Chem 57:2247-57|
|Trujillo, Jonathan A; Croft, Nathan P; Dudek, Nadine L et al. (2014) The cellular redox environment alters antigen presentation. J Biol Chem 289:27979-91|
|Trujillo, Jonathan A; Gras, Stephanie; Twist, Kelly-Anne et al. (2014) Structural and functional correlates of enhanced antiviral immunity generated by heteroclitic CD8 T cell epitopes. J Immunol 192:5245-56|
|Zhao, Jingxian; Fett, Craig; Pewe, Lecia et al. (2013) Development of transgenic mice expressing a coronavirus-specific public CD4 T cell receptor. J Immunol Methods 396:56-64|
|Chen, I-Jung; Yuann, Jeu-Ming P; Chang, Yu-Ming et al. (2013) Crystal structure-based exploration of the important role of Arg106 in the RNA-binding domain of human coronavirus OC43 nucleocapsid protein. Biochim Biophys Acta 1834:1054-62|
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