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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS036592-15
Application #
8423310
Study Section
Clinical Neuroimmunology and Brain Tumors Study Section (CNBT)
Program Officer
Utz, Ursula
Project Start
1997-09-01
Project End
2017-01-31
Budget Start
2013-02-01
Budget End
2014-01-31
Support Year
15
Fiscal Year
2013
Total Cost
$317,891
Indirect Cost
$106,797
Name
University of Iowa
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
062761671
City
Iowa City
State
IA
Country
United States
Zip Code
52242
Perlman, Stanley; Gallagher, Tom (2018) Not your usual tRNA synthetase: hWARS serves as an enterovirus entry factor. J Clin Invest 128:4767-4769
Fehr, Anthony R; Jankevicius, Gytis; Ahel, Ivan et al. (2018) Viral Macrodomains: Unique Mediators of Viral Replication and Pathogenesis. Trends Microbiol 26:598-610
Wheeler, D Lori; Sariol, Alan; Meyerholz, David K et al. (2018) Microglia are required for protection against lethal coronavirus encephalitis in mice. J Clin Invest 128:931-943
Athmer, Jeremiah; Fehr, Anthony R; Grunewald, Matthew E et al. (2018) Selective Packaging in Murine Coronavirus Promotes Virulence by Limiting Type I Interferon Responses. MBio 9:
Grunewald, Matthew E; Fehr, Anthony R; Athmer, Jeremiah et al. (2018) The coronavirus nucleocapsid protein is ADP-ribosylated. Virology 517:62-68
Hua, Xiaoyang; Vijay, Rahul; Channappanavar, Rudragouda et al. (2018) Nasal priming by a murine coronavirus provides protective immunity against lethal heterologous virus pneumonia. JCI Insight 3:
Vijay, Rahul; Fehr, Anthony R; Janowski, Ann M et al. (2017) Virus-induced inflammasome activation is suppressed by prostaglandin D2/DP1 signaling. Proc Natl Acad Sci U S A 114:E5444-E5453
Perlman, Stanley; Zhao, Jingxian (2017) Roles of regulatory T cells and IL-10 in virus-induced demyelination. J Neuroimmunol 308:6-11
Wheeler, D Lori; Athmer, Jeremiah; Meyerholz, David K et al. (2017) Murine Olfactory Bulb Interneurons Survive Infection with a Neurotropic Coronavirus. J Virol :
Athmer, Jeremiah; Fehr, Anthony R; Grunewald, Matthew et al. (2017) In Situ Tagged nsp15 Reveals Interactions with Coronavirus Replication/Transcription Complex-Associated Proteins. MBio 8:

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