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(American Journal of Pathology. 2006;169:209-222.)
© 2006 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2006.051308

Pathogenic Role for Virus-Specific CD4 T Cells in Mice with Coronavirus-Induced Acute Encephalitis

Daniela Anghelina*, Lecia Pewe{dagger} and Stanley Perlman*{dagger}{ddagger}

From the Interdisciplinary Program in Neuroscience* and Departments of Pediatrics{dagger} and Microbiology,{ddagger} University of Iowa, Iowa City, Iowa

Acute viral encephalitis is believed to result from direct virus destruction of infected cells and from virus-induced host immune response, but the relative contribution of each remains largely unknown. For example, C57BL/6 (B6) mice infected with mouse hepatitis virus (JHM strain, JHMV) develop severe encephalitis, with death occurring within 7 days. Here, we show that the host response to a single JHMV-specific immunodominant CD4 T-cell epitope is critical for severe disease. We engineered a recombinant JHMV with mutations in the immunodominant CD4 T-cell epitope (rJ.MY135Q). Infection of naïve B6 mice with this virus resulted in mild disease with no mortality. However, introduction of a CD4 T-cell epitope from Listeria monocytogenes into rJ.MY135Q generated a highly virulent virus. The decrease in disease severity was not due to a switch from Th1 to Th2 predominance in rJ.MY135Q-infected mice, an effect on CD8 T-cell function, or differential expression of tumor necrosis factor-{alpha} by JHMV-specific CD4 T cells. These results show that the response to a single virus-specific CD4 T-cell epitope may contribute to a pathogenic host response in the setting of acute viral disease and that abrogation of this response ameliorates clinical disease without diminishing virus clearance.




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