The objective of this proposal is to determine the role of the Fc receptor-like activity of the mouse hepatitis virus (MHV) S protein in the pathogenesis of the demyelinating disease induced by this virus. We have demonstrated that the spike (S) proteins of MHV and certain other coronaviruses (but not all) was a molecular mimic of the Fc? receptor II (Fc?RII). The MHV S protein non-specifically binds IgG with low to modest affinity and was recognized by a monoclonal antibody raised against the low affinity Fc?RII. Herpesviruses, in particular herpes simplex viruses, also encode genes which have an Fc receptor activity and it has been shown that this activity plays a role in immune evasion by HSV type 1. We hypothesize that the Fc?RII activity of the MHV S protein also plays a role in immune evasion and/or immunopathogenesis during infection with MHV. In this proposal we intend to utilize recently developed reverse genetic systems for MHV-A59 to determine the role of this activity in the demyelinating disease produced in mice by infection with this virus, and to investigate if this activity facilitates immune evasion by this virus.
The specific aims of this proposal are: (1) To identify residues in the MHV S protein that are essential for molecular mimicry of the Fc?RII;(2) To isolate MHV-A59 recombinant viruses carrying mutations in the S protein that inactivate its Fc?RII activity. These mutants will be characterized and compared with the parental isogenic MHV-A59 as to their replication in cell culture, their susceptibility to neutralization by antibody in the presence and absence of complement, and their ability to persist in the CNS and produce disease in mice. A number of human diseases have been linked to persistent infections of the CNS and others such as multiple sclerosis (MS) are suspected to be triggered by viral infections.
The MHV mouse model is a widely studied model for MS. Although the mechanism is not completely understood, MHV is able to avoid complete elimination from the CNS by the immune system. The proposed studies are relevant to increasing our understanding of mechanisms by which MHV evades immunological elimination from the CNS. This proposal addresses the role of a functional activity of an important MHV protein in evading the host immune response and producing disease. This functional activity, binding antibody by its non-antigen recognizing Fc end (molecular mimicry of the Fc receptor), is also present in human herpesviruses, and may also illuminate the persistence of these viruses in the CNS. In addition, two of three other coronaviruses tested also exhibited molecular mimicry of the Fc receptor. Thus, the results obtained from this research may be relevant to other human coronavirus diseases such as the lower respiratory illnesses caused SARS-CoV and the HCoV-NL3.
| Kaufman, Gili; Liu, Pinghua; Leibowitz, Julian L (2014) Identification of novel functional regions within the spike glycoprotein of MHV-A59 based on a bioinformatics approach. Virus Res 189:177-88 |
| Leibowitz, Julian; Kaufman, Gili; Liu, Pinghua (2011) Coronaviruses: propagation, quantification, storage, and construction of recombinant mouse hepatitis virus. Curr Protoc Microbiol Chapter 15:Unit 15E.1 |
