Dr. Susan R. Weiss, Professor of Microbiology and Associate Dean for Postdoctoral Research Training at the University of Pennsylvania School of Medicine, will deliver the 2010 Bill Narayan Lectureship. Dr. Weiss received a BA in Biology from Brandeis University. After completing graduate studies at Harvard School of Medicine on paramyxovirus transcription and four years of post-doctoral training, in retrovirus molecular biology at the University of California in San Francisco, Dr. Weiss joined the UPENN Faculty in 1980. With the guidance of her colleagues, Drs. Neal Nathanson and Don Gilden, she developed an interest and research program in coronavirus pathogenesis, and became a leader in that field. Using murine coronavirus, mouse hepatitis virus (MHV), infection of its natural host, Dr. Weiss' research has provided the scientific community with a greater understanding of the viral and host determinants of tropism and neurovirulence.
Murine coronavirus strains induce disease in several organ systems of mice, including the central nervous system (CNS) and the liver. The outcome of MHV infection is determined by a combination of viral genes and host cell response. Infection with neurotropic strains causes acute encephalitis, and in survivors, chronic demyelination, the latter of which serves as an animal model for multiple sclerosis. Dr. Weiss describes her long-term research goal as the elucidation of viral and cellular determinants of tropism and pathogenesis in both the brain and the liver. Towards this end, her group has developed a well-characterized animal model and has contributed to the development of two reverse genetic systems with which to manipulate the viral genome.
The highly neurovirulent JHM strain spreads rapidly thoughout the CNS inducing a minimal T-cell response, resulting in lack of viral clearance and mortality of all infected mice, even when very low levels of virus are administered. The more neuroattenuated A59 strain spreads less extensively in the CNS and induces a robust T-cell response, resulting in viral clearance; surviving mice develop a chronic demyelinating disease. A chimeric virus, expressing the JHM spike within the background of A59, like JHM, spreads rapidly in the CNS but, also like A59, induces a robust CD8 T-cell response. Thus, multiple genes contribute to the high neurovirulence of JHM. On the other hand, JHM, unlike A59, can induce lethal CNS disease in the absence of the only known MHV receptor, CEACAM1a; this mechanism likely contributes to the extensive viral spread in neurons observed during JHM infection, despite the low level of CEACAM1a expression in the CNS, especially in neurons. There may also be a neuron-specific mechanism and/or an additional neuronal receptor that enhances the spread of JHM in the CNS. In this context, two mechanisms likely contribute to the very high neurovirulence of JHM: (1) JHM infects and spreads more efficiently in the CNS, due in part to CEACAM1a-independent spread, and (2) JHM elicits a weak antiviral T-cell response resulting from an inability to prime a CD8 T-cell response in the CNS.
In addition to the crucial role of the T-cell response, the type I interferon (IFN-α/β) response is essential for protection from MHV. This is demonstrated by the uniformly rapid death of IFN receptor knockout mice, infected with low doses of either A59 or JHM. Paradoxically, infection of cell lines such as murine L2 and human 293T cells induces only a low level of IFN-β mRNA, but no detectable IFN-β protein, and replication in these cells is not inhibited by pretreatment with IFN-β. However, in primary cell types such as pDCs and macrophages, IFN is induced by MHV infection and an antiviral state is established. MHV induction of type I IFN depends primarily on MDA5 in macrophages. The CNS expresses a much lower basal level of IFN signaling molecules than the liver, and this may contribute to permissiveness for MHV infection in the CNS despite the very low CEACAM1a receptor expression. Cell types such as neurons and astrocytes fail to produce IFN following infection, and in vivo, likely depend on IFN produced by pDCs and macrophages for protection from MHV. Thus, MHV induction of IFN-α/β and the ability to induce an antiviral state in response to IFN is both organ and cell-type dependent. IFN-induced protection from MHV pathogenesis in the CNS likely requires the orchestrated activities of several cell types; however, the cell types involved in limiting MHV replication may be different in the immune privileged CNS.