Description of Research Expertise

Research Interests
- Murine coronavirus pathogenesis, central nervous system, liver and lung
-murine coronavirus antagonism of the OAS-RNase L pathway
- SARS coronavirus gene expression and pathogenesis

Key words: murine coronavirus, SARS associated coronavirus, viral pathogenesis.

Description of Research

Susan Weiss, Ph.D.

Professor of Microbiology

Office Address:
University of Pennsylvania School of Medicine
203 A Johnson Pavilion
3610 Hamilton Walk
Philadelphia, PA 19104-6076

TEL 215-898-8013
LAB 215-898-3551
FAX 215-573-4858
weisssr@mail.med.upenn.edu

RESEARCH SUMMARY

My lab is involved in the study of pathogenesis of coronaviruses. We have been studying the murine coronavirus, mouse hepatitis virus (MHV) for many years. The murine coronavirus virus (MHV) infection of rodents with MHV provides a model system for the study of: 1) acute viral infection of the central nervous system (CNS) and both innate and acquired immune response to this infection; 2) a chronic persistent infection which proceeds in the presence of virus specific CD8T cells and provides one of the best models for the human demyelinating diseases such as Multiple Sclerosis and 3) virus-induced hepatitis. Our long term goal is to elucidate the viral and cellular determinants of tropism and pathogenesis in both the brain and the liver. In order to conduct these investigations, we have the important tools of a well developed animal model system and two reverse genetic systems with which to manipulate the viral genome.

Currently we are carrying out the following studies.

1. Interaction of MHV with the type I interferon response. Interferon (IFN)a/b is important in the protection of the mouse from MHV infection in vivo. However, MHV fails to induce IFNa/b in fibroblasts in tissue culture. We have found recently that MHV does induce IFNa/b in macrophage type cells and that induction requires expression of MDA5. We are further investigating induction of IFNa/b by MHV through this pathway in vitro and in vivo. MHV is highly resistant to the effects of IFN in cultured cells in vitro. We have found recently that MHV inhibits the expression certain interferon stimulated genes (ISGs) and we are investigating the steps in IFN signaling pathways at which this occurs and the viral genes that mediate the inhibition of IFN signaling.

2. Role of receptor in MHV pathogenesis. The only known receptor for MHV is the carcinoembryonic antigen protein, CEACAM 1. However, the highly neurovirulent MHV-JHM strain spreads cell to cell in the absence of the expression of this receptor. Using transgenic CEACAM 1 deficient mice (ceacam 1a -/-), we have found that JHM can replicate and cause CNS disease and mortality in the absence of viral receptor. We are using primary cells derived from wild type and ceacam 1a-/- mice to understand the expression of CEACAM 1 in neural cells types and to elucidate the role of receptor independent spread in disease. We are also plan to discover alternate receptors used by MHV in the absence of ceacam1a.

3. Virus induced demyelination. Following acute infection, MHV RNA genome persists in the CNS and expresses mRNA, in the absence of infectious virus; during this stage of infection, demyelination develops. Virus specific CD8T cells also persist during this late disease stage. We are investigating the state of the viral genome and the integrity of viral mRNAs during persistent disease. We are also investigating the phenotype and functionality of the persisting CD8T cells. Our goal is to determine how the persistent virus and CD8T cells co-exist and we are testing the hypothesis that this co-existence contributes to demyelinating disease.


SARS CORONAVIRUS (SARS-CoV: We are using our experience and knowledge about murine coronaviruses to study the SARS associated virus. We are currently working with the MHV-1 model of SARS, in which a murine coronavirus produces similar pathology to SARS in a mouse model. We are interested in using this model along with recombinant viruses to express SARS protein in the lung to determine the contribution to pathogenesis of individual SARS coronavirus proteins. We are also interested in understanding the interaction of SARS-CoV with its host as far as interaction with the type I interferon response, as we are doing for MHV.

Rotation Projects
.
1. Interaction of MHV and the type I interferon response. This includes studies of MHV induced inhibition of induction of interferon and/or interferon signaling or expression of MDA5 and its role MHV induction of interferon. This project involves studies of virus in primary cell types or cell lines in tissue culture and also in vivo experiments in mice; this project also involve the use of real time PCR.

2. Role of viral receptor in neurovirulence. This project involves determining expression level of the viral receptor CEACAM 1a in various primary cell types in vitro and in the mouse brain and spinal cord in vivo. It also involves studies of virus replication in transgenic mice deficient in expression of CEACAM 1a receptor and the characterization of viral mutants derived by passage of virus in these mice.

3. Role of persistent virus and CD8T cells in demyelinating disease. a. Investigation of the state of the viral genome and mRNAs found in the brain and spinal cord during late infection. B. Investigation of the phenotypes of CD8T cells in the central nervous system during persistent infection and comparison of the these T cells with memory cells generated in the spleens or livers of infected mice under conditions where virus is completely cleared.

Lab personnel:
Susan Bender - Graduate Student
Ming Ming Chua - Research Specialist
Tim Cowley - Graduate Student
Ruth Elliott - Research Specialist
Judy Phillips- Postdoctoral Researcher
Kristine Rose - Postdoctoral Researcher
Ling Zhao- Postdoctoral Researcher