Susan R. Weiss, Ph.D.

faculty photo
Professor of Microbiology
Department: Microbiology
Graduate Group Affiliations

Contact information
203A Johnson Pavilion
3610 Hamilton Walk
Philadelphia, PA 19104-6076
Office: (215) 898-8013
Fax: (215) 573-4858
Lab: 215-898-3551
Education:
B.A. (Biology)
Brandeis University, 1971.
Ph.D. (Microbiology and Molecular Genetics)
Harvard University, 1975.
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Description of Research Expertise

Research Interests
- Murine coronavirus pathogenesis, central nervous system, liver and lung
- Murine coronavirus antagonism of the OAS-RNase L pathway
- Organ specific virus- host interactions
- Viral and cellular phosphodiesterases
- Middle Eas Respiratory Syndrome Coronavirus pathogenesis
- Role of inflammasome related cytokines in murine coronavirus acute disease and chronic demyelination


Key words: murine coronavirus, human respiratory coronavirus, viral pathogenesis, interferon antagonist.

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 studies coronavirus pathogenesis. We use murine coronavirus, mouse hepatitis virus (MHV) infection of mice as a model system for the study of: 1) acute viral encephalitis; 2) chronic demyelinating diseases such as Multiple Sclerosis and 3) virus-induced hepatitis. We have the important tools of a well-developed animal model system and two reverse genetic systems with which to manipulate the viral genome. Human coronaviruses are primarily respiratory viruses, and include the common cold viruses OC43 and 229E as well as the emerging viruses MERS and SARs that cause severe and life threatening diseases. We are beginning to study human coronavirus interactions with respiratory tract cells. Our long-term goal is to elucidate the viral and cellular determinants of coronavirus tropism and pathogenesis in the brain, the liver and the lung. Much of our current work focuses on coronavirus-encoded antagonists of type I interferon, specifically virus-encoded phosphodiesterase that antagonize the OAS-RNase L pathway. Another direction in our lab is the study of the role of inflammasome related cytokines in viral clearance as well as both acute and chronic MHV induced disease.


Currently we are carrying out the following studies:

1. Virus-encoded phosphodiesterases (PDE), that act as type I interferon antagonists. The MHV ns2 gene encodes a phosphodiesterase activity that specifically cleaves 2-5A, the activator of Ribonuclease (RNase) L, a potent antiviral response induced by type I interferon and infection. Homologous proteins with RNase L antagonist activates are also expressed by some other coronaviruses, toroviruses, other members of the coronavirus superfamily as well as type A rotaviruses, that cause severe gastrointestinal infections of children. Activation of RNase is cell type specific and most most robust in myeloid cells and antagonism of RNase L is required for the induction of hepatitis by MHV. We are currently investigating the mechanisms underlying activation of this pathway and antagonism by virus induced phosphodiesterase and their role in pathogenesis.

2. Human coronaviruses and RNase L antagonism. A group of other group 2a Betacorovaviruses encode ns2 homologs that we have recently found to have phosphodiesterase activity. We are characterizing these PDEs now and beginning to investigate a possible role for RNase L antagonism in the respiratory tract, the major target of most human coronaviruses including the lethal, emerging pathogen SARS and MERS.

2. Inflammasome associated cytokines and MHV acute and chronic disease pathogenesis. We are investigating the roles of the two inflammasome related cytokines IL-1 an IL-18 in coronavirus pathogenesis. This includes understanding their roles in protection against and contribution to acute encephalitis and hepatitis and in addition a possible role in the chronic demyelinating disease.

3. Role of receptor in MHV entry, spread and 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 a selection of MHV mutants and tropism variants in combination with primary cells derived from wild type and ceacam 1a-/- mice to elucidate the mechanism of viral neuron to neuron spread and the role of receptor independent spread in disease. We also plan to discover alternate receptors used by MHV in the absence of ceacam1a.


Rotation Projects

1. Coronavirus RNase L antagonists: Investigation of the mechanism by which MHV ns2 as well as human coronavirus ns2 homologs inhibit the oligoadenylate synthetase (OAS)-ribonuclease (RNase) L interferon stimulated anti-viral pathway. This includes understanding the contributions of host OAS and RNase L gene expression, host interferon response as well as virus encoded phosphodiesterase in the activation and antagonism of RNase L. Projects also include investigation of activation of the OAS-RNase L pathway in myeloid cells versus other cell types and how this impacts on pathogenesis. These projects involve studies of virus in primary cell types as well as in vivo experiments in mice and involve carrying out a wide variety of techniques, including viral pathogenesis, cell culture, cloning, in vitro protein expression and real time qPCR.

2. Mechanisms of MHV neurovirulence. Investigation of the roles of IL-1 and IL-18 in MHV pathogenesis and clearance (comparing effects in the brain and liver) as well as virus induced demyelination. This includes comparison of viral replication and clearance during infection of IL-1R and IL-18R knockout mice with C57/Bl6 wild type mice and the mechanisms underlying difference between pathgoenesis of wild type an knockout mice. This project includes cell culture, infections of mice, isolation of immune cells, flow cytometry as well as Western blots.




Lab personnel:

Dillon Birdwell- Graduate Student
Ruth Elliott - Research Specialist
Stephen Goldstein- Graduate Student
Yize (Henry) Li- Postdoctoral Researcher
Judith Phillips- Research Associate
Yuyan Wang, Visiting Scholar

Selected Publications

Li Yize, Banerjee Shuvojit, Goldstein Stephen A, Dong Beihua, Gaughan Christina, Rath Sneha, Donovan Jesse, Korennykh Alexei, Silverman Robert H, Weiss Susan R: Ribonuclease L mediates the cell-lethal phenotype of double-stranded RNA editing enzyme ADAR1 deficiency in a human cell line. eLife 6, Mar 2017.

Thornbrough Joshua M, Jha Babal K, Yount Boyd, Goldstein Stephen A, Li Yize, Elliott Ruth, Sims Amy C, Baric Ralph S, Silverman Robert H, Weiss Susan R: Middle East Respiratory Syndrome Coronavirus NS4b Protein Inhibits Host RNase L Activation. mBio 7(2): e00258, Mar 2016.

Li Yize, Banerjee Shuvojit, Wang Yuyan, Goldstein Stephen A, Dong Beihua, Gaughan Christina, Silverman Robert H, Weiss Susan R: Activation of RNase L is dependent on OAS3 expression during infection with diverse human viruses. Proceedings of the National Academy of Sciences of the United States of America 113(8): 2241-6, Feb 2016.

Zhao Ling, Jha Babal K, Wu Ashley, Elliott Ruth, Ziebuhr John, Gorbalenya Alexander E, Silverman Robert H, Weiss Susan R: Antagonism of the Interferon-Induced OAS-RNase L Pathway by Murine Coronavirus ns2 Protein Is Required for Virus Replication and Liver Pathology. Cell host & microbe 11(6): 607-16, Jun 2012.

Case James Brett, Li Yize, Elliott Ruth, Lu Xiaotao, Graepel Kevin W, Sexton Nicole R, Smith Everett Clinton, Weiss Susan R, Denison Mark R: Murine Hepatitis Virus nsp14 Exoribonuclease Activity Is Required for Resistance to Innate Immunity. Journal of virology 92(1), 01 2018.

Zhang Rong, Li Yize, Cowley Timothy J, Steinbrenner Adam D, Phillips Judith M, Yount Boyd L, Baric Ralph S, Weiss Susan R: The nsp1, nsp13, and M proteins contribute to the hepatotropism of murine coronavirus JHM.WU. Journal of virology 89(7): 3598-609, Apr 2015.

Birdwell L Dillon, Zalinger Zachary B, Li Yize, Wright Patrick W, Elliott Ruth, Rose Kristine M, Silverman Robert H, Weiss Susan R: Activation of RNase L by Murine Coronavirus in Myeloid Cells Is Dependent on Basal Oas Gene Expression and Independent of Virus-Induced Interferon. Journal of virology 90(6): 3160-72, Jan 2016.

Goldstein Stephen A, Thornbrough Joshua M, Zhang Rong, Jha Babal K, Li Yize, Elliott Ruth, Quiroz-Figueroa Katherine, Chen Annie I, Silverman Robert H, Weiss Susan R: Lineage A Betacoronavirus NS2 Proteins and the Homologous Torovirus Berne pp1a Carboxy-Terminal Domain Are Phosphodiesterases That Antagonize Activation of RNase L. Journal of virology 91(5), Mar 2017.

Drappier Melissa, Jha Babal Kant, Stone Sasha, Elliott Ruth, Zhang Rong, Vertommen Didier, Weiss Susan R, Silverman Robert H, Michiels Thomas: A novel mechanism of RNase L inhibition: Theiler's virus L* protein prevents 2-5A from binding to RNase L. PLoS pathogens 14(4): e1006989, 04 2018.

Zalinger Zachary B, Elliott Ruth, Rose Kristine M, Weiss Susan R: MDA5 Is Critical to Host Defense during Infection with Murine Coronavirus. Journal of virology 89(24): 12330-40, Dec 2015.

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Last updated: 10/29/2018
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