Coronavirus Activation and Antagonism of Interferon Signaling Pathways: from MHV to SARS-CoV-2
Susan R. Weiss, Ph.D.
Professor of Microbiology
Vice Chair, Department of Microbiology
Co-Director, Penn Center for Research on Coronaviruses and Other Emerging Pathogens
University of Pennsylvania, Perelman School of Medicine
Our lab studies murine and human coronavirus pathogenesis, including MHV, MERS-CoV and SARS-CoV. We use 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 and 4) severe acute respiratory diseases. We have the important tools of a well-developed animal model system and reverse genetic systems with which to manipulate the viral genome. We also investigate pathogenesis of human coronaviruses both the lethal MERS-CoV and SARS-CoV-2 as well as the common cold viruses OC43 and 229E and NL63. We are investigating these both in epithelial cell lines and primary cells and in primary human nasal epitheli culutres gwon on air liquid interface. Much of our current work focuses on coronavirus-encoded antagonists of host innate responses. Other foci of the lab are on activation and antagonism of the OAS-RNase L pathway in human and bat cells, the pathogenic effects of endogenous host dsRNA and pathogenesis of Zika virus and other flaviviruses.
Summary
https://videocast.nih.gov/watch=52621
Coronavirus interactions with the interferon signaling response are crucial for antiviral defense especially at the early stages of infection. Murine coronavirus, MHV, has taught us a lot about the basic biology of this family of viruses as well as antagonism of innate immune response, a hallmark of coronavirus infection. Building on our MHV data, we have more recently worked with human coronaviruses. We have optimized methods for comparing human coronaviruses in a primary nasal cell air liquid interface (ALI) culture system, which models the initial site of respiratory virus infection. Common cold coronaviruses as well as unrelated human rhinovirus exhibit early induction of interferon (IFN) signaling and IFN-mediated clearance, and preferential replication at nasal airway temperature (33ºC) which confers muted host IFN responses. In contrast, lethal SARS-CoV-2 and MERS-CoV encode antagonist proteins that prevent IFN-mediated clearance. Our studies highlight nasal innate immune responses as predictive of infection outcomes and nasally-directed IFNs as potential therapeutics.
Presentation objectives:
- Summarize the role of the 2’,5’-phosphodiesterase (PDE) in RNase L antagonism and murine coronavirus pathogenesis
- Compare antagonism of host interferon signaling responses in lethal and common coronavirus replication
- Discuss the relationship between temperature optima for replication and interferon signaling response during coronavirus infection
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