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a t I n .c0RoNAVIRUSES: Emerging pathogens I "f !t {-. 1, Susan R. Wei$$.'. a Department of ffl \- Penn CenterJorResaprift on Coronaviruses -1| t {.1 Other.Hrnergiff Pbthogens . and .s: ' i, ..t Peieldan *hool" of Medicine f "pniter$ity of Pennsylvania , . ta * I Coronavirus virion spike (s) Nucleocapsid (N) I entry: binding & fusion ltropism U immune Membrane (M) response virulence Small membrane Protein (E) Coronaviruses are a family within the Nidovirus order single-stranded, non-segmented, positive sense RNA Hemagglutinin-esterase (H E) genome Coronavirus Timeline Bat reservoir SARS.CoV MERS-CoV SARS-CoV-2 oc43 Basic CoV Biology 229E HKUl NL63 Common cold OC43 can infect HKUI; Pneumonia lower respiratory Nt63; Bronchiolitis, p tract 1960-70 1980 1990 2000 20LO 2020 Severe acute respiratory disease Coronavirus disease-2019 or COVID-19 SARS-CoV interspecies transmission (20021 --* Human Horseshoe bat Civet Human to human close contact How many times did this happen? Over in eight months, ( 8098 infections, 9.6% mortality 87%in China and Hong Kong t lmages from various internet sites M ERS-CoV interspecies transmission (2OI2l + limited human Human to human spread Neoromicia capensis Camel 1;l -. rl I Mostly in Arabian peninsula Camels are a reservoir for MERS-CoV Still new cases 2O2O 2562 cases, 35% mortality Korea SARS-C oV -2 i nterspecies tra nsm ission (2o1el ---> + lntermediate species Bat Malayan pangolin Human Human to human I spread 40.1 M t,fa infections tt I T't t F .bltiF F kb f. L,L14,750 t deaths :i US ! .r {r l ,"1 fr .r t (10.1s.20) 8.L6 M infections 2L9,680 deaths How do we know SARS-CoV-2 was not engineered by humans? .Similar viruses are found in bats .lt does not resemble any known recombinant viruses . Not possible for anyone to know how to design a virus with the properties of SARS-CoV-2 Coronavirus genome Conserved replicase proteins 16 nsps Accessory proteins Alphacoronaviruses 1a A/M3' 229E, N LG3 SPIKE EMN Betacoronaviruses 5a 2a Lineage a, s', A/M3' OC4g, H KU1 Embecovirus H SPIK EM IN E 7al7b Lineage b, 6 s', Sarbecovirus A/AA3' SARS-CoV SPIKE E SARS-CoV-2 M N 1a 4a5 Lineage c, 1b 5 Merbecovirus A/M3, MERS-CoV SPIKE 3 E MSbN Coronavirus conserved replicase proteins ORFIa ORF 1b nspL2 3 4 5 5 7 8 910 Lt t2 13 !4 15 15 Activdtor Mulitple host Papain-like 3C-like Primase mRNA antagonist Protease (s) protease EndoU; capping RNA dependent Helicase dctivities processes protease dsRNA Main RNA polymerase NTPase polyprotein processes accumulotion Replicdtion of genome polyprotein and transcription of Host antagonist mRNAs octivities ExoN DUB Proof reading macrodomain remdesivir mRNA capping To prepare for future emergent viruses .Vaccine development; monoclonal antibody treatment . Develop pan coronavirus antivirals for future outbreaks .Continue to identify and charactenze coronaviruses and other viruses from bats and other species .support basic virology research ACKNOWLEDG EM ENTS Courtney Comar Alejandra Fausto Yize (Henry) Li Erick Perez Jimenez Rebecca Nusbaum Nicholas Parenti David Renner Hanako Reyes Nikki Tanneti Jill Whelan Funding NIH lris Zhang NrArD/NTNDS PENN Center for Research on Coronavirus and Other Emerging Pathogens ffiffi OMB No. 0925-0001 and 0925-0002 (Rev. 03/2020 Approved Through 0212812023) BIOGRAPHICAL SKETCH Provide the following information for the Senior/key personnel and other significant contributors. Follow this format for each person. DO NOT EXCEED FIVE PAGES. NAME: :Weiss, Susan R. eRA COMMONS USER NAME (credential, €.g., agency login): SRWEISS POSITION TITLE: Professor of Microbiology, Vice Chair, Department of Microbiology EDUCATIONffRAINING (Begin with baccalaureate or other initial professional education, such as nursing, include postdoctoral training and residency training if applicable. Add/delete rows as necessary.) DEGREE Completion (if Date FIELD OF STUDY INSTITUTION AND LOCATION applicable) MMATYYY Brandeis University, Waltham, MA BA 1971 Biology Harvard University, Cambridge, MA PhD 1975 Microbiology and Molecular Genetics University of California, San Francisco, CA Post doc 1976-1980 Molecular Virology; Retroviruses A. Personal Statement. The overall goal of my lab over the last 40 years has been to understand the viral and host determinants of coronavirus tropism and virulence. Much of our work during the last approximately ten years has been on understanding the interactions of coronaviruses with the innate immune responses, primarily dsRNA induced anti-viral pathways. These include the canonical MAVS-dependent interferon synthesis and signaling system, the oligoadenylate synthetase-ribonuclease L (OAS-RNase L) pathway leading to limitation of virus replication and spread and the PKR pathway that leads to limitation of initiation of protein synthesis. We have extensively investigated activation the OAS-RNase L pathway and the antagonism of this pathway by coronavirus encoded phosphodiesterases. We worked with the human coronavirus severe acute syndrome coronavirus (SARS-CoV) in the past and have ongoing studies on the pathogenesis of the Middle East respiratory syndrome coronavirus (MERS-CoV). We have recently initiated investigation of the newly emerged severe acute respiratory coronavirus 2 (SARS-CoV-2) the agent of COVID-19. We need the equipment requested in this supplement application for BSL3 studies of SARS-CoV-2 1. Adedeji, A., Singh, K., Kassim, A., Coleman, C.M., Elliott, R., Weiss, S.R., Frieman, M., Sarafianos, S. 2014. SSYA10-001 lnhibits Replication of SARS, MHV and MERS Coronaviruses. Antimicrob Agents Chemother, 58:4894-8. PMCID:PMC41 36041. 2. Thornbrough, J.M., Jha, B.K., Yount, B., Elliott, R., Li, Y., Goldstein, S.A., Sims, A.C., Baric, R.S., Silverman, R.H., Weiss, S.R. 2016. Middle East respiratory syndrome coronavirus NS4b protein inhibits host RNase L activation. MBio.7(2). pii: e00258-16. doi: 10.11281m8io.00258-16. PMCID:PMC4817253 3. Comar, CE, Goldstein, SA, Li, Y, Yount, B, Baric, RS, Weiss, SR. 2019. Antagonism of dsRNA-induced innate immune pathways by NS4a and NS4b accessory proteins during MERS coronavirus infection. mBio10(2). pii: e00319-19. PMCID: PMC6437052. 4. Li, Y, Comar, CE, Renner, DM, Whelan, JN, Reyes, HM, Cardenas-Diaz, FL, Truitt, R, Tan, HL, Dong, B, Alysandratos, K, Huang, J, Kotton, DN, Silverman, RH, Yang,W, Morrissey, E, Cohen, N, Weiss, SR. SARS-CoV-2 induces double-stranded RNA-mediated innate immune responses in respiratory epithelial de rived cel ls a nd card iomyocytes, B io Rxiv/2020 I 31 2553. PM C I D : PMCT 5231 29. B. Positions and Honors Professional Experience: 1971-1975 Graduate School. Laboratory of Dr. Michael Bratt, Department of Microbiology and Molecular Genetics, Harvard Medical School and Department of Microbiology, University of Massachusetts Medical School. Ph.D. thesis work: Studies on the messenger RNA and poly(A) of Newcastle disease virus. 1 976-1 980 Postdoctoral training in the laboratory of Dr. J. Michael Bishop, Department of Microbiology and lmmunology, University of California, San Francisco. Purification, characterization and cell-free translation of the messenger RNAs of avian sarcoma-leukosis viruses. 1980-present Assistant Professor, Associate Professor (1986), Professor (1992), Vice Chair (2018), Department of Microbiology, Perelman School of Medicine, University of Pennsylvania. Molecular Biology of coronaviruses, Pathogenesis of coronavirus CNS disease and hepatitis, MERS-CoV. 1 994-1 995 Sabbatical in the Department of Biochemistry, University of California, San Francisco with Dr. Robert Fletterick. Expression of the murine coronavirus papain like protease 2010-2019 Associate Dean for Postdoctoral Research Training and Director of Biomedical Postdoctoral Programs, School of Medicine, University of Pennsylvania. 2018-present Vice Chair, Department of Microbiology, Perelman School of Medicine, University of Pennsylvania 2020-present Co-Director of the Penn Center for Research on Coronaviruses and Other Emerging Pathogens Honors 1971 Phi Beta Kappa Professional societies 1975-present AmericanSocietyforMicrobiology 1982-present American Society for Virology 1994-present Fellow of the American Academy of Microbiology 2019-present Governor, American Academy of Microbiology 2008-present Fellow of the American Association for the Advancement of Science Grant reviews committees 1990-1994 , 2001-2005 Virology Study Section 1995-1998 NIH Reviewers Reserve 1995-1999 National Multiple Sclerosis Society Study Section 1997, 1998 ASM/CDC Postdoctoral Fellowship review 1985- Ad hoc NIH reviews- CSR, NINDS, NIAID 2012-2106 Ad hoc reviewer, CNBT study section, CSR 7/201G-present Permanent member, CNBT study section, CSR 612018 Ad hoc external reviewer, NIAID RML G. Contributions to Science 1. Establishment of murine coronavirus (MHV) animal model of acute encephalitis and chronic demyelinating disease. We established a mouse model of encephalitis, hepatitis and immune-mediated chronic demyelination, which we have used extensively for the mapping of viral determinants of virulence and for the study of coronavirus-host interactions. Using highly neurovirulent MHV-JHM.SD and weakly neurovirulenUhepatovirulent MHV-A59, this model formed the basis for numerous of our early studies and findings as detailed below and allowed we and others to compare infection of the CNS and the peripheral organ, the liver and to identify CNS specific aspects of virus-host interactions. We have used the A59 model, one of the few accepted animal models for Multiple Sclerosis, for studies of chronic demyelinating
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  • Innate Immune Antagonism by Diverse Coronavirus Phosphodiesterases Stephen Goldstein University of Pennsylvania, Steve21986@Gmail.Com

    Innate Immune Antagonism by Diverse Coronavirus Phosphodiesterases Stephen Goldstein University of Pennsylvania, [email protected]

    University of Pennsylvania ScholarlyCommons Publicly Accessible Penn Dissertations 2019 Innate Immune Antagonism By Diverse Coronavirus Phosphodiesterases Stephen Goldstein University of Pennsylvania, [email protected] Follow this and additional works at: https://repository.upenn.edu/edissertations Part of the Allergy and Immunology Commons, Immunology and Infectious Disease Commons, Medical Immunology Commons, and the Virology Commons Recommended Citation Goldstein, Stephen, "Innate Immune Antagonism By Diverse Coronavirus Phosphodiesterases" (2019). Publicly Accessible Penn Dissertations. 3363. https://repository.upenn.edu/edissertations/3363 This paper is posted at ScholarlyCommons. https://repository.upenn.edu/edissertations/3363 For more information, please contact [email protected]. Innate Immune Antagonism By Diverse Coronavirus Phosphodiesterases Abstract Coronaviruses comprise a large family of viruses within the order Nidovirales containing single-stranded positive-sense RNA genomes of 27-32 kilobases. Divided into four genera (alpha, beta, gamma, delta) and multiple newly defined subgenera, coronaviruses include a number of important human and livestock pathogens responsible for a range of diseases. Historically, human coronaviruses OC43 and 229E have been associated with up to 30% of common colds, while the 2002 emergence of severe acute respiratory syndrome- associated coronavirus (SARS-CoV) first raised the specter of these viruses as possible pandemic agents. Although the SARS-CoV pandemic was quickly contained and the virus has not returned, the 2012 discovery of Middle East respiratory syndrome-associated coronavirus (MERS-CoV) once again elevated coronaviruses to a list of global public health threats. The eg netic diversity of these viruses has resulted in their utilization of both conserved and unique mechanisms of interaction with infected host cells. Like all viruses, coronaviruses encode multiple mechanisms for evading, suppressing, or otherwise circumventing host antiviral responses.