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Lack of Innate Interferon Responses During SARS Coronavirus Infection in a Vaccination and Reinfection Ferret Model

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Lack of Innate Interferon Responses During SARS Coronavirus Infection in a Vaccination and Reinfection Ferret Model Lack of Innate Interferon Responses during SARS Coronavirus Infection in a Vaccination and Reinfection Ferret Model Mark J. Cameron1,2, Alyson A. Kelvin10, Alberto J. Leon1,5, Cheryl M. Cameron1,2, Longsi Ran1, Luoling Xu1, Yong-Kyu Chu6, Ali Danesh1,2,4, Yuan Fang1,2,4, Qianjun Li6, Austin Anderson6, Ronald C. Couch7, Stephane G. Paquette1,2,3, Ndingsa G. Fomukong7, Otfried Kistner8, Manfred Lauchart8, Thomas Rowe1,2, Kevin S. Harrod7, Colleen B. Jonsson9, David J. Kelvin1,2,3,4,5,7,11* 1 Division of Experimental Therapeutics, Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada, 2 University of Toronto, Toronto, Ontario, Canada, 3 Institute of Medical Science, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada, 4 Department of Immunology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada, 5 International Institute of Infection and Immunity, Shantou University Medical College, Shantou, Guangdong, China, 6 Department of Biochemistry and Molecular Biology, Southern Research Institute, Birmingham, Alabama, United States of America, 7 Lovelace Respiratory Research Institute, Albuquerque, New Mexico, United States of America, 8 Baxter Innovations GmbH, Vienna, Austria, 9 Center for Predictive Medicine, Louisville, Kentucky, United States of America, 10 Immune Diagnostics & Research, Toronto, Ontario, Canada, 11 Sezione di Microbiologia Sperimentale e Clinica, Dipartimento di Scienze Biomediche, Universita` degli Studi di Sassari, Sassari, Italy Abstract In terms of its highly pathogenic nature, there remains a significant need to further define the immune pathology of SARS- coronavirus (SARS-CoV) infection, as well as identify correlates of immunity to help develop vaccines for severe coronaviral infections. Here we use a SARS-CoV infection-reinfection ferret model and a functional genomics approach to gain insight into SARS immunopathogenesis and to identify correlates of immune protection during SARS-CoV-challenge in ferrets previously infected with SARS-CoV or immunized with a SARS virus vaccine. We identified gene expression signatures in the lungs of ferrets associated with primary immune responses to SARS-CoV infection and in ferrets that received an identical second inoculum. Acute SARS-CoV infection prompted coordinated innate immune responses that were dominated by antiviral IFN response gene (IRG) expression. Reinfected ferrets, however, lacked the integrated expression of IRGs that was prevalent during acute infection. The expression of specific IRGs was also absent upon challenge in ferrets immunized with an inactivated, Al(OH)3-adjuvanted whole virus SARS vaccine candidate that protected them against SARS-CoV infection in the lungs. Lack of IFN-mediated immune enhancement in infected ferrets that were previously inoculated with, or vaccinated against, SARS-CoV revealed 9 IRG correlates of protective immunity. This data provides insight into the molecular pathogenesis of SARS-CoV and SARS-like-CoV infections and is an important resource for the development of CoV antiviral therapeutics and vaccines. Citation: Cameron MJ, Kelvin AA, Leon AJ, Cameron CM, Ran L, et al. (2012) Lack of Innate Interferon Responses during SARS Coronavirus Infection in a Vaccination and Reinfection Ferret Model. PLoS ONE 7(9): e45842. doi:10.1371/journal.pone.0045842 Editor: Volker Thiel, Kantonal Hospital St. Gallen, Switzerland Received April 5, 2012; Accepted August 23, 2012; Published September 24, 2012 Copyright: ß 2012 Cameron et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This study was supported by the Canadian Institutes of Health Research (CIHR), and Baxter Innovations GmbH and the National Institutes of Health and National Institute of Allergy and Infectious Disease (NIH/NIAID) through Contract No. N01-AI-30063 Task Order No. 03. The CIHR and NIH/NIAID had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Baxter supplied the SARS vaccine and were involved in the design of vaccination study. Competing Interests: Otfried Kistner and Manfred Lauchart work for Baxter and supplied the SARS vaccine and were involved in the design of vaccination study. This does not alter the authors’ adherence to all the PLOS ONE policies on sharing data and materials. * E-mail: [email protected] Introduction disease with symptoms ranging from flu-like and viral pneumonia to acute respiratory distress syndrome (ARDS) and fatal outcome Severe Acute Respiratory Syndrome (SARS) disease hit the [2–5]. The virus emerged from the Guangdong Province in China world in late 2002 and in 4 months swiftly spread to 29 countries where it crossed to humans from a zoonotic reservoir. The most infecting over 8,000 people and killing over 700 [1]. The established theory puts horseshoe bats as the ultimate reservoir for etiological agent of SARS disease was determined to be of the the SARS-CoV and implicates palm civets as the intermediate coronavirus (CoV) family; the largest family of single-stranded, species that passed the virus to humans [1]. Aggressive public positive-sense RNA genomes known [1]. The overall mortality health intervention strategies are credited with successfully rate of SARS corona virus (SARS-CoV) infection was ,10% but minimizing the SARS-CoV infection range, although it is this rate was 50% in patients over 65. Prior to the emergence of uncertain if these same public health strategies would sufficiently the SARS virus, coronaviruses were known to cause mild upper- contain a future SARS-CoV or SARS-like-CoV outbreak due to respiratory tract diseases in humans. In contrast, SARS-CoV virus evolution. infection caused severe disease in the lower respiratory tract PLOS ONE | www.plosone.org 1 September 2012 | Volume 7 | Issue 9 | e45842 IFN Responses of SARS CoV Infection in Ferrets Importantly, coronaviruses have a propensity toward frequent Results host-shifting events and over the past 30 years there have been many CoV cross-species transmission incidents giving rise to new Effective Immune Responses to SARS-CoV Reinfection animal and human CoV -based diseases. Coronaviruses infect a Previously, the lack of a representative SARS-CoV infection broad range of species lending further chance for recombination animal model has limited the ability to uncover immunopatho- events and the advent of new CoV species. Moreover, genic mechanisms of SARS and has impeded progress in coronaviruses can change cell type, tissue and host species vaccination strategies. Currently, a mouse model for SARS-CoV barriers with ease [6,7]. Typically, the spike (S) protein of infection has described aspects of SARS-CoV pathogenesis coronaviruses determines the host infectivity and the organiza- although these studies utilized a mouse adapted SARS virus tion of the SARS-CoV S protein shows significant similarity with [12,13,15]. The ferret, Mustela putorius furo, displays many of the other aggressive class I viral fusion proteins: influenza virus HA, symptoms and pathological features seen in SARS-CoV infected HIV-1 Env, Simian virus 5, and Ebola virus Gp2 [1]. The humans and is susceptible to unadatped SARS-CoV strains promiscuity of coronaviruses coupled with the tendency for therefore suggesting it as a useful animal model for the study of mutations to occur gives reason for concern that another CoV SARS-CoV infection and vaccination strategies [5,22–24]. Here outbreak is likely and highlights the need for continuous viral ferrets were assigned to three treatment groups for this study: (A) a surveillance and forward development of CoV vaccination mock infection control group, (B) a single infection group, and (C) strategies and therapeutics. a group that was infected at the same time as group B, then Although entry of SARS-CoV into mammalian cells has been subsequently reinfected 29 days later. The infected groups were 3 determined to be facilitated by the angiotensin-1 converting innoculated intranasally (IN) with 10 TCID50 (50% tissue culture enzyme 2 (ACE2) molecule [8], the mechanisms by which the infective dose) of SARS-CoV TOR2 strain, while the mock virus evades host immune responses causing generalized inflam- infected animals received intranasal instillation of vehicle (serum- mation, increasing viral burden, and severe lung pathology still free cell culture medium (SFM)). remain a significant scientific problem. Previous studies have Ferrets were monitored for clinical signs of disease twice daily. shown substantial problems with potential CoV vaccines where The most significant symptom observed in SARS-CoV infected the vaccines cause disease exacerbation opposed to initiating animals was sneezing, which was observed in one third of the immunological protection [9,10]. Recently, several groups have infected ferrets between 4 and 11 days post-infection (DPI). described the immunologic response during SARS-CoV infection Sneezing was not observed in ferrets from the control group (A), [11] and some have investigated the use of a mouse adapted nor in group (C) at any time post- reinfection. SARS-CoV in the mouse model [12–15]. The mouse-adapted Neutralising antibody titers rose above baseline from 6 DPI to SARS-CoV (MA15) is a valuable animal model for investigating maximal post-infection levels at 15 DPI (Figure
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