Research Article: Lack of Innate Interferon Responses during SARS Coronavirus Infection in a Vaccination and Reinfection Ferret Model

Date Published: September 24, 2012

Publisher: Public Library of Science

Author(s): Mark J. Cameron, Alyson A. Kelvin, Alberto J. Leon, Cheryl M. Cameron, Longsi Ran, Luoling Xu, Yong-Kyu Chu, Ali Danesh, Yuan Fang, Qianjun Li, Austin Anderson, Ronald C. Couch, Stephane G. Paquette, Ndingsa G. Fomukong, Otfried Kistner, Manfred Lauchart, Thomas Rowe, Kevin S. Harrod, Colleen B. Jonsson, David J. Kelvin, Volker Thiel.


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.

Partial Text

Severe Acute Respiratory Syndrome (SARS) disease hit the world in late 2002 and in 4 months swiftly spread to 29 countries infecting over 8,000 people and killing over 700 [1]. The etiological agent of SARS disease was determined to be of the coronavirus (CoV) family; the largest family of single-stranded, positive-sense RNA genomes known [1]. The overall mortality rate of SARS corona virus (SARS-CoV) infection was ∼10% but this rate was 50% in patients over 65. Prior to the emergence of the SARS virus, coronaviruses were known to cause mild upper-respiratory tract diseases in humans. In contrast, SARS-CoV infection caused severe disease in the lower respiratory tract disease with symptoms ranging from flu-like and viral pneumonia to acute respiratory distress syndrome (ARDS) and fatal outcome [2]–[5]. The virus emerged from the Guangdong Province in China where it crossed to humans from a zoonotic reservoir. The most established theory puts horseshoe bats as the ultimate reservoir for the SARS-CoV and implicates palm civets as the intermediate species that passed the virus to humans [1]. Aggressive public health intervention strategies are credited with successfully minimizing the SARS-CoV infection range, although it is uncertain if these same public health strategies would sufficiently contain a future SARS-CoV or SARS-like-CoV outbreak due to virus evolution.

Currently there exists a paucity of information surrounding the molecular events associated with protection from SARS-CoV infection. Furthermore, due to the evolutionary and promiscuous nature of the SARS-CoV and other coronaviruses there is a current need to develop vaccination and therapeutic strategies for humans and mammals. Our time course analysis of differential gene expression in the lungs of SARS-CoV infected and SARS-CoV reinfected ferrets identified three key clusters of functionally related genes. Early (2–14 DPI) expression of IL-6 signaling/complement and IFN response genes followed immediately (14 DPI) by antigen processing and presentation gene expression correlated with peak SARS-CoV titres in the lungs and peak neutralizing antibody titers, respectively. Reinfecting the ferrets with SARS-CoV did not reinitiate the same organized expression of antiviral innate immune response genes; however adaptive immunity in the form of SARS-specific antibody production quickly appeared at 3 DPR. These correlations suggested that a period of IFN-driven innate antiviral responses mediates acute SARS-CoV infection, after which specific adaptive immune responses confer protection. These findings are specifically imperative to the understanding of SARS-CoV and SARS-like-CoV infections and provide a comprehensive baseline for the development of CoV antiviral therapeutics and vaccines tailored to account for the specific IFN responses and subsequent antibody production.



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