Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) is a zoonotic pathogen that likely emerged from bats, was amplified in civet cats and raccoon dogs and then transmitted to humans causing severe acute respiratory disease, pneumonia, and high mortality rates in the elderly. The molecular mechanisms governing SARS-CoV pathogenicity are unknown because of the lack of well defined animal models that exhibit severe pulmonary disease in the most vulnerable aged populations. We constructed a panel of isogenic SARS-CoV strains bearing spike (S) glycoproteins derived from animal and human strains (e.g., civet, raccoon dog, human). In aged rodent models, two recombinant viruses (icGZ02-S-early human phase;icHC/SZ/61/03-S- civet) caused severe disease with diffuse alveolar damage, hyaline membranes, and death, but little disease in young mice. A mouse adapted strain, icMA15, produced severe disease and death in both young and old animals. We use an interdisciplinary approach coupled with lethal young and senescent rodent models to elucidate the molecular mechanisms governing SARS-CoV pathogenesis. Our central hypotheses are that determinants in the S glycoprotein promote severe disease by corrupting the role of antgiotensin 1 converting enzyme 2 (ACE2) in the prevention of acute lung injury and by the induction of innate immunity and complement. We will identify the genetic factors in the virus and host that regulate SARS-CoV pathogenesis.
In aim 1, we study the pathogenesis of lethal and nonlethal SARS-CoV infection in young and senescent mice, determining if chronic disease manifestations of pulmonary fibrosis occur in survivors. Using immunologic, pathologic and microarray technology, we evaluate host transcription profiles and cytokine levels at different times post infection.
In Aim 2, we test the hypotheses that ACE2 dysregulation and the complement signaling pathway promote inflammatory tissue destruction and lethal SARS-CoV infection.
In Aim 3, we test the hypothesis that a select subset of mutations in the S glycoprotein and the replicase gene strongly influence disease outcomes in young and senescent mice. The impact of these studies are high, garnering well defined models of virus induced acute respiratory distress syndrome and pulmonary fibrosis while simultaneously revealing the host and viral interactions that contribute to these devastating clinical diseases with high mortality. Narrative for Old mouse application

Public Health Relevance

Acute respiratory distress syndrome (ARDS) is a lung disease that can lead to pulmonary fibrosis (hardening of the lung tissue), respiratory failure and death due to multi-organ failure. Mortality rates for ARDS, the most severe form of acute lung injury, approaches 50%, effects ~1,000,000 people/year worldwide, and ranks among the most difficult challenges in critical care medicine. Pulmonary fibrosis is a devastating disease with an almost universally terminal outcome affecting five million people worldwide, including some 200,000 cases culminating in 40,000 deaths/year in the US. There are no good model systems currently available to study ARDS or pulmonary fibrosis. Infection with the severe acute respiratory syndrome coronavirus (SARS-CoV) induces ARDS in humans often leading to fatality. The mutant SARS-CoV viruses studied in the application have recapitulated the ARDS phenotype in a mouse model and will allow investigation of the viral and host responses that contribute to ARDS providing a much needed model of virally induced ARDS and pulmonary fibrosis.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Special Emphasis Panel (ZRG1-IDM-M (02))
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Salomon, Rachelle
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University of North Carolina Chapel Hill
Public Health & Prev Medicine
Schools of Public Health
Chapel Hill
United States
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Ishimaru, Daniella; Plant, Ewan P; Sims, Amy C et al. (2013) RNA dimerization plays a role in ribosomal frameshifting of the SARS coronavirus. Nucleic Acids Res 41:2594-608
Chan, Renee W Y; Chan, Michael C W; Agnihothram, Sudhakar et al. (2013) Tropism of and innate immune responses to the novel human betacoronavirus lineage C virus in human ex vivo respiratory organ cultures. J Virol 87:6604-14
Graham, Rachel L; Becker, Michelle M; Eckerle, Lance D et al. (2012) A live, impaired-fidelity coronavirus vaccine protects in an aged, immunocompromised mouse model of lethal disease. Nat Med 18:1820-6
Totura, Allison L; Baric, Ralph S (2012) SARS coronavirus pathogenesis: host innate immune responses and viral antagonism of interferon. Curr Opin Virol 2:264-75
Frieman, Matthew; Yount, Boyd; Agnihothram, Sudhakar et al. (2012) Molecular determinants of severe acute respiratory syndrome coronavirus pathogenesis and virulence in young and aged mouse models of human disease. J Virol 86:884-97
Sheahan, Timothy; Whitmore, Alan; Long, Kristin et al. (2011) Successful vaccination strategies that protect aged mice from lethal challenge from influenza virus and heterologous severe acute respiratory syndrome coronavirus. J Virol 85:217-30
Bolles, Meagan; Deming, Damon; Long, Kristin et al. (2011) A double-inactivated severe acute respiratory syndrome coronavirus vaccine provides incomplete protection in mice and induces increased eosinophilic proinflammatory pulmonary response upon challenge. J Virol 85:12201-15
Rockx, Barry; Feldmann, Friederike; Brining, Douglas et al. (2011) Comparative pathogenesis of three human and zoonotic SARS-CoV strains in cynomolgus macaques. PLoS One 6:e18558
Graham, Rachel L; Baric, Ralph S (2010) Recombination, reservoirs, and the modular spike: mechanisms of coronavirus cross-species transmission. J Virol 84:3134-46
Frieman, Matthew B; Chen, Jun; Morrison, Thomas E et al. (2010) SARS-CoV pathogenesis is regulated by a STAT1 dependent but a type I, II and III interferon receptor independent mechanism. PLoS Pathog 6:e1000849

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