PT  - JOURNAL ARTICLE
AU  - Hua Qing
AU  - Lokesh Sharma
AU  - Brandon K. Hilliard
AU  - Xiaohua Peng
AU  - Anush Swaminathan
AU  - Justin Tian
AU  - Kavita Israni-Winger
AU  - Cuiling Zhang
AU  - Delva Leão
AU  - Seungjin Ryu
AU  - Victoria Habet
AU  - Lin Wang
AU  - Xuefei Tian
AU  - Yina Ma
AU  - Shuta Ishibe
AU  - Lawrence H. Young
AU  - Sergei Kotenko
AU  - Susan Compton
AU  - Carmen J. Booth
AU  - Aaron M. Ring
AU  - Vishwa Deep Dixit
AU  - Craig B. Wilen
AU  - João P. Pereira
AU  - Charles S. Dela Cruz
AU  - Andrew Wang
TI  - Type I Interferon Limits Viral Dissemination-Driven Clinical Heterogeneity in a Native Murine Betacoronavirus Model of COVID-19
AID  - 10.1101/2020.09.11.294231
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.09.11.294231
4099  - http://biorxiv.org/content/early/2020/09/12/2020.09.11.294231.short
4100  - http://biorxiv.org/content/early/2020/09/12/2020.09.11.294231.full
AB  - Emerging clinical data demonstrates that COVID-19, the disease caused by SARS-CoV2, is a syndrome that variably affects nearly every organ system. Indeed, the clinical heterogeneity of COVID-19 ranges from relatively asymptomatic to severe disease with death resultant from multiple constellations of organ failures. In addition to genetics and host characteristics, it is likely that viral dissemination is a key determinant of disease manifestation. Given the complexity of disease expression, one major limitation in current animal models is the ability to capture this clinical heterogeneity due to technical limitations related to murinizing SARS-CoV2 or humanizing mice to render susceptible to infection. Here we describe a murine model of COVID-19 using respiratory infection with the native mouse betacoronavirus MHV-A59. We find that whereas high viral inoculums uniformly led to hypoxemic respiratory failure and death, lethal dose 50% (LD50) inoculums led to a recapitulation of most hallmark clinical features of COVID-19, including lymphocytopenias, heart and liver damage, and autonomic dysfunction. We find that extrapulmonary manifestations are due to viral metastasis and identify a critical role for type-I but not type-III interferons in preventing systemic viral dissemination. Early, but not late treatment with intrapulmonary type-I interferon, as well as convalescent serum, provided significant protection from lethality by limiting viral dissemination. We thus establish a Biosafety Level II model that may be a useful addition to the current pre-clinical animal models of COVID-19 for understanding disease pathogenesis and facilitating therapeutic development for human translation.Competing Interest StatementThe authors have declared no competing interest.