4.6 Article

Kinetic Multi-omic Analysis of Responses to SARS-CoV-2 Infection in a Model of Severe COVID-19

期刊

JOURNAL OF VIROLOGY
卷 95, 期 20, 页码 -

出版社

AMER SOC MICROBIOLOGY
DOI: 10.1128/JVI.01010-21

关键词

SARS-CoV-2; COVID-19; proteomics; phosphoproteomics; RNA-seq; hamster

类别

资金

  1. National Center for Advancing Translational Sciences, National Institutes of Health [UL1 TR002645]
  2. UT-Health San Antonio
  3. The President's COVID-19 fund
  4. Long School of Medicine
  5. UT Health San Antonio
  6. NIH-NCI [P30 CA054174]
  7. NIH Shared Instrument grant [1S10OD021805-01]
  8. CPRIT Core Facility Award [RP160732]
  9. JCVI Start-up funds
  10. NIH [1R21AI148722-01A1]
  11. Pathology Core in the San Antonio Nathan Shock Center [P30-AG013319]

向作者/读者索取更多资源

The study reports a Syrian hamster model that develops severe COVID-19-like disease, showing dynamic innate immune responses and immune pathologies consistent with severe human disease. Using an integrated multiorgan analysis, changes in gene transcription and protein expression over the course of infection were evaluated to provide a kinetic overview of host responses to infection. The model will be valuable for understanding the pathogenesis of severe COVID-19 and testing interventions.
The host response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is poorly understood due to a lack of an animal model that recapitulates severe human disease. Here, we report a Syrian hamster model that develops progressive lethal pulmonary disease that closely mimics severe coronavirus disease 2019 (COVID-19). We evaluated host responses using a multi-omic, multiorgan approach to define proteome, phosphoproteome, and transcriptome changes. These data revealed both type I and type II interferon-stimulated gene and protein expression along with a progressive increase in chemokines, monocytes, and neutrophil-associated molecules throughout the course of infection that peaked in the later time points correlating with a rapidly developing diffuse alveolar destruction and pneumonia that persisted in the absence of active viral infection. Extrapulmonary proteome and phosphoproteome remodeling was detected in the heart and kidneys following viral infection. Together, our results provide a kinetic overview of multiorgan host responses to severe SARS-CoV-2 infection in vivo. IMPORTANCE The current pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has created an urgent need to understand the pathogenesis of this infection. These efforts have been impaired by the lack of animal models that recapitulate severe coronavirus disease 2019 (COVID-19). Here, we report a hamster model that develops severe COVID-19-like disease following infection with human isolates of SARS-CoV-2. To better understand pathogenesis, we evaluated changes in gene transcription and protein expression over the course of infection to provide an integrated multiorgan kinetic analysis of the host response to infection. These data reveal a dynamic innate immune response to infection and corresponding immune pathologies consistent with severe human disease. Altogether, this model will be useful for understanding the pathogenesis of severe COVID-19 and for testing interventions.

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