SARS-CoV-2 infection in the lungs of human ACE2 transgenic mice causes severe inflammation, immune cell infiltration, and compromised respiratory function

BioRxiv : the Preprint Server for Biology
Emma S WinklerMichael S Diamond

Abstract

Severe Acute Respiratory Syndrome Coronavirus -2 (SARS-CoV-2) emerged in late 2019 and has spread worldwide resulting in the Coronavirus Disease 2019 (COVID-19) pandemic. Although animal models have been evaluated for SARS-CoV-2 infection, none have recapitulated the severe lung disease phenotypes seen in hospitalized human cases. Here, we evaluate heterozygous transgenic mice expressing the human ACE2 receptor driven by the epithelial cell cytokeratin-18 gene promoter (K18-hACE2) as a model of SARS-CoV-2 infection. Intranasal inoculation of SARS-CoV-2 in K18-hACE2 mice results in high levels of viral infection in lung tissues with additional spread to other organs. Remarkably, a decline in pulmonary function, as measured by static and dynamic tests of respiratory capacity, occurs 4 days after peak viral titer and correlates with an inflammatory response marked by infiltration into the lung of monocytes, neutrophils, and activated T cells resulting in pneumonia. Cytokine profiling and RNA sequencing analysis of SARS-CoV-2-infected lung tissues show a massively upregulated innate immune response with prominent signatures of NF-kB-dependent, type I and II interferon signaling, and leukocyte activation pathways. Thus, the K18-hACE...Continue Reading

Citations

Aug 21, 2020·Mucosal Immunology·M D JohansenP M Hansbro
Sep 24, 2020·Nature·César Muñoz-FontelaDan H Barouch
Oct 22, 2020·The Journal of Clinical Investigation·Rudragouda Channappanavar, Stanley Perlman
Apr 30, 2021·ILAR Journal·Rebecca T Veenhuis, Caroline J Zeiss

Methods Mentioned

BETA
transgenic
bronchoalveolar lavage
scRNA-seq
cytokine
this

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