SARS-CoV-2 infection of human ACE2-transgenic mice causes severe lung inflammation and impaired function

Abstract

Although animal models have been evaluated for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, none have fully recapitulated the lung disease phenotypes seen in humans who have been hospitalized. Here, we evaluate transgenic mice expressing the human angiotensin I-converting enzyme 2 (ACE2) receptor driven by the cytokeratin-18 (K18) 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 lungs, with spread to other organs. A decline in pulmonary function occurs 4 days after peak viral titer and correlates with infiltration of monocytes, neutrophils and activated T cells. SARS-CoV-2-infected lung tissues show a massively upregulated innate immune response with signatures of nuclear factor-κB-dependent, type I and II interferon signaling, and leukocyte activation pathways. Thus, the K18-hACE2 model of SARS-CoV-2 infection shares many features of severe COVID-19 infection and can be used to define the basis of lung disease and test immune and antiviral-based countermeasures.

Sequential infection with influenza A virus followed by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) leads to more severe disease and encephalitis in a mouse model of COVID-19

“…As has recently been reported in studies using K18-hACE2 transgenic mice 23,30 , pathology revealed brain involvement in some of the SARS-CoV-2 singly infected and coinfected mice at day 10 which manifested as non-suppurative meningoencephalitis predominantly affecting the midbrain and brainstem. Previous studies using K18-hACE2 mice focusing on SARS-CoV have shown that the virus spreads throughout the brain around 3 days post intranasal inoculation 21,23,31 however the mechanism of entry is unclear as one study reported abundant infection of the olfactory bulb 31 while the other showed little involvement 21 . Unlike SARS-CoV-2, SARS-CoV has been shown to enter the brain earlier at 3dpi but does not elicit notable inflammation in this secondary site of infection 31 .…”

“…The K18-hACE2 transgenic (K18-hACE2) mouse, where hACE2 expression is driven by the epithelial cell cytokeratin-18 (K18) promoter, was developed to study SARS-CoV pathogenesis 21 . This mouse is now being used as a model that mirrors many features of severe COVID-19 infection in humans to develop understanding of the mechanistic basis of lung disease and to test pharmacological interventions 22,23 .…”

Potent mouse monoclonal antibodies that block SARS-CoV-2 infection

“…Our mouse antibodies will not be applicable for use in clinical treatment, if not chimeric and humanized, due to their immunogenicity (Hansel et al, 2010; Reichert et al, 2005). On the other hand, they may be valuable for investigating the mechanism of immune responses to the virus during passive immunization using mouse models for SARS-CoV-2 infection (Bao et al, 2020; Dinnon et al, 2020; Hassan et al, 2020; Israelow et al, 2020; R. D. Jiang et al, 2020; Winkler et al, 2020). They could show stable performance due to lot-to-lot consistency and act as benchmarks for other antibodies and drug developments.…”

Immunopathogenesis of SARS-CoV-2-induced pneumonia: lessons from influenza virus infection

“…These observations indicate again that unlike seasonal IAV which replicate first in the upper respiratory tract and can spread downward to the lower part and may cause pneumonia, SARS-CoV-2 can directly infect the lower respiratory tract and rapidly induce alveolar lesions without causing much systemic symptoms. SARS-CoV-2 infection of human ACE2-transgenic mice in which ACE2 expression is driven by the cytokeratin-18 promoter [55] also revealed a progressive inflammatory process starting at PID 2 in perivascular sites. By PID 7, massive neutrophil and monocyte infiltration has extended throughout the lungs causing consolidation.…”