Mouse model of SARS-CoV-2 reveals inflammatory role of type I interferon signaling

Abstract

Severe Acute Respiratory Syndrome-Coronavirus 2 (SARS-Cov-2) has caused over 5,000,000 cases of Coronavirus disease (COVID-19) with significant fatality rate. 1-3 Due to the urgency of this global pandemic, numerous therapeutic and vaccine trials have begun without customary safety and efficacy studies. 4 Laboratory mice have been the stalwart of these types of studies; however, they do not support infection by SARS-CoV-2 due to the inability of its spike (S) protein to engage the mouse ortholog of its human entry receptor angiotensin-converting enzyme 2 (hACE2). While hACE2 transgenic mice support infection and pathogenesis, 5 these mice are currently limited in availability and are restricted to a single genetic background. Here we report the development of a mouse model of SARS-CoV-2 based on adeno associated virus (AAV)-mediated expression of hACE2. These mice support viral replication and antibody production and exhibit pathologic findings found in COVID-19 patients as well as non-human primate models. Moreover, we show that type I interferons are unable to control SARS-CoV2 replication and drive pathologic responses. Thus, the hACE2-AAV mouse model enables rapid deployment for in-depth analysis following robust SARS-CoV-2 infection with authentic patientderived virus in mice of diverse genetic backgrounds. This represents a much-needed platform for rapidly testing prophylactic and therapeutic strategies to combat COVID-19. Development of SARS-CoV-2 mouse model

Human angiotensin-converting enzyme 2 transgenic mice infected with SARS-CoV-2 develop severe and fatal respiratory disease

“…Other recently reported SARS-CoV-2 murine models involved transduction of mouse lungs with a replication-incompetent Adenovirus virus or an adeno associated virus (AAV) encoding the hACE2 gene (35,36). Transduced lung cells expressing hACE2 supported SARS-CoV-2 replication and lung pathology ensued along with weight loss.…”

mRNA induced expression of human angiotensin-converting enzyme 2 in mice for the study of the adaptive immune response to severe acute respiratory syndrome coronavirus 2

“…As was shown for SARS-CoV [13], specific interactions between the spike glycoprotein, specifically the receptor binding motif of SARS-CoV-2 and hACE2, likely explain why SARS-CoV-2 infection of wild type mice does not occur [8]. Therefore, to establish a susceptible mouse model to study pathogenesis and immune responses to SARS-CoV-2, we must either alter the SARS-CoV-2 virus to recognize the mACE2 [14] or express the hACE2 in mice [2,[15][16][17][18][19][20][21]. Various strategies have been employed by multiple groups to facilitate the expression of hACE2 in mice, from CRISPR/Cas9 mediated hACE2 transgenics [2,15,[18][19][20][21], to adenovirus [16] or adeno associated virus (AAV) expressing hACE2 [17].…”

“…Therefore, to establish a susceptible mouse model to study pathogenesis and immune responses to SARS-CoV-2, we must either alter the SARS-CoV-2 virus to recognize the mACE2 [14] or express the hACE2 in mice [2,[15][16][17][18][19][20][21]. Various strategies have been employed by multiple groups to facilitate the expression of hACE2 in mice, from CRISPR/Cas9 mediated hACE2 transgenics [2,15,[18][19][20][21], to adenovirus [16] or adeno associated virus (AAV) expressing hACE2 [17]. SARS-CoV-2 intranasal infections in these systems have achieved detectable virus in the lungs and trachea leading to viral pneumonia histologically [16,17,22].…”

“…Various strategies have been employed by multiple groups to facilitate the expression of hACE2 in mice, from CRISPR/Cas9 mediated hACE2 transgenics [2,15,[18][19][20][21], to adenovirus [16] or adeno associated virus (AAV) expressing hACE2 [17]. SARS-CoV-2 intranasal infections in these systems have achieved detectable virus in the lungs and trachea leading to viral pneumonia histologically [16,17,22]. Alternatively, targeted mutagenesis of the SARS-CoV-2 spike protein, facilitating enhanced interactions with murine ACE2, results in a similar phenotype [23].…”

Immune response to vaccine candidates based on different types of nanoscaffolded RBD domain of the SARS-CoV-2 spike protein

“…All P values are from one-way ANOVA followed by Tukey's multiple comparisons test.Immunization by RBD-bann facilitates protection in the surrogate animal infection modelMouse ACE2 is not able to bind RBD of the SARS-CoV-2, thus human ACE2 needs to be introduced to make mice sensitive to SARS-CoV-2 infection. A previous study introduced human ACE2 gene by the AAV delivery74 . Here, we developed a model where hACE2 and TMPRRS was introduced into mice by intranasal transfection.…”