Developing a Novel, More Accessible Model of COVID-19 Acute Respiratory Distress Syndrome
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Pulmonary, Infection, 2022
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INTRODUCTION: Acute respiratory distress syndrome (ARDS) is the leading cause of mortality in COVID-19. A pertinent preclinical model would greatly facilitate our understanding of COVID-19 ARDS and the development of novel therapies. However, current models using live SARS-CoV2 are limited by costly biosafety level (BSL) 3 facilities which are not widely available. This study aimed to create an animal model of COVID-19 ARDS that is inexpensive, broadly accessible and unrestricted by biohazard requirements. METHODS: Since rodent ACE2 does not bind to SARS-CoV2 spike protein, K18 human (h) ACE2 transgenic mice were intratracheally inoculated with vesiculovirus harboring the SARS-CoV2 spike protein (VSV-CoV2-S) to induce acute lung injury (ALI, preclinical ARDS). Disease severity score (0-30), temperature and weight were recorded daily. Clinically relevant features of ALI including lung permeability, inflammation and histological injury score (0-1) were analyzed. Data are shown as mean±SEM. RESULTS: In a dose ranging study, 1E7 and 2.4E7 (but not 1E5 or 1E6) pfu of VSV-CoV2-S induced clinical, molecular and histological evidence of ALI in K18-hACE2 mice by day 5. To ascertain if ARDS requires hACE2 expression, we inoculated transgenic and wildtype mice with VSV-CoV2-S (1E7 pfu). In K18-hACE2 mice, 100% mortality was observed by day 6 with a 10-fold greater disease severity score (17.0±1.2; P < 0.001) and marked declines in weight/temperature (~25%, P < 0.001). This was associated with increased immune cell infiltration, inflammatory cytokine levels and alveolar permeability (P < 0.01). Histological lung injury score was 4-fold higher in K18-hACE2 mice (0.73±0.04, P < 0.001) and revealed diffuse alveolar damage, pneumocyte hyperplasia and pulmonary hemorrhage. In contrast, all wildtype mice survived until day 10 with no evidence of ALI, which is consistent with the requirement of hACE2 expression for VSV-CoV2-S to induce lethal lung injury. CONCLUSIONS: Our findings indicate that intratracheal VSV-CoV2-S peudovirus causes a severe ALI/ARDS in hACE2 transgenic mice, mirroring the reported effects of live SARS-CoV2. Thus, we have established a novel mouse model of COVID-19 ARDS that can be used in standard BSL2 facilities, thereby enabling more widespread research into its pathogenesis and the development of novel therapies.
Meta Tag
Content Type Presentation
Knowledge Area Pulmonary
Knowledge Area Infection
Knowledge Level Intermediate
Knowledge Level Advanced
Membership Level Select
Tag Acute Respiratory Distress Syndrome ARDS
Tag Acute Lung Injury
Tag Respiratory Failure
Tag COVID-19
Year 2022
animal model
transgenic mice


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