Inactivated SARS-CoV-2 induces acute respiratory distress syndrome in human ACE2-transgenic mice

Zhenfei Bi,Shuaiyao Lu,Li Chen,Xiawei Wei,Cai He,Jingyun Yang,Haiying Que,Tianqi Lu,Weiqi Hong,Wenyan Ren,Xiaozhong Peng

doi:10.1038/s41392-021-00851-6

Abstract

The development of animal models for COVID-19 is essential for basic research and drug/vaccine screening. Previously reported COVID-19 animal models need to be established under a high biosafety level condition for the utilization of live SARS-CoV-2, which greatly limits its application in routine research. Here, we generate a mouse model of COVID-19 under a general laboratory condition that captures multiple characteristics of SARS-CoV-2-induced acute respiratory distress syndrome (ARDS) observed in humans. Briefly, human ACE2-transgenic (hACE2) mice were intratracheally instilled with the formaldehyde-inactivated SARS-CoV-2, resulting in a rapid weight loss and detrimental changes in lung structure and function. The pulmonary pathologic changes were characterized by diffuse alveolar damage with pulmonary consolidation, hemorrhage, necrotic debris, and hyaline membrane formation. The production of fatal cytokines (IL-1β, TNF-α, and IL-6) and the infiltration of activated neutrophils, inflammatory monocyte-macrophages, and T cells in the lung were also determined, suggesting the activation of an adaptive immune response. Therapeutic strategies, such as dexamethasone or passive antibody therapy, could effectively ameliorate the disease progression in this model. Therefore, the established mouse model for SARS-CoV-2-induced ARDS in the current study may provide a robust tool for researchers in the standard open laboratory to investigate the pathological mechanisms or develop new therapeutic strategies for COVID-19 and ARDS.

Highlights

The high mortality of SARS-CoV-2 infection is closely associated with the disease progression to a severe COVID-19 induced acute respiratory distress syndrome (ARDS).[1]
To investigate whether the mouse model in this study recapituhACE2 mice are highly susceptible to intratracheal instillation of lates the pathologies observed in COVID-19 ARDS patients, we inactivated SARS-CoV-2 examined the lung tissues at 6 h, and on 1, 3, 5, and 7 days after
We found the induction of intratracheal instillation with 2 × 10^6 plaque-forming units (PFU) the lungs of the bigger size, with the patches of dark-colored of inactivated SARS-CoV-2

Summary

Introduction

The high mortality of SARS-CoV-2 infection is closely associated with the disease progression to a severe COVID-19 induced acute respiratory distress syndrome (ARDS).[1] The mortality rate in COVID-19 ARDS patients is up to 50% and reaches 94% in those who received mechanical ventilation.[2] The lethal features include increased leukocyte infiltration in the lungs, hyperinflammatory responses, thick mucus secretion in the airways, and microthrombosis, leading to the diffuse alveolar damage and extensive pulmonary injury.[3,4] the mechanisms underlying how the host response towards SARS-CoV-2 results in ARDS and severe. CoV-2 and increased mortality caused by ARDS have put an enormous strain on the health care system all over the world.

Methods

Results

Conclusion