Animal Models of COVID-19: Transgenic Mouse Model

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), emerged in December 2019 in Wuhan, China, and rapidly spread throughout the world, threatening global public health. An animal model is a valuable and a crucial tool that allows understanding of nature in the pathogenesis of SARS-CoV-2 and its associated COVID-19 disease. Here we introduce detailed protocols of SARS-CoV-2 infection and COVID-19 disease using C57BL/6 (B6) transgenic mice expressing the human angiotensin-converting enzyme 2 (hACE2) from the human cytokeratin 18 promoter (K18 hACE2). To mimic natural SARS-CoV-2 infection, K18 hACE2 transgenic mice are infected intranasally under anesthesia. Upon infection, viral pathogenesis is determined by monitoring changes in body weight (morbidity) and monitoring survival (mortality), cytokine/chemokine responses, gross-lung pathology, histopathology, and viral replication in tissues. The presence of the virus and viral replication is evaluated by immunohistochemistry (IHC) and viral titrations, respectively, from the upper (nasal turbinate) and the lower (lungs) respiratory tracts, and nervous system (brain). Also, the immune response to SARS-CoV-2 infection is measured by cytokine/chemokine enzyme-linked immunosorbent assay (ELISA) from lung, spleen and brain homogenates to characterize the cytokine storm that hallmarks as one of the major causes of death caused by SARS-CoV-2 infection. This small rodent animal model based on the use of K18 hACE2 transgenic mice represents an excellent option to understand the pathogenicity of natural SARS-CoV-2 strains and its recently described Variants of Concern (VoC), and will be applicable to the identification and characterization of prophylactic (vaccine) and therapeutic (antiviral and/or neutralizing monoclonal antibodies) strategies for the prevention or treatment of SARS-CoV-2 infection or its associated COVID-19 disease.

Keywords: COVID-19; K18 hACE2 transgenic mice; Mouse model; SARS-CoV-2; hACE2.