The ongoing COVID-19 pandemic continues to affect the lives, wellbeing, and stability of communities worldwide. The race to save human lives is critical, and the development of useful translational animal models to elucidate disease pathogenesis and prevention, and to test therapeutic interventions, is essential to this response. However, significant limitations exist with the currently employed animal models that slow our ability to respond to the pandemic. Non-human primates serve as an excellent animal model for SARS-CoV-2 disease and interventions, but the availability of these animals is scarce, and few facilities are able to house and utilize this model. Adapted murine models are accessible and improving but lack natural hACE-2 receptors and are only moderate representatives of human COVID-19 disease, transmission, and immune responses. On the other hand, there are several animal species that are both naturally and experimentally infected, such as domestic cats, hamsters, ferrets, and mink. Several of these have proven animal-to-animal transmission and evidence of significant clinical and histopathologic disease that mimics acute COVID-19 in humans. Mobilizing these nontraditional animal models could have a crucial role in SARS-CoV-2 research efficiency and impact. This review focuses on what is known about these nontraditional animal models, including their immune responses to SARS-CoV-2 infection, evidence of clinical and histopathologic disease, transmission potential, and the practicality of each model in a research setting. Comparative insight into these animal models for COVID-19 can strengthen the efforts to mitigate this pandemic.
Continued emergence of SARS-CoV-2 variants highlights the critical need for adaptable and translational animal models for acute COVID-19. Limitations to current animal models for SARS CoV-2 (e.g., transgenic mice, non-human primates, ferrets) include subclinical to mild lower respiratory disease, divergence from clinical COVID-19 disease course, and/or the need for host genetic modifications to permit infection. We therefore established a feline model to study COVID-19 disease progression and utilized this model to evaluate infection kinetics and immunopathology of the rapidly circulating Delta variant (B.1.617.2) of SARS-CoV-2. In this study, specific-pathogen-free domestic cats (n = 24) were inoculated intranasally and/or intratracheally with SARS CoV-2 (B.1.617.2). Infected cats developed severe clinical respiratory disease and pulmonary lesions at 4- and 12-days post-infection (dpi), even at 1/10 the dose of previously studied wild-type SARS-CoV-2. Infectious virus was isolated from nasal secretions of delta-variant infected cats in high amounts at multiple timepoints, and viral antigen was co-localized in ACE2-expressing cells of the lungs (pneumocytes, vascular endothelium, peribronchial glandular epithelium) and strongly associated with severe pulmonary inflammation and vasculitis that were more pronounced than in wild-type SARS-CoV-2 infection. RNA sequencing of infected feline lung tissues identified upregulation of multiple gene pathways associated with cytokine receptor interactions, chemokine signaling, and viral protein–cytokine interactions during acute infection with SARS-CoV-2. Weighted correlation network analysis (WGCNA) of differentially expressed genes identified several distinct clusters of dysregulated hub genes that are significantly correlated with both clinical signs and lesions during acute infection. Collectively, the results of these studies help to delineate the role of domestic cats in disease transmission and response to variant emergence, establish a flexible translational model to develop strategies to prevent the spread of SARS-CoV-2, and identify potential targets for downstream therapeutic development.
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