Thinking Outside the Box: Utilizing Nontraditional Animal Models for COVID-19 Research

Abstract

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.

SARS‐CoV‐2 and natural infection in animals

“…Through related experimental infection studies, it was found that the Syrian hamsters showed mild to moderate clinical signs after infection, such as weight loss, respiratory distress, lethargy, and hunchback. The animals also exhibited lung lesions similar to those of human COVID‐19, such as macrophage and neutrophil infiltration in the alveoli and bronchi, pulmonary edema, inflammation, and severe alveolar hemorrhage 93 . In addition, SARS‐CoV‐2 replication was mainly observed in the upper and lower respiratory tracts.…”

“…The animals also exhibited lung lesions similar to those of human COVID‐19, such as macrophage and neutrophil infiltration in the alveoli and bronchi, pulmonary edema, inflammation, and severe alveolar hemorrhage. 93 In addition, SARS‐CoV‐2 replication was mainly observed in the upper and lower respiratory tracts. Syrian hamsters can mimic the clinical, virological, and histopathological features of human mild to moderate COVID‐19.…”

“…Cats are highly susceptible to SARS‐CoV‐2, but most present with subclinical or mild disease after infection. Interstitial pneumonia, pulmonary edema, and efficient replication of the virus in the upper and lower respiratory tracts have been reported in cats after experimental infection 93,94,98 . Therefore, cats may also serve as a model for asymptomatic or mild COVID‐19.…”

“…Interstitial pneumonia, pulmonary edema, and efficient replication of the virus in the upper and lower respiratory tracts have been reported in cats after experimental infection. 93,94,98 Therefore, cats may also serve as a model for asymptomatic or mild COVID-19. In addition, SARS-CoV-2 can be transmitted among cats and from cats to humans.…”

SARS CoV-2 (Delta Variant) Infection Kinetics and Immunopathogenesis in Domestic Cats

“…Translational animal models are a critical step in delineating immunopathogenesis of disease and developing and testing mitigation strategies and vaccine prototypes prior to human cohort studies, and this is especially crucial under recent circumstances where prior vaccine-or infection-induced immunity does not fully impart cross-protective immunity to newly arising VOCs [9][10][11]. Animal models commonly used for SARS-CoV-2 studies include mice, ferrets, hamsters, mink, non-human primates, cats, and deer [12][13][14][15][16]. However, the utility of these animal models is often limited by one or more factors such as a lack of natural viral-entry receptors (wild-type mice), lack of severe pulmonary disease and acute respiratory distress syndrome (ARDS) (huACE2 transgenic mice, hamsters, ferrets), scarce availability and zoonotic risks (non-human primates), or difficulty in acquiring and handling specific pathogen free (SPF) animals (mink).…”