Experimental Models of COVID-19

Abstract

COVID-19 is the most consequential pandemic of the 21st century. Since the earliest stage of the 2019-2020 epidemic, animal models have been useful in understanding the etiopathogenesis of SARS-CoV-2 infection and rapid development of vaccines/drugs to prevent, treat or eradicate SARS-CoV-2 infection. Early SARS-CoV-1 research using immortalized in-vitro cell lines have aided in understanding different cells and receptors needed for SARS-CoV-2 infection and, due to their ability to be easily manipulated, continue to broaden our understanding of COVID-19 disease in in-vivo models. The scientific community determined animal models as the most useful models which could demonstrate viral infection, replication, transmission, and spectrum of illness as seen in human populations. Until now, there have not been well-described animal models of SARS-CoV-2 infection although transgenic mouse models (i.e. mice with humanized ACE2 receptors with humanized receptors) have been proposed. Additionally, there are only limited facilities (Biosafety level 3 laboratories) available to contribute research to aid in eventually exterminating SARS-CoV-2 infection around the world. This review summarizes the most successful animal models of SARS-CoV-2 infection including studies in Non-Human Primates (NHPs) which were found to be susceptible to infection and transmitted the virus similarly to humans (e.g., Rhesus macaques, Cynomolgus, and African Green Monkeys), and animal models that do not require Biosafety level 3 laboratories (e.g., Mouse Hepatitis Virus models of COVID-19, Ferret model, Syrian Hamster model). Balancing safety, mimicking human COVID-19 and robustness of the animal model, the Murine Hepatitis Virus-1 Murine model currently represents the most optimal model for SARS-CoV-2/COVID19 research. Exploring future animal models will aid researchers/scientists in discovering the mechanisms of SARS-CoV-2 infection and in identifying therapies to prevent or treat COVID-19.

Long-Term Sequelae of COVID-19 in Experimental Mice

“…We recently reported COVID-19 symptoms, clinical status, weight loss, and animal death in a murine hepatitis virus-1 (MHV-1) coronavirus mouse model of COVID-19 [ 1 , 8 – 10 ], which were similar to those observed in humans with SARS-CoV-2 infection.…”

“…MHV-1 was purchased from American Type Culture Collection (ATCC, cat# VR-261, Manassas, VA). Mice were inoculated with 5000 PFU intranasally [ 1 , 8 – 10 ]. Briefly, 5 × 10 3 PFU MHV-1 was mixed with 50 μl of ice-cold Dulbecco’s Modified Eagle’s Medium (DMEM, Gibco Cat# 11,965–092, Lot# 2,186,816, Thermo Fisher Scientific, Waltham, MA) and instilled into the nares immediately, and mice were observed until the virus was inhaled.…”

“…Mice inoculated with MHV-1 were monitored for clinical signs of disease as described earlier [ 1 , 8 – 10 ]. Clinical signs were scored by stages of (0) no clinical signs, (I) drowsy and lack of movement; (II) slightly ruffled fur and altered hind limb posture; (III) ruffled fur and mildly labored breathing; (IV) ruffled fur, inactive, moderately labored breathing; (V) ruffled fur, labored breathing, and lethargy; and (VI) moribund and death.…”

“…Recent reports indicate that patients who survived after acute severe SARS-CoV-2 infection experience breathing difficulties [ 33 ], heart problems (inflammation of the heart muscle and increased heart rate, [ 34 ], and damage to the kidney [ 35 ], suggesting the possible lifelong defects in multiple organs post-SARS-CoV-2 infection. Therefore, we examined the long-term sequelae of COVID-19 using the MHV-1 mouse model of COVID-19, which we have established [ 1 , 8 – 10 ]. While our findings show a partial recovery in the liver and kidney long-term after infection, severe pathological changes in the brain, lung, and heart were observed 1-year post-MHV-1 coronavirus infection.…”

Animal Models for COVID-19 Therapeutic Development: Where We Are and Where We Need to Go

“…Vaccination remains the best choice to protect susceptible populations; therefore, many institutions and companies have developed vaccines against SARS-CoV-2 infection and many therapeutics are under clinical investigations. For these undertakings, it is essential to use suitable COVID-19 animal models (Caldera-Crespo et al, 2021;Munoz-Fontela et al, 2022).…”