Natural and genetically-modified animal models to investigate pulmonary and extrapulmonary manifestations of COVID-19

Abstract Coronavirus disease-19 (COVID-19), a pandemic caused by Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), is a primarily respiratory tract disease. Suitable animal models for COVID-19 are required to study various aspects of pathogenesis, drug discovery, effective and safe vaccine development. Several laboratory animals including, non-human primates, hamsters, ferrets, transgenic mice, and zebrafish, have been used and proven their significance experimentally. Currently available animal models of SARS-CoV-2 can be broadly classified into two categories 1) natural animal models 2) genetically-modified that exhibit different degrees of susceptibility of SARS-CoV-2, tissue damage in respiratory and other organ systems. Not all the available animal models mimic COVID-19-like phenotype completely. Therefore, understanding various aspects of COVID-19 requires different animal models. In this review article, we provide an update on the immune response and clinical manifestations observed in naturally occurring and genetically-modified animals of COVID-19. We then review the transmission, viral replication, lung pathology, immunological aspects, and extrapulmonary phenotypes observed in various animal models. In the end, we put forth our perspective on the anticipated uses, disadvantages, and limitations of each type of animal model. Graphical Abstract PLAIN LANGUAGE SUMMARY SARS-CoV-2 infected individuals can experience a range of clinical features ranging from no symptoms to critical illness associated with respiratory failure, septic shock, and multi-organ failure. Additionally, SARS-CoV-2 infection is not restricted to the respiratory tract due to the multi-organ expression of ACE2. Further, the emergence of SARS-CoV-2 variants-of-concern demands continuous research on host transmission, evasion from host immune response, and development of effective and durable vaccines. A better understanding of the pathogenesis, severity, incubation period, scorable symptoms, effective treatment modalities with the least side effects, and boosting of the immune system can reduce the disease obstacles for the society as well as an individual person. Therefore, to investigate various aspects of SARS-CoV-2 infection and COVID-19 requires suitable animal models. Several laboratory animals including, non-human primates (NHPs), hamsters, ferrets, transgenic mice, zebrafish, guinea pigs, minks, have been considered and proven their significance experimentally. Currently available animal models of COVID-19, either natural host or genetically modified, exhibit different degrees of susceptibility of SARS-CoV-2 tissue damage in respiratory and other organ systems. Not all the available animal models mimic the COVID-19 like phenotype completely. Therefore, understanding different aspects of COVID-19 will require different animal models. In the proposed article, we have reviewed the immunological and clinical manifestations observed in various natural, and genetically-modified animal models of numerous COVID-19 studies. We also summarized the up-to-date laboratory findings on available on significant COVID-19 animal models, and put forth our perspective for the objective dependent usage of animal models.