Of Mice and Men: The Coronavirus MHV and Mouse Models as a Translational Approach to Understand SARS-CoV-2

Abstract

The fatal acute respiratory coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Since COVID-19 was declared a pandemic by the World Health Organization in March 2020, infection and mortality rates have been rising steadily worldwide. The lack of a vaccine, as well as preventive and therapeutic strategies, emphasize the need to develop new strategies to mitigate SARS-CoV-2 transmission and pathogenesis. Since mouse hepatitis virus (MHV), severe acute respiratory syndrome coronavirus (SARS-CoV), and SARS-CoV-2 share a common genus, lessons learnt from MHV and SARS-CoV could offer mechanistic insights into SARS-CoV-2. This review provides a comprehensive review of MHV in mice and SARS-CoV-2 in humans, thereby highlighting further translational avenues in the development of innovative strategies in controlling the detrimental course of SARS-CoV-2. Specifically, we have focused on various aspects, including host species, organotropism, transmission, clinical disease, pathogenesis, control and therapy, MHV as a model for SARS-CoV and SARS-CoV-2 as well as mouse models for infection with SARS-CoV and SARS-CoV-2. While MHV in mice and SARS-CoV-2 in humans share various similarities, there are also differences that need to be addressed when studying murine models. Translational approaches, such as humanized mouse models are pivotal in studying the clinical course and pathology observed in COVID-19 patients. Lessons from prior murine studies on coronavirus, coupled with novel murine models could offer new promising avenues for treatment of COVID-19.

Remdesivir Metabolite GS-441524 Effectively Inhibits SARS-CoV-2 Infection in Mouse Models

“…MHV belongs to the coronavirus family of RNA viruses, sharing a common genus with SARS-CoV-2. 40 MHV-A59 (A59 strain of MHV) infection causes hepatitis in mice. Because MHV is a both a naturally occurring pathology in mice and closely related to SARS-CoV-2, MHV-infected mice could serve as a rapid experimental model to evaluate anti-CoV agents.…”

Potential intestinal infection and faecal–oral transmission of SARS-CoV-2

“…According to several cohort studies, 40–70% of patients infected with H5N1 had gastrointestinal symptoms 38 , 44 , 45 and, in one case report, diarrhoea preceded respiratory manifestations by up to 1 week 46 . Interestingly, influenza is actually an enteric virus in birds 47 , 48 and other coronaviruses, such as mouse hepatitis virus and bovine coronavirus 49 , 50 , also establish intestinal infection in animals.…”

Drawing Comparisons between SARS-CoV-2 and the Animal Coronaviruses

“…Differences in organotropism within the same CoV species have been shown to influence virus transmission routes, such as enterotropic MHV being shed in high titers in feces, whilst the respiratory MHV are transmitted via direct contact with infected mice [ 23 ]. Prolonged/recurrent shedding of virus/viral RNA without clinical signs, or subclinically from animals, has been reported with certain animal CoVs, mirroring similar findings with SARs-CoV-2; however, these shedding patterns might not always reflect the transmission potential of CoVs [ 17 , 18 , 19 , 20 , 21 , 124 ].…”

“…The CNS is involved in the pathogenesis of MHV and PHEV. Two organotropic forms have been identified in MHVs: respiratory (polytropic) and enterotropic [ 23 ]. Following initial replication in the nasal respiratory and olfactory epithelium, the respiratory (polytropic) MHV strains spread into the brain, liver, lung, bone marrow, lymphoid tissue, and reproductive organs, whilst enterotropic MHV strains primarily replicate in the intestine, but can also spread to the liver, lymphoid tissue, and spleen [ 23 ].…”

“…Animal CoVs have been known to cause important diseases in livestock and companion animals [ 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 ]. Although human CoVs received attention only after the SARS-CoV outbreak of 2002–2003 [ 24 ], animal CoVs have been studied extensively for many decades, providing a plethora of important information on their complex genetic diversity, transmission, tissue tropism and pathology, host immune responses, therapeutics, and prophylaxis, some of which have striking resemblance to those seen with SARS-CoV-2.…”