Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) is the causative agent of coronavirus disease 2019 (COVID‐19), the most consequential pandemic of this century, threatening human health and public safety. SARS‐CoV‐2 has been continuously evolving through mutation of its genome and variants of concern have emerged. The World Health Organization R&D Blueprint plan convened a range of expert groups to develop animal models for COVID‐19, a core requirement for the prevention and control of SARS‐CoV‐2 pandemic. The animal model construction techniques developed during the SARS‐CoV and MERS‐CoV pandemics were rapidly deployed and applied in the establishment of COVID‐19 animal models. To date, a large number of animal models for COVID‐19, including mice, hamsters, minks and nonhuman primates, have been established. Infectious diseases produce unique manifestations according to the characteristics of the pathogen and modes of infection. Here we classified animal model resources around the infection route of SARS‐CoV‐2, and summarized the characteristics of the animal models constructed via transnasal, localized, and simulated transmission routes of infection.

Characteristics of animal models for COVID‐19

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) is a positive-sense-single stranded RNA virus and the cause of the coronavirus disease 2019 (COVID-19). The World Health Organisation has confirmed over 250 million cases with over 5.1 million deaths as a result of this pandemic since December 2019. A global outbreak of such intensity and perseverance is due to the novelty of SARS-CoV2 virus, meaning humans lack any pre-existing immunity to the virus. Humanised animal models, from rodents to primates, simulating SARS-CoV2 transmission, cell entry and immune defence in humans have already been crucial to boost understanding of its molecular mechanisms of infection, reveal at-risk populations, and study the pathophysiology in vivo. Focus is now turning towards using this knowledge to create effective vaccines and therapeutic agents, as well as optimise their safety for translatable use in humans. SARS-CoV2 possesses remarkable adaptability and rapid mutagenic capabilities thus exploiting innovative animal models will be pivotal to outmanoeuvre it during this pandemic. In this review, we summarise all generated SARS-CoV2-related animal models to date, evaluate their suitability for COVID-19 research, and address the current and future state of the importance of animal models in this field.

Advances in Modelling COVID-19 in Animals

Abstract Angiotensin-converting enzyme 2 (ACE2) is required for the cellular entry of the severe acute respiratory syndrome coronavirus 2. ACE2, via the Ang-(1-7)-Mas-R axis, is part of the antihypertensive and cardioprotective effects of the renin-angiotensin system. We studied hospitalized COVID-19 patients with hypertension and hypertensive human(h) ACE2 transgenic mice to determine the outcome of COVID-19 with or without AT1 receptor (AT1R) blocker treatment. The severity of the illness and the levels of serum cardiac biomarkers (CK, CK-BM, cTnI), as well as the inflammation markers (IL-1, IL-6, CRP), were lesser in hypertensive COVID-19 patients treated with AT1R blockers than those treated with other antihypertensive drugs. Hypertensive hACE2 transgenic mice, pretreated with AT1R blocker, had increased ACE2 expression and SARS-CoV-2 in the kidney and heart, 1 day post-infection. We conclude that those hypertensive patients treated with AT1R blocker may be at higher risk for SARS-CoV-2 infection. However, AT1R blockers had no effect on the severity of the illness but instead may have protected COVID-19 patients from heart injury, via the ACE2-angiotensin1-7-Mas receptor axis. 

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The Effects of ATIR Blocker on the Severity of COVID-19 in Hypertensive Inpatients and Virulence of SARS-CoV-2 in Hypertensive hACE2 Transgenic Mice

The distribution of ACE2 and accessory proteases (ANAD17 and CTSL) in cardiovascular tissue and the host cell receptor binding of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are crucial to understanding the virus's cell invasion, which may play a significant role in determining the viral tropism and its clinical manifestations.We conducted a comprehensive analysis of the cell type-specific expression of ACE2, ADAM17, and CTSL in myocardial tissue from 10 patients using RNA sequencing. Our study included a meta-analysis of 2 heart single-cell RNA-sequencing studies with a total of 90,024 cells from 250 heart samples of 10 individuals. We used co-expression analysis to locate specific cell types that SARS-CoV-2 may invade.Our results revealed cell-type specific associations between male gender and the expression levels of ACE2, ADAM17, and CTSL, including pericytes and fibroblasts. AGT, CALM3, PCSK5, NRP1, and LMAN were identified as potential accessory proteases that might facilitate viral invasion. Enrichment analysis highlighted the extracellular matrix interaction pathway, adherent plaque pathway, vascular smooth muscle contraction inflammatory response, and oxidative stress as potential immune pathways involved in viral infection, providing potential molecular targets for therapeutic intervention. We also found specific high expression of IFITM3 and AGT in pericytes and differences in the IFN-II signaling pathway and PAR signaling pathway in fibroblasts from different cardiovascular comorbidities.Our data indicated possible high-risk groups for COVID-19 and provided emerging avenues for future investigations of its pathogenesis.(Not applicable). 

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Single-cell analysis of adult human heart across healthy and cardiovascular disease patients reveals the cellular landscape underlying SARS-CoV-2 invasion of myocardial tissue through ACE2

Jie Wang

Papers

The Effects of ATIR Blocker on the Severity of COVID-19 in Hypertensive Inpatients and Virulence of SARS-CoV-2 in Hypertensive hACE2 Transgenic Mice

Single-cell analysis of adult human heart across healthy and cardiovascular disease patients reveals the cellular landscape underlying SARS-CoV-2 invasion of myocardial tissue through ACE2