Molecular simulation studies of the interactions between the human/pangolin/cat/bat ACE2 and the receptor binding domain of the SARS-CoV-2 spike protein.

The recent outbreak of SARS-CoV-2 has had a profound effect on the world. Similar to that in SARS-CoV, the entry receptor of SARS-CoV-2 is ACE2. The binding of SARS-CoV-2 spike protein to ACE2 is the critical to the virus infection. Recently multiple species (human, Chinese chrysanthemum, Malay pangolin and cat) have been reported to be susceptible to the virus infection. However, the binding capacity and the detailed binding mechanism of SARS-CoV-2 spike protein to ACE2 of these species remains unexplored. Herein free energy calculations with MM-GBSA and Potential of Mean Forces together reveal that the Human-SARS-CoV-2 has a higher stability tendency than Human-SARS-CoV. Meanwhile, we uncover that SARS-CoV-2 has an enhanced ability to bind with the ACE2 in humans, pangolins and cats compared to that in bats. Analysis of key residues with energy decomposition and residue contact maps reveal several important consensus sites in ACE2s among the studied species, and determined the more favorable specified residues among the different types of amino acids. These results provide important implications for understanding SARS-CoV-2 host range which will make it possible to control the spread of the virus and use of animal models, targeted drug screening and vaccine candidates against SARS-CoV-2.

Animal Hosts and Experimental Models of SARS-CoV-2 Infection.

Viruses arise through cross-species transmission and can cause potentially fatal diseases in humans. This is the case of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) which recently appeared in Wuhan, China, and rapidly spread worldwide, causing the outbreak of coronavirus disease 2019 (COVID-19) and posing a global health emergency. Sequence analysis and epidemiological investigations suggest that the most likely original source of SARS-CoV-2 is a spillover from an animal reservoir, probably bats, that infected humans either directly or through intermediate animal hosts. The role of animals as reservoirs and natural hosts in SARS-CoV-2 has to be explored, and animal models for COVID-19 are needed as well to be evaluated for countermeasures against SARS-CoV-2 infection. Experimental cells, tissues, and animal models that are currently being used and developed in COVID-19 research will be presented.

Zoonotic origins and animal hosts of coronaviruses causing human disease pandemics: A review.

The first known severe disease caused by a coronavirus (CoV) in humans emerged with the severe acute respiratory syndrome (SARS) epidemic in China, which killed 774 people during its 2002/2003 outbreak. The Middle East respiratory syndrome (MERS) was the second human fatal disease, which started in 2012 in Saudi Arabia and resulted in 858 fatalities. In December 2019, a new virus, SARS-CoV-2 (COVID-19), originating from China, began generating headlines worldwide because of the unprecedented speed of its transmission; 5.2 million people were infected and 338 480 had been reported dead from December 2019 to May 2020. These human coronaviruses are believed to have an animal origin and had reached humans through species jump. Coronaviruses are well known for their high frequency of recombination and high mutation rates, allowing them to adapt to new hosts and ecological niches. This review summarises existing information on what is currently known on the role of wild and domesticated animals and discussions on whether they are the natural reservoir/amplifiers hosts or incidental hosts of CoVs. Results of experimental infection and transmission using different wild, domesticated and pet animals are also reviewed. The need for a One Health approach in implementing measures and practices is highlighted to improve human health and reduce the emergence of pandemics from these zoonotic viruses.

Severe acute respiratory syndrome coronavirus-2 natural animal reservoirs and experimental models: systematic review.

The current severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) outbreak has been rapidly spreading worldwide, causing serious global concern. The role that animal hosts play in disease transmission is still understudied and researchers wish to find suitable animal models for fundamental research and drug discovery. In this systematic review, we aimed to compile and discuss all articles that describe experimental or natural infections with SARS-CoV-2, from the initial discovery of the virus in December 2019 through to October 2020. We systematically searched four databases (Scopus, PubMed, Science Direct and Web of Science). The following data were extracted from the included studies: type of infection (natural or experimental), age, sample numbers, dose, route of inoculation, viral replication, detection method, clinical symptoms and transmission. Fifty-four studies were included, of which 34 were conducted on animal reservoirs (naturally or experimentally infected), and 20 involved models for testing vaccines and therapeutics. Our search revealed that Rousettus aegyptiacus (fruit bats), pangolins, felines, mink, ferrets and rabbits were all susceptible to SARS-CoV-2, while dogs were weakly susceptible and pigs, poultry, and tree shrews were not. In addition, virus replication in mice, mink, hamsters and ferrets resembled subclinical human infection, so these animals might serve as useful models for future studies to evaluate vaccines or antiviral agents and to study host-pathogen interactions. Our review comprehensively summarized current evidence on SARS-CoV-2 infection in animals and their usefulness as models for studying vaccines and antiviral drugs. Our findings may direct future studies for vaccine development, antiviral drugs and therapeutic agents to manage SARS-CoV-2-caused diseases.

Broad and Differential Animal Angiotensin-Converting Enzyme 2 Receptor Usage by SARS-CoV-2.

The COVID-19 pandemic has caused an unprecedented global public health and economic crisis. The origin and emergence of its causal agent, SARS-CoV-2, in the human population remains mysterious, although bat and pangolin were proposed to be the natural reservoirs. Strikingly, unlike the SARS-CoV-2-like coronaviruses (CoVs) identified in bats and pangolins, SARS-CoV-2 harbors a polybasic furin cleavage site in its spike (S) glycoprotein. SARS-CoV-2 uses human angiotensin-converting enzyme 2 (ACE2) as its receptor to infect cells. Receptor recognition by the S protein is the major determinant of host range, tissue tropism, and pathogenesis of coronaviruses. In an effort to search for the potential intermediate or amplifying animal hosts of SARS-CoV-2, we examined receptor activity of ACE2 from 14 mammal species and found that ACE2s from multiple species can support the infectious entry of lentiviral particles pseudotyped with the wild-type or furin cleavage site-deficient S protein of SARS-CoV-2. ACE2 of human/rhesus monkey and rat/mouse exhibited the highest and lowest receptor activities, respectively. Among the remaining species, ACE2s from rabbit and pangolin strongly bound to the S1 subunit of SARS-CoV-2 S protein and efficiently supported the pseudotyped virus infection. These findings have important implications for understanding potential natural reservoirs, zoonotic transmission, human-to-animal transmission, and use of animal models.IMPORTANCE SARS-CoV-2 uses human ACE2 as a primary receptor for host cell entry. Viral entry mediated by the interaction of ACE2 with spike protein largely determines host range and is the major constraint to interspecies transmission. We examined the receptor activity of 14 ACE2 orthologs and found that wild-type and mutant SARS-CoV-2 lacking the furin cleavage site in S protein could utilize ACE2 from a broad range of animal species to enter host cells. These results have important implications in the natural hosts, interspecies transmission, animal models, and molecular basis of receptor binding for SARS-CoV-2.