COVID-19: animals, veterinary and zoonotic links

1. Introduction

In the early days of December 2019, where people planned to welcome New Year 2020, as well as the Chinese New Year, on January 25, 2020, news channels reported suffering of people with sporadic and clustered incidences of “pneumonia of unknown origin” in the city of Wuhan under Hubei province, China (Gao 2020; Lu et al. 2020a). Subsequently, after a month of the first report of infection on December 12, 2019, the causative agent was swiftly identified as a member of Coronaviridae family, and on January 12, 2020, the World Health Organization (WHO) designated this fast-spreading virus as “2019-novel coronavirus (2019-nCoV)”, and Novel Coronaviral Pneumonia and CoV-associated diseases were referred to as “COVID-19” by WHO on February 11, 2020 (Du et al. 2020; Gralinski and Menachery 2020). Later, this emerging virus was designated as “SARS-CoV-2” by the Coronavirus Study Group (CSG) of the International Committee on Taxonomy of Viruses (ICTV) (Gorbalenya et al. 2020). On March 11, 2020 the WHO declared the situation as a pandemic which is threatening mankind to a great extent (Chatterjee et al. 2020; Zheng 2020; Phadke and Saunik 2020; Rundle et al. 2020). As of now, SARS-CoV-2 is considered as the seventh coronavirus that infects humans. The other coronaviruses (CoVs) include HKU1, NL63, OC43, 229E, SARS-CoV, and MERS-CoV. Among which SARS-CoV and MERS-CoV are zoonotic and have resulted in high mortality outbreaks in the last two decades, while the others are usually associated with mild upper-respiratory tract illnesses (Wei et al. 2020), and sometimes leading to complicated disease, when occurring in immunocompromised individuals (Villamil-Gómez et al. 2020).

The culinary habits of Chinese people involve the consumption of wild animal meat. The common motivation that is responsible for the human consumption of wild animal meat in China is due to their believed medicinal value as well as the health-promoting effects associated with the consumption of certain wild game animal meats and their products (Harypursat and Chen 2020). The circumstantial evidence that links the first case of COVID-19 to the Huanan South Seafood Market that sells various exotic live animals and our previous knowledge that coronaviruses are animal-derived made us conclude the possible zoonotic transmission in SARS-CoV-2. Nevertheless, it is too early to jump into conclusions since our knowledge of the primary source of infection is limited (Jalava 2020). Identifying the origin of SARS-CoV-2 will help us to unravel the exact mechanism responsible for its initial transmission. After attaining a remarkable progress in developing field oriented as well as high accuracy lab-based diagnostics, much attention has been paved upon developing effective vaccine and therapeutics for blocking person-person transmission, old age infections and health-care workers infection (Chen et al. 2020). That is critical for developing appropriate preventive and control strategies against the fast-spreading SARS-CoV-2 infection. Looking at the beneficial propositions of hydroxychloroquine a multicentric randomised study is underway to assess its effectiveness as a prophylactic measure in curbing secondary SARS-CoV-2 infections as well as associated clinical symptoms progression reducing overall the spread of the virus (Mitjà and Clotet 2020)

Originating from the central part of China, the SARS-CoV-2 pandemic not only dispersed in 369 other cities of China but also crossed the international boundaries within a short period (December to March 2020). As of May 2, 2020, COVID-2019 has affected persons in more than 210 countries and territories in Asia, Europe, Africa, North America, and Latin America (Rodríguez-Morales et al. 2020a; WHO 2020). Hence, due to very high transmissibility across the borders, it was declared as public health emergency of international concern by the WHO on January 30, 2020, and later as pandemic situation (Du Toit 2020; Habibzadeh and Stoneman 2020; Liu et al. 2020a, 2020b; Wood 2020; WHO 2020).

At the beginning of 21^st century, other coronaviruses like SARS-CoV and MERS-CoV, in 2002 and 2012, respectively have also caused severe acute respiratory distress (SARD) in the form of outbreaks but the current SARS-CoV-2 pandemic affected wider population accounting a total number of nearly 4.71 million confirmed cases along with death toll of nearly 0.31 million by May 17, 2020 (WHO 2020). These numbers are comparatively higher than SARS-CoV and MERS-CoV cases but with lower case fatality rate. The occurrence of this pandemic has adversely affected the global economy, especially in developing nations. This outbreak not only dejected the multinational businesses, disrupted the global market trading, tourism, transportation, export-import, but also reduced the income generated from the market (Ayittey et al. 2020).

China is home for several farms that rears several animal species such as deer, snakes, porcupines, foxes, civets, bears, turtles, bamboo rats, mink, and birds. Such farms can be targeted to find the origin of SARS-CoV-2 (Zhai et al. 2020). Before declaring snakes, pangolins or even dogs as the reservoir host of SARS-CoV-2, a set of established principles called as the Koch’s postulates have to be satisfied. Hence, it is unethical to cull these animals without any conclusive evidence of SARS-CoV-2 transmission from animals-to-humans (Brownlie 2020). The recent reports of SARS-CoV-2 in animals such as dogs, cats, and a tiger have resulted in unnecessary fear among the general public as well as pet owners and have negatively impacted the welfare of animals (Parry 2020).

The present compilation highlights, in brief, abut SARS-CoV-2, causing emerging coronavirus disease (COVID-19) in humans with regards to the role of animals, veterinary importance, zoonotic aspects, and salient prevention and control strategies focusing on One-health approaches to restrain and combat this pandemic virus.

2. The virus (SARS-CoV-2)

Coronaviruses are positive-sense RNA viruses. The newly identified SARS-CoV-2 (2019-nCoV) is a member of the order Nidovirales, family Coronaviridae, sub-family Orthocoronavirinae under which four genera, namely, Alphacoronavirus, Betacoronavirus, Gammacoronavirus, and Deltacoronavirus, are categorized. The SARS-CoV-2 belongs to the genus Betacoronavirus and subgenus Sarbecovirus. SARS-CoV and MERS-CoV were also part of the Betacoronavirus genus, but SARS-CoV-2 is different from these two at genetic level. The SARS-CoV-2 has been found 88-89% identical to two bat origin SARS coronaviruses (bat-SL-CoVZC45 and bat-SL-CoVZXC21, also named as ZC45 and ZXC21), while it is 82% identical to human SARS-CoV Tor2 and human SARS-CoV BJ01 2003 at the nucleotide level (Drexler et al. 2014; Hu et al. 2017; Hu et al. 2018; Chan et al. 2020; Malik et al. 2020a). Only 50-51.8% identity was observed between SARS-CoV-2 and MERS-CoV and 79% between SARS-CoV-2 and SARS-CoV; further molecular level phylogenetic analyses reveal that SARS-CoV-2 is more close to bat origin SARS-CoV (Mohd et al. 2016; Ramadan and Shaib 2019; Ren et al. 2020; Malik et al. 2020a). The advanced, in-depth genome analysis identified the presence of 380 amino acid substitutions between the sequences of SARS-CoV-2 (HB01) in comparison to the corresponding consensus sequences of SARS-CoV and SARS-CoV like viruses. This amino acid substitution might have contributed to the functional as well as the pathogenic divergence of this novel virus (Wu et al. 2020a).

3. Host range

Coronaviruses (CoVs) infect man as well as domestic and wild animal species and usually infections remain sub-clinical in most cases (Ji et al. 2020a; Li et al. 2020a; Salata et al. 2020). The clinical form varies from enteritis in cattle, horses and swine, upper respiratory tract disease in cattle, dogs, felines, and poultry, and common cold to highly fatal respiratory infections in humans (Dhama et al. 2020a, 2020b). Among the four genera in the Coronaviridae family, Alphacoronavirus and Betacoronavirus usually infect mammals and have probable bat origin, while Gammacoronavirus and Deltacoronavirus infect birds, fishes, and mammals and are assumed to have swine origin (Woo et al. 2012; Hu et al. 2017; Cui et al. 2019). The genus Betacoronavirus possess potential zoonotic pathogens like SARS-CoV and MERS-CoV which have bats as primary host and palm civet cat and dromedary camels as intermediate hosts, respectively (Wang and Eaton 2007; Ar Gouilh et al. 2018; Ramadan and Shaib 2019). Many CoVs have been recovered from birds such as Wigeon coronavirus HKU20, Bulbul coronavirus HKU11, Munia coronavirus HKU13, White-eye coronavirus HKU16, Night-heron coronavirus HKU19 and Common moorhen coronavirus HKU21. The common pig infecting coronaviruses include Porcine Coronavirus HKU15, Transmissible Gastroenteritis Virus (TGEV), Porcine Epidemic Diarrhea Virus (PEDV), and Porcine Hemagglutinating Encephalomyelitis virus (PHEV) which are being reported from many parts of the world (Ma et al., 2008). A list of other animal species also reported harbouring the CoVs such as cattle, horses, swine, dogs, cats, camels, rabbits, rodents, birds, ferrets, mink, bats, snake (such as Chinese cobra and krait), frogs, marmots, hedgehogs (Erinaceus europaeus), Malayan or Javan or Sunda pangolin (Manis javanica), many other wild animals and their role as carrier/reservoir needs urgent attention (WHO 2003; Dhama et al. 2014a, 2014b, 2020a; Monchatre-Leroy et al. 2017; Ji et al. 2020a; Malik et al., 2020b; Xu 2020).

4. Covid-19/SARS-CoV-2: animals, veterinary, zoonotic links and transmission

5. Animal models

Though animal model studies are currently lacking for SARS-CoV-2, a recent study explored the utility of non-human primates, rhesus macaque, as a model for carrying out SARS-CoV-2 studies. Earlier, these non-human primates were used in evaluating the vaccines and antivirals against the MERS-CoV (de Wit et al. 2020). While working on SARS-CoV-2, rhesus macaques showed the establishment of SARS-CoV-2 infection with detection of high virus amount in oral-naso and rectal swabs. The apparent lesions of disease in lung radiographs and clinical signs lasting for up to 16 days proved the effectiveness of the model in studying the pathogenesis of this disease and aiding further in developing and testing vaccines and antivirals (Munster et al. 2020).

Isolation SARS-CoV-2 from dogs is also reported (OIE. 2020). Most recently, Shi et al. (2020) have demonstrated the susceptibility of ferrets, cats, dogs, and different domestic animal species to SARS-CoV-2 by experimental inoculation and reported that SARS-CoV-2 replicates poorly in dogs, pigs, chickens, and ducks, but efficiently in ferrets and cats. Cats can spread infection via droplets (Shi et al. 2020). However, accurate exploration requires specific animal models, especially animals with ACE2 receptors similar to those of humans (Andersen et al. 2020). Establishing suitable animal models will not only help in understanding the disease process but will also help in developing prophylactics and therapeutics (TBRI 2020; Dhama et al. 2020c). Non-human primates are considered to be the appropriate models of human diseases, whereas for exploring etio-pathogenesis of the disease and immune response, other animal models are preferred (TBRI 2020). Non-human primates, mice, and hamsters (Gretebeck and Subbarao 2015) have been used as animal models for SARS and MERS, and some may have the possibility in SARS-CoV-2. Golden Syrian hamsters have been investigated for vaccine protection studies against SARS-CoV strains (Roberts et al. 2008), and suggested to be potential animal model for revealing CoV pathology and pathogenesis along with vaccine efficacy to be tested. Transgenic animals (e.g., mice) have better relevance of simulating SARS-CoV-2 since there are structural differences in ACE 2 receptors in various animal species to which receptor binding domain of spike protein of SARS-CoV-2 binds (Liu et al. 2020b; Wang 2020). On the modeling of ACE2 receptors between various animal species of pigs, ferrets, cats, orangutans, monkeys, bat species, and humans have similar levels of affinity for SARS-CoV-2 based on the structural similarity of their ACE2 receptors (Jarvis 2020). Hence these may have a possible role to be used as animal models with further investigative studies. Small animal models are generally preferred, like mice and rabbits being cheap, easy to manipulate, and ease of availability (Dhama et al. 2020c). Initially, mice appeared to be challenging owing to the difference in receptor ACE2 usage pattern, but transgenic mice are now believed to be relevant models for SARS-CoV-2 (Liu et al. 2020a, 2020b Wang 2020,; Zhou et al. 2020b). Ace2 Knockout Mouse, Tmprss2 Knockout Mouse, Stat1 Knockout Mouse, inbred mice, and Transgenic HLA Mice are being evaluated as animal models for SARS-CoV-2/COVID-19 (Hoffmann et al. 2020; Taconic Biosciences 2020; Wang 2020).

6. Prevention and control

The past decade and recent episodes of Zika, Ebola, Nipah, and Bird flu viruses (Munjal et al. 2017; Dhama et al. 2012, 2018; Singh et al. 2019), and lessons learned from previous threats of coronaviruses (SARS- and MERS-CoVs) along with advances in science have paved pace to counter emerging pathogens including the SARS-CoV-2. For this purpose, high efforts are being made to contain and control the spread of this emerging virus haunting the lives of humans and posing even now a pandemic situation. Efforts for rapid diagnosis, strict vigilance, appropriate isolation, and quarantine procedures to halt its further spread, enhanced surveillance and monitoring, strengthening of medical facilities and intensive care units, networking programs, rapid communication and providing updates, knowledge awareness of its public health risks to the general population, high efforts to develop effective vaccines and therapeutics/drugs are being explored optimally. International collaborative efforts and readiness to tackle further heightened emergency to a level of pandemic potential along with following suitable One health approach to combat this emerging virus haunting the lives of billions of human population are being followed effectively (Bonilla-Aldana et al. 2020; Dhama et al. 2013a, 2013b; 2020a, 2020c; Malik et al. 2020a, 2020b; Rodriguez-Morales et al. 2020c). Vaccines appear to be the long-lasting solution for the COVID-19 pandemic. However, currently, there are no vaccines available against it (Shang et al. 2020; Chen et al. 2020). Clues are being taken from the viral structures, pathogenesis, and related coronaviruses (Ahmed et al. 2020; Shang et al. 2020).

Various vaccines are being evaluated by different institutes and companies (Shang et al. 2020), with a few under trials. Moderna, Cambridge, Ma, USA, a biopharma company, started with the mRNA-1273 vaccine in collaboration with CanSino, Hong Kong Special Administrative Region, China (Flanagan 2020). The University of Alabama at Birmingham (UAB), Birmingham, Al, USA, in coordination with Altimmune Inc., Gaithersburg, Md, USA, is developing an intranasal vaccine against COVID-19 and named it as AdCOVID on the pattern of pandemic influenza vaccine and inhalation anthrax vaccine (Hansen et al. 2020). The Clover Biopharmaceuticals company, Chengdu, China, has come out with a SARS-CoV-2 S-protein based subunit vaccine (Clover Biopharmaceuticals 2020).

As of March 20, 2020, WHO has tabulated approximately 44 vaccine candidates targeting SARS-CoV-2, among which few are under clinical evaluation and some under development by various companies and institutions. They included live attenuated, formaldehyde inactivated, protein subunit, DNA, m-RNA, VLP, replicating, and non-replicating vector-based SARS-CoV-2 vaccines. Adenovirus type 5 vector vaccine by CanSino biological Inc., Hong Kong Special Administrative Region, China, and Beijing Institute of Biotechnology, Beijing, China, and LNP-encapsulated mRNA vaccine developed by Moderna/NIAID, Bethesda, Md, USA, is under phase-1 clinical evaluation. Few in pre-clinical stage of clinical evaluation against COVID-19 include DNA plasmid vaccine by Zydus Cadila, Ahmedabad, India, DNA plasmid vaccine through electroporation device by Inovio pharmaceuticals, Plymouth Meeting, Pa, USA, DNA vaccine by Takis/Applied DNA Sciences/Evvivax, Rome, Italy, formaldehyde inactivated alum vaccine by Sinovac, Beijing, China, live attenuated virus vaccine by Codagenix, Farmingdale, New York, USA/Serum Institute of India, Pune, India, MVA encoded VLP by GeoVax/BravoVax, Smyrna, Ga, USA, Ad 26 by Janssen pharmaceutical companies, Beerse, Belgium, ChAdOx1 by university of Oxford, Oxford, UK, adenovirus-based NasoVAX expressing SARS-CoV-2 spike protein by Altimmune, Gaithersburg, Md, USA, Ad5 S (named as GREVAX™) by Greffex, Aurora, Co, USA, oral vaccine by Vaxart, South San Francisco, Ca, USA, Drosophila S2 insect cell expression system using VLPs as protein subunit vaccine by ExpreS2ion, Horsholm, Denmark, S protein based by WRAIR/USAMRIID, Fort Detrick, Md, USA, another S protein by AJ Vaccines, København, Denmark, S-trimer by Clover Biopharmaceuticals Inc., Chengdu, China/GSK, Brentford, UK, peptide based vaccine by Vaxil Bio, Toronto, Ontario, Canada, S protein through baculovirus production system by Sanofi Pasteur company, Swiftwater, Pa, USA, full length S trimers nanoparticle with Matrix M by Novavax, Rockville, Md, USA, gp-96 backbone based vaccine by Heat Biologics, Morrisville, Nc, USA, or University of Miami, Miami, Fl, USA, S1 or RBD protein based by Baylor College of Medicine, Houston, Tx, USA, adjuvanted microsphere peptide vaccine candidate by University of Saskatchewan, Saskatoon, Saskatchewan, Canada, LNP encapsulated mRNA encoding RBD by Fudan University/Shanghai JiaoTong University/RNACure Biopharma, Shanghai, China, sa-RNA (small activating ds-RNA) based COVID-19 vaccine by Imperial College London, London, UK, among others. (https://www.who.int/blueprint/priority-diseases/key-action/novel-coronavirus-landscape-ncov.pdf?ua=1). Though till April 1^st, 2020 US Food and Drug Administration (FAO) had not announced any confirmed commercial therapeutic or prophylactic vaccine against SARS-CoV-2, nevertheless they have enlisted few potential vaccine candidates which are currently under either preclinical or clinical trials such as mRNA-1273 by Moderna Inc., Bethesda, Md, USA, Inovio’s DNA vaccine INO-4800 against COVID-19 by Inovio Pharmaceuticals, Plymouth Meeting, Pa, USA, along with Ology Bioservices, Alachua, Fl, USA, BNT162 a mRNA vaccine by BioNTech, Mainz, Germany, plant-based COVID-19 vaccine by Medicago, Quebec, Quebec, Canada, oral recombinant COVID-19 vaccine by Vaxart, South San Francisco, Ca, USA, Ii-Key peptide COVID-19 vaccine by Generex Biotechnology, Toronto, Ontario, Canada, among others (Precision Vaccinations 2020). (https://www.precisionvaccinations.com/vaccines/coronavirus-vaccines).

Till the vaccines are developed, alternate disease prevention and control strategies need to be focused on. There is a need for strengthening infrastructure and capacity building with a trained workforce, hospital, health workers to identify the SARS affected patient with the isolation of patients after being doubted for COVID-2019. To apply any prevention, measure the first and foremost step is to diagnose the case with accuracy and speed. While confirming any deadly case, the guidelines of Centers for Disease Control and Prevention (CDC) must be adopted. As the suspected case is a good source of nosocomial spread, the health workers must follow all the precautionary practices while handling the COVID-2019 case. Notably, a facility with negative air pressure is recommended for keeping confirmed patients of SARS-CoV-2.

The applications of telemedicine having tele-visits and supervision, monitoring, interpretation, and consultation (Serper and Volk 2018) have proven effective in mitigating chronic diseases. The tele-model has been applied on present-day COVID-19 pandemic, especially in the remote areas having limited medical backups saving both manpower as well as resources (Au 2020).

Although respiratory tract infections and spread of the virus from naso-oral secretions is well discussed, the first isolation of SARS-CoV-2 in China from a COVID-19 positive patient highlighted the significance of the digestive tract in conjunction to the respiratory tract. Since then, while planning the control strategies, this alternative route of virus spread must be kept in mind, including a focus on clinical sufferers, and asymptomatic patients or individuals having no or mild signs (Gu et al. 2020).

Further spread of SARS-CoV-2 can be controlled by immediate isolation of confirmed cases along with contact tracing. According to the analysis made by using transmission models, the COVID-19 outbreak could be controlled within three months by following active contact tracing in combination with the isolation of infected individuals (Hellewell et al. 2020). It is not the first time that live-animal markets in China have been identified as the epicenter of emerging novel zoonotic diseases. For preventing the likelihood of another zoonotic outbreak, closure of all the live-animal markets is a necessity (Peeri et al. 2020). However, the deep connection existing between these live markets and the Chinese culture makes the permanent ban practically impossible. Due to the possible role played by live-markets in the origin of SARS-CoV-2, a temporary ban was imposed on the wildlife trade in China (Harypursat and Chen 2020; Mallapaty 2020), which was again cancelled merely after 4 months of the outbreak as COVID-19 seemed under control in China. Purchase of live-dead animals like dogs, cats, bats, birds, ostriches, rabbits, hamsters, scorpions, badgers, pangolins (with peculiar scaly anteaters), minks, palm civet, snapping turtles, ducks, fishes, Siamese crocodiles (Knowles 2020) (https://www.dailymail.co.uk/news/article-8163761/Chinese-markets-selling-bats.html) again started in more than hundreds of animal markets without imposing strict hygienic preventive measures, and this may again be a predisposing factor for recurrence of health ailment due to COVID-19 in China (Anonymous 2020) (https://metrosaga.com/wuhan-virus-chinese-animal-markets-reopened-with-almost-no-precautions/). A bold decision on the future of wild animal trade in China is a necessity to prevent possible future outbreaks due to zoonotic spillover and hence International agencies like WHO, FAO and OIE must frame strict guidelines with regulations and conditional penalties on purchase of food animals in markets for safer future (Blakeman 2020)(https://thehill.com/opinion/international/490528-china-must-close-down-wet-markets-now). A total ban on the wild animal trade will affect the livelihood of a substantial proportion of the population. Hence such a move will only shift the trade of wild animals to the black market (Mallapaty 2020).

The significance of rapid sharing of the technical facts during the COVID-19 outbreak situations in minimizing the panic perpetuation in public was assessed recently by Song and Karako (2020). It was pointed out that scientific data sharing further enriches the epidemiologists, healthcare workers, and forecasting models to comprehend the usefulness of available interferences from new real-time information (Song and Karako 2020). Furthemore, Habibi et al. (2020) emphasized the significance of following International Health Regulations (IHR) measures to defeat the spread of SARS-CoV-2 across the globe (Zhang et al., 2020).

7. Conclusion and future prospects

The live-animal markets, just like the Huanan South China Seafood Market, will continue to act as an ideal point that promotes inter-species contact between the wild and domestic animal species. Hence, the possibility of inter-species transmission of CoV infections at such hot spots is a point of concern to human beings due to the adaptive genetic recombination that occurs in these viruses. The permanent ban on the wild animal trade should not be implemented as it will only shift the trade to the black market. Rather than going for the complete ban, it is better to regulate the trade of wild animal species all around the country. The emergence of newer zoonotic infections like SARS-CoV-2 is inevitable in the future. Hence, local and international regulatory authorities need to develop and implement robust disease control mechanisms that effectively decrease the possibility of human exposure to wild animals. The SARS-CoV-2 outbreak is just another critical example that proves the existence of a close but straightforward interaction between humans, animals, and the environmental health that can potentially result in the emergence of a deadly pandemic. The past decades have shown us the destructive potential of several zoonotic coronavirus infections like SARS, MERS, and now SARS-CoV-2 that calls for the implementation of One Health as a framework to protect humankind from emerging pathogens soon.

Disclosure statement

All authors declare that there exist no commercial or financial relationships that could, in any way, lead to a potential conflict of interest.