By Tammie Tam, Microbiology ‘22

Author’s Note: Since taking the class One Health Fundamentals (PMI 129Y), I have been acutely aware of this One Health idea that the health of humankind is deeply intertwined with the health of animals and our planet. This COVID-19 pandemic has been a perfect model as a One Health issue. Through this article, I hope to introduce readers to a fuller perspective of COVID-19 as a zoonotic disease. 

The COVID-19 pandemic has escalated into a human tragedy, measured daily by an increasing number of infection cases and a piling death toll. Yet, to understand the current and future risks of the SARS-CoV-2 virus, one must account for the virus’s relationship with animals in the context of its zoonotic nature, as the transmission between animals and humans is often overlooked. Uncovering the range of intermediary hosts of the virus may provide clues to the virus’s origin, point to potential reservoirs for a mutating virus, and help inform future public health policies. As a result, a small but growing body of researchers is working to predict and confirm potential human-animal transmission models.

The origin of the SARS-CoV-2

Currently, the World Health Organization (WHO) and other disease detectives are still working to unravel the complete origin of the virus. Scientists have narrowed down the primary animal reservoir for the virus through viral genomic analysis, between strains of human and animal coronaviruses [1]. They suspect bats to be the most likely primary source of the virus because the SARS-CoV-2 strain is a 96.2 percent match for a bat coronavirus, bat-nCoV RaTG13 [1]. Despite the close match, the differences in key surface proteins between the two viruses are distinct enough to suggest that the bat coronavirus had to have undergone mutations through one or more intermediary hosts in order to infect humans [2]. 

To identify potential intermediate hosts, scientists are examining coronaviruses specific to different animal species [1]. If SARS-CoV-2 is genetically similar to another animal-specific coronavirus, SARS-CoV-2 may also possess similar viral proteins to the animal-specific coronaviruses. With similar proteins, similar host-virus interactions can theoretically take place, allowing for SARS-CoV-2 to infect the animal in question. For example, besides bats, a pangolin coronavirus, pangolin-nCoV, has the second highest genetic similarity to SARS-CoV-2, which positions the pangolin as a possible intermediate host [3]. Because of the similarity, viral proteins of the pangolin coronavirus can interact with shared key host proteins in humans just as strongly as in pangolin [4]. However, more epidemiological research is needed to determine whether a pangolin had contracted coronavirus from a human or a human had contracted coronavirus from a pangolin. Alternatively, the intermediate host could have been another animal, but there are still no clear leads [1]. 

What it takes to be a host for SARS-CoV-2

In any viable host, the SARS-CoV-2 virus operates by sneaking past immune defenses, forcing its way into cells, and co-opting the cell’s machinery for viral replication [5]. Along the way, the virus may acquire mutations—some deadly and some harmless. Eventually, the virus has propagated in a high enough quantity to jump from its current host to the next [5].

Most importantly for the virus to infect a host properly, the virus must recognize the entranceway into cells quickly enough before the host immune system catches on to the intruder and mounts an attack [5]. SARS-CoV-2’s key into the cell is through its spike glycoproteins found on the outer envelope of the virus. Once the spike glycoproteins interact with an appropriate angiotensin-converting enzyme 2 (ACE2) receptor found on the host cell surfaces, the virus blocks the regular functions of the ACE2 receptor, such as regulating blood pressure and local inflammation [6,7]. At the same time, the interaction triggers the cell to take in the virus [5]. 

Since the gene encoding for the ACE2 receptor is relatively similar among humans, the virus can travel and infect the human population easily. Likewise, most animals closely related to humans like great apes possess a similar ACE2 receptor in terms of structure and function, which allows SARS-CoV-2 a path to hijack the cells of certain non-human animals [8]. Despite the overall similar structure and function, the ACE2 receptor varies between animal species at key interaction sites with the spike glycoproteins due to natural mutations that are kept to make the ACE2 receptor the most efficient in the respective animal. Thus, while there are other proteins involved in viral entry into the host cells, the ACE2 receptor is the one that varies between animals and most likely modulates susceptibility to COVID-19 [9]. 

As a result, scientists are particularly interested in the binding of the ACE2 receptor with the viral spike glycoprotein because of its implications for an organism’s susceptibility to COVID-19. Dr. Xuesen Zhao and their team from Capital Medical University examined the sequence identities and interaction patterns of the binding site between ACE2 receptors of different animals and the spike glycoproteins of the SARS-CoV-2 [10]. They reasoned that the more similar the ACE2 receptor of an animal is to humans, the more likely the virus could infect the animal. For example, they found ACE2 receptors of rhesus monkeys, a closely related primate, had similar interaction patterns as humans [10]. Meanwhile, they found rats and mice to have dissimilar ACE2 receptors and poor viral entry [10].

While entrance into the cell is a major part of infection, there are other factors to also consider, such as the ability for viral replication to subsequently take place [11]. With so many different organisms on the planet, the models simply provide a direction for where to look next. SARS-CoV-2 is unable to replicate efficiently in certain animals despite having the entrance key to get in. For example, the virus is able to replicate well in ferrets and cats, making them susceptible to the virus [12]. In dogs, the virus can only weakly replicate. Meanwhile in pigs, chickens, and ducks, the virus is unable to replicate [12]. Outside of the laboratory, confirmed cases in animals include farm animals such as minks; zoo animals such as gorillas, tigers, lions, and snow leopards; and domestic animals such as cats and dogs [13].

The future for SARS-CoV-2

Due to the multitude of intermediary hosts, COVID-19 is unlikely to disappear for good even if every person is vaccinated [14]. Viral spillover from human to animal can spill back to humans. Often, as the virus travels through a new animal population, the virus population will be subjected to slightly different pressures and selected for mutations that will confer a favorable advantage for virus survival and transmission within the current host population [15]. Sometimes, this could make the virus weaker in humans. However, there are times when the virus becomes more virulent and dangerous to humans if it spills back over from the animal reservoir [15]. Consequently, it is important to understand the full range of hosts in order to put in place preventative measures against viral spillover. 

As of now, most of the known susceptible animals usually do not get severely sick with some known exceptions like minks [1]. Nevertheless, people must take precautions when interacting with animals, since research into this area is still developing and there are many unknown factors involved. This is especially important for endangered species to not become sick, because they already face other threats that make them vulnerable to extinction [8]. As a result, some researchers are taking it into their own hands to keep certain animals safe. For example, after the San Diego Zoo’s resident gorillas contracted COVID-19 in January, the zoo proactively began using the experimental Zoetis vaccine to vaccinate their orangutans and bonobos, which are great apes that are considered closely related to humans and susceptible to COVID-19 [16]. Due to an assumed COVID-19 immunity in the gorillas and a limited supply of the Zoetis vaccines, they decided to not vaccinate the gorillas [16]. Now, scientists are trying to modify the Zoetis vaccine for minks, because minks are very susceptible to severe symptoms from COVID-19 and have shown to be able to transmit the virus back to humans [17]. 

Besides the virus mutating into different variants through basic genetic mutations, people must be cautious of potential new coronaviruses which can infect humans [18]. The human population has encountered other novel coronaviruses over the past several years, so it is not out of the question. In animals, if two coronaviruses of a human and an animal infect the same animal host, it could cause a recombination event and create a new hybrid coronavirus [19]. 

For the SARS-CoV-2 virus, Dr. Maya Wardeh and their team at the University of Liverpool found over 100 possible host species where recombination events could take place [18]. These hosts are animals who can contract two or more coronaviruses with one of them being the SARS-CoV-2 virus. For instance, the lesser Asiatic yellow bat, a well-known host of several coronaviruses, is predicted to be one of these recombination hosts [18]. Also, species closer to home such as the domestic cat is another possible recombination host [18]. While it will take many different rare events, from co-infection to human interaction with the particular animal for recombination to be possible, scientists are on the lookout.

Even without a full picture, the Center for Disease Control (CDC) understands the potential risks of animal reservoirs and advises COVID-19-infected patients to stay away from animals—wildlife or domestic—to prevent spillover [20]. COVID-19 has also brought to light zoonotic disease risks from illegal animal trades and wet markets. Once research into the human-animal transmission model becomes more well-developed, public health officials will have a clearer picture as to how the pandemic spiraled to its current state and help develop policies to prevent it from happening again. 

References: 

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