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  • Writer's pictureP.K. Peterson

SARS-CoV-2 Reservoirs Are Filling Fast: Spillovers and Spillbacks

“Even if you have an efficient vaccine program and eradicate [the coronavirus] in humans, which is difficult enough, if it’s continuing in wildlife that will be a problem.”

- W. Ian Lipkin, M.D., director, Columbia University Center for Infection and Immunity

“Swift action is necessary to effectively combat the COVID-19 pandemic, prevent the loss of human life, and the spread of disease to wild animals.”

- Utah Animal Rights Commission

In an article in the March 2021 issue of Nature News “The search for animals harbouring coronavirus—and why it matters,” Smitri Mallapathy reported “[S]cientists are monitoring pets, livestock, and wildlife to determine where SARS-CoV-2 could hide, and whether it could resurge from such an animal reservoir.” The goal of this Germ Gems post is to provide an update on animals in which SARS-CoV-2 is now found.

Zoonoses and reverse zoonoses (anthroponoses). Regular readers of Germ Gems know that the transmission of pathogens from animals to humans (called zoonoses) played a pivotal role in 60% or more of “emerging infectious diseases”—the 140 or more infections that cropped up in humans over the past 50 years. The most notable of these zoonotic “spillovers” are HIV/AIDS, pandemic influenza, Ebola virus, Zika virus, and in the 21st century, the coronaviruses that cause severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), and most recently, COVID-19.

Although bats are considered the primary animal source of all three of the emerging coronavirus infections, intermediary animal species can also harbor these viruses from which they can spillover to humans. In so doing, these animals serve as viral reservoirs. Perhaps the best example of the importance of a reservoir animal is the civet. Early on in the SARS pandemic, infected civets were sold in wildlife markets in China as these small cat-like mammals are considered a culinary delicacy by some people. The SARS pandemic was relatively short-lived (2002-2004), however, ending rather abruptly after the culling of civets from wildlife markets.

Original sin: the animal spillover that ignited COVID-19. The hunt for the animal origin of COVID-19 is ongoing and thorny. Sparked by controversy about a “natural” origin (for example, a spillover from an infected horseshoe bat) versus a virus engineered in the Wuhan Institute of Virology that “leaked” into the community, the World Health Organization is poised once again to send another team of scientists and public health experts to Wuhan, China, the epicenter of COVID-19, to determine its origin.

Shortly after the COVID-19 pandemic erupted in Wuhan in December 2019, one of the wildlife or so-called “wet” markets—the Hunan Seafood Wholesale Market—was incriminated as the point source of the pandemic. Soon thereafter, this idea was discredited. But a publication in Science on November 18, 2021, “Dissecting the early COVID-19 cases in Wuhan,” revived the hypothesis. This recent report also changed the chronology of COVID-19 by concluding that the first patient to fall ill was a female seafood vendor at this market.

While this recent Science article keeps alive the intense interest in how COVID-19 got its start, it doesn’t shed light on which animal species was involved in the initial spillover event. While most bets are on the Chinese horseshoe bat, nobody has nailed this down. Thus, the search for a putative animal reservoir continues (initially pangolins, a docile scaly mammal that some people dine on, were a major contender).

The promiscuous nature of SARS-CoV-2. To understand how SARS-CoV-2 operates as a pathogen it’s useful to know something about tropism—one of the fundamental principles of microbiology. In the case of viruses, a given virus can productively infect particular types of cells (cellular tropism) found in particular host species (host tropism). A good example of a very successful human pathogen is HIV. HIV’s cellular tropism is very limited: it can only infect lymphocytes or macrophages that possess CD4 receptors and a co-receptor, CXCR5 or CXCR4, on their surface. Its species tropism is also very narrow, that is, HIV can only infect Homo sapiens—it has zero interest in any other animal species.

ACE2 is the cellular receptor for the spike protein of SARS-CoV-2. ACE2 receptors are present in arterial and venous endothelial cells and arterial smooth muscle cells in all organs. ACE2 receptors are also abundantly present in the epithelial cells of the lung and small intestine. Thus, SARS-CoV-2 is provided entry into diverse cell types. With this kind of broad cell tropism, it is not surprising that this virus inflicts damage in a wide variety of organs.

Similar to its broad cell tropism, SARS-CoV-2 is now known to be capable of infecting a large number of animal species. At the start of the COVID-19 pandemic, the only animal that was known to be infected with SARS-CoV-2 was Homo sapiens. Similar, but not identical, coronaviruses were found in Chinese horseshoe bats, but animal reservoir(s) were unknown. Subsequently, numerous veterinary medicine experts and environmental biologists combed through a variety of animal enclaves in search of SARS-CoV-2.

Early-on in the hunt, pets and zoo animals, including dogs, cats, tigers, and lions were found to be susceptible to SARS-CoV-2 infection. Recently, three snow leopards at the Children’s Zoo in Lincoln, Nebraska were added to the list of SARS-CoV-2 casualties. So far, studies have identified a range of other animals—such as, ferrets, hamsters, non-human primates, mink, tree shrews, raccoon dogs, fruit bats, rabbits, and white-tailed deer— that are susceptible and permissive to SARS-CoV-2 infection. In most, if not all, instances the infections in these animals originated in humans and spilled into them from us—they are instances of reverse zoonoses or anthroponoses. This is the reason some experts strongly advise those infected with SARS‑CoV‑2 to restrict contact with animals.

Underscoring the broad species tropism (or promiscuity) of SARS-CoV-2, in a November 17 article in the Proceedings of the Royal Society of Biology, “AI predicts which mammals are most likely to spread covid-19,” researchers describe an Artificial Intelligence tool to predict which of 540 mammalian species are most likely to spread SARS-CoV-2. In addition to Sunda pangolins, mink and white-tailed deer were among the most concerning animal reservoirs. In 2020, mink farms in the Netherlands and Denmark were scuttled because of COVID-19 outbreaks. In the U.S., the first farmed mink with SARS-CoV-2 infection were identified in Utah in August, 2020, and, according to the U.S. Department of Agriculture, outbreaks have since occurred at 16 mink farms.

Although white-tailed deer only recently were added to the species watch list as a potential animal reservoir for SARS-CoV-2, they are perhaps most worrisome. In a November 10 article in NPR’s Goats and Soda, “How SARS-CoV2 in American deer could alter the course of the global pandemic,” Dr. Michaeleen Doucleff points out that a recent survey of white-tailed deer in the Northeast and Midwest found that 40% of them had antibodies against SARS-CoV-2. According to Dr. Vivek Kapur, a veterinary microbiologist at Penn State University, the genomic sequences of viral isolates from lymph nodes of the deer suggest that during the pandemic, deer have caught the virus from people multiple times. His view is, “The data are very consistent again with frequent spillover events from humans into deer and then transmission among the animals.”

What we’re learning from animal spillovers. In this Germ Gems post, I’ve barely scratched the surface of what virologists and environmental biologists are discovering about the intimate intersection of human and wildlife biology. Personally, I find the epidemiology of SARS-CoV-2 infections in animals (the ebb and flow, aka surges) just as mysterious and difficult to comprehend as is the epidemiology of the COVID-19 pandemic in humans.

It appears that there’s plenty more trouble and puzzlement to come. We’re told by the virologists that there are an estimated 1.7 million kinds of viruses that exist in mammals and birds, and that nearly half of them could potentially follow the deadly trajectory of SARS-CoV-2, meaning they could jump from animals to humans and kick off another pandemic. In response to this piece of alarming news, all I can say is: Yikes!

I find the perspective of wildlife ecologist Dr. Raina Plowright at Montana State University particularly insightful. She focuses on disease dynamics between humans and animal populations. According to Professor Plowright, “What I like is that [we’re] thinking very broadly about the risk factors, in particular the stresses on the ecosystem where the reservoir host resides and the potential interaction that humans have with these hosts. We’re intruding into the last wild spaces and coming into contact with wildlife and taking away key resources that animals need to survive.” Let’s hope we can learn, in time, from these animals how to better treat not only other members of our own young, often obtrusive species, but also the myriad number of wildlife species. Our lives may well depend upon it.

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Main Page images courtesy of Shuxian Hu, MD. Dr. Hu is a scientist in the Neuroimmunology Research Laboratory at the University of Minnesota.

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