This article is part of an ongoing collaboration between the Colorado School of Public Health, the Denver Museum of Nature & Science, and the Institute for Science & Policy. Watch the full recording of this session and find all of our previous COVID-19 webinars and recaps here.

COVID-19 isn’t the first virus to make the leap from animals to humans, and if history is any guide, it won’t be the last. Novel zoonotic diseases can persist benignly inside an animal host for years, waiting patiently for an opportunity to jump to a new species and wreak havoc. We’ve seen other high-profile examples of these “spillover” events in recent decades, notably AIDS, Ebola, and SARS. Scientists have been working to better understand these transmission pathways in order to warn of new emerging threats. But there is still much to learn. Which conditions allow an animal-borne virus like COVID-19 to take hold in human populations? And what have researchers learned that might help us prevent future global outbreaks?

The Institute’s Senior Policy Advisor Kristan Uhlenbrock recently chatted with Brian Foy, PhD, and Tony Schountz, PhD ─ both Professors in the Department of Microbiology, Immunology, and Pathology at Colorado State University ─ to discuss the science behind animal-to-human transmission and how COVID-19 has played out thus far.

KRISTAN UHLENBROCK: Good morning to you both. Dr. Foy, could you give us an overview of zoonotic diseases and the concept of spillover?

DR. BRIAN FOY: Good morning, and thanks to the Denver Museum of Nature & Science, ISP, and the Colorado School of Public Health for inviting me to be here today.

Zoonotic diseases are pathogens spread between animals and people. It’s important to note that transmission can go both ways: Animals can spread things to us and we can spread things back to animals. And of course, that's because we are animals too and we have evolved to depend on many non-human animals. We can’t just get rid of a certain animal species that is spreading a pathogen because animals provide many benefits to us. We're all part of one planet. Bats, for example, are thought of as the “farmers of the tropics” because they fertilize plants and are really good at seed dispersal. So even though you might think of bats as scary, they're not. They're really helpful to humans.

Nonetheless, more than six out of 10 known infectious diseases can spread from animals to humans including about three out of every four new emerging diseases. This is probably an underestimate. I work on malaria that's transmitted via plasmodium and that parasite has adapted to humans over thousands of years even if the original spillover event probably happened from primates hundreds of thousands of years ago and since then it's just simply adapted to humans specifically. Most, if not all infectious diseases probably have their origins from other animals.

Wild animals are constantly sharing zoonotic pathogens, and spillovers happen even amongst themselves. For example, maybe a monkey catches a rat and eats it and you might have a pathogen that spreads from that rat to the monkey. But we don't see these events. Maybe it causes a disease in the monkey population, but we don't see that because it happens out in the wild. Every once in a while, these eventually spill over into humans. Most often, they first spill over into a domestic animal reservoir that’s kept close to human populations – those used for agriculture or kept as pets like camels, cows, or chickens. In some cases, the vector interacts with the domestic animal and you get amplification only within the animal population. In other cases, the domestic animal infects humans and you get amplification in the human population.

There are few ways we can deal with these types of events. The first is forecasting readiness. This involves monitoring animal populations in the wild and seeing if we are encroaching onto that animal or they are encroaching on us. Early surveillance efforts, if they're funded well, can help us track infections to see how often a spillover might occur or is already occurring and is just in the early phase of outbreak and epidemic before it reaches pandemic proportions. We should also have control operations ready to go, which includes everything from vaccines that are very broad to target many different viruses to therapeutics to control tools for controlling vectors. And then finally, a rapid response that includes public health measures to help flatten the curve of any outbreak.

We’ve been seeing an increasing number of these pathogens over the last several decades. HIV. Mad cow disease. SARS. A disproportionate number of these emerging zoonotic pathogens are viral species and there's many reasons for that, the main one being that viruses are incredibly diverse and incredibly numerous. There has been good research on microbial and viral adaptation. We can think of adaptation in four stages: the exposure of a new animal species to the zoonotic pathogen; the infection that ensues; the spread from the initial patient zero; and ultimately the adaptation of the microbe to many people as it spreads. It’s always that linear, either.

As humans, we're more closely related to rabbits and rodents than we are, for example, to marsupials. Rodents are extremely numerous in terms of species, as are bats. The likelihood of spillover has to do in part with our mammalian relatives, but also with which species we’re interacting with most frequently. That's why we see a lot of these zoonotic pathogens in fact, as rodent-borne. They're very overlapping with us in ecology. Same goes for bats, especially in tropical areas and dense tropical cities like Rio de Janeiro.

This also affects the ease in which a pathogen can spread from a donor species. You can have a very steep fitness valley, meaning that it is hard for that pathogen to jump from the donor to the recipient because we are so different (for example, from a marsupial). But coming over from a rabbit, maybe it has an easier time replicating in humans because we’re more closely related. That would be considered a shallow valley.

We can also think about spread in terms of microbial application and change. Certain strains can spread much easier out amongst people because of their pathology in certain cells. We can compare two different strains of influenza, H1N1 and H5N1. H1N1 has a predilection for cells in our upper respiratory tract. This means that it’s not as fatal as H5N1 because it's not really affecting those deep lung tissues. But it is much easier to spread via coughs and sneezes. So H1N1 can be spread around much more quickly than H5N1, even though the latter is more fatal. Unfortunately, COVID-19 is probably a good combination of both of these traits.

I want to touch on a few points about mutation as well as re-assortment and recombination. Viruses are quasi species; they replicate like crazy and they don't have good proofreading mechanisms when they replicate their genetic material. (Humans have very good proofreading.) Fast replication and poor proofreading leads to rapid mutation, and we see this already in the coronavirus genome, which has allowed it to become more efficient within cells. But viruses also undergo reassortment and recombination. Reassortment is very common and we see it in influenza, which is why we have to have a new vaccine every year. The segments can reshuffle like cards in a deck, giving you a completely different strain. We can also have recombination, where a splicing event can occur to put parts of two different viruses together. There is already evidence of this with COVID-19.

Many complicated factors drive the emergence of zoonotic pathogens, but climate change is certainly important. It’s a bit complicated, because while things are getting warmer all across the globe, it's also predicted that some places will become wetter and others drier. Some pathogens thrive in dryness, some pathogens thrive in moisture. And so, the pathogens that arise over time because of climate change will really depend on the type of virus and where they happen to emerge.

International travel and commerce cannot be underestimated. We have been running across the globe, for many hundreds of years now, but it has really taken off even since the 1980s. Human populations are so much more mobile and they're becoming wealthier. Earlier, flights were the realm of rich people. Now, many middle class people can take flights, and a lot of people in poor areas can even jump on a motorbike to travel long distances. Diseases spread through vectors are most often transmitted by just travel and introducing either the mosquito or tick into new places. We think this is probably what happened with West Nile virus introduction to the United States in 2001 and probably why the Zika virus had a large pandemic in 2016.

Commerce has also been a big driver of the spread of zoonotic diseases. Wet markets, where exotic wild animals are first kept and then later slaughtered in open air markets, seemed to act as at least an amplification if not an introduction into very large human populations in large cities in China. There are also agricultural practices that can drive the spread. For example, think about a pig sty underneath a fruit tree. Bats, who are natural reservoirs with these viruses, would be eating the fruit above the pigs and salivating into that fruit. Maybe that fruit drops and then the pigs eat it and become infected. Ultimately, that spreads to the human farmers and you’ve got an outbreak on your hands.

KU: Thank you, Brian. Dr. Schountz, could you take it from there and give us a sense of your research focus areas?

TONY SCHOUNTZ: Good morning, and thanks for having me. I’ll try to build on what Brian said here. He primarily studies mosquito borne diseases and those are really important terms of global health. My history has been primarily with deer mice and hantaviruses, as well as bats and their status as reservoir hosts.

So far, there have been thousands of viruses detected in bats. I want to emphasize that the great majority of these viruses are likely incapable of causing disease in humans. But like any statistically unlikely event, if you do something enough times, it becomes statistically likely. And so, considering that we know of thousands of viruses in bats and probably thousands or tens of thousands more that we don't know about, then this is going to be an ongoing and persistent threat to human health in the coming decades.

I want to talk a little bit about the viruses and how they reside in their reservoir hosts. If you're a virus and you are completely dependent upon the life of that animal for your own livelihood, then you either have to infect your reservoir without causing disease or simply get out of the house before you cause substantial pathology and jump into the next susceptible animal that can then set up the second round of infection. These are the two strategies that most viruses can take when they're trying to exist in nature. Because viruses are just like all other biological entities: they have to figure out a way to replicate and have their offspring passed on.

In most of these infections, we’ve observed that viruses take the first path. The virus infects the reservoir host and sometimes there is abundant virus replication early on, but then it sort of subsides. The virus can persist for weeks or months or even the lifetime of the animal with periods of where virus re-emerges and gets shed in higher amounts to maintain the lifecycle. Generally speaking, these viruses want to stay in their reservoir hosts. When we want to understand how these viruses behave and how they get into humans, you have to understand the ecology and biology of viruses. You can't just study the virus. You have to study the reservoir, and unfortunately, most laboratory scientists never set foot on the field. They spent their entire careers in a laboratory wearing a coat or a biosafety suit. And then you can’t really understand the biology and ecology of these viruses in the context of the rest of our species.

We're all interested in bats right now because of the viruses that they carry. Most rabies cases in the United States now are from bats, and that's not because bats are suddenly more important. It's because we've gotten rabies in dogs and cats under control, as well as in skunks and raccoons to such a great extent that there are very few cases that come from those animals. The mumps virus that we vaccinate our children is probably a bat virus, and that now makes us rethink the chances of us ever eradicating that virus. If you want to eradicate a virus by vaccination, as we did with smallpox for example, then that virus should only infect humans. But you could eliminate it in people and still have a future event where it spills back over and starts over again.

The biggest issue for many of us is that these viruses either require biosafety level three or biosafety level four containment. Those are the two highest levels. Here at CSU, we have BSL3 containment, but we don't have BSL4 containment. So we can't work with Nipah virus or Hendra virus or the Ebola viruses, but we can work on all of the coronaviruses. If you saw the movie Contagion, the virus depicted there was the Nipah virus that had undergone a recombination event with an influenza virus and created a hybrid. I’d Most of the movies that we see today are really disappointing to me as a scientist, because I know it's mostly BS, but that movie, in particular was actually pretty good in terms of the fidelity to the science.

A note on field work: it has a number of challenges and we have to take precautions. I have a custom-built biosafety cabinet that I can plug into the cigarette lighter of a truck and it runs an electric motor that pulls air in through sterile filters, allowing me to work in a sterile environment that also protects me from exposure to any virus during sample processing. If you're going to go into a cave that's loaded with bats, you have to have all this personal protective equipment including a face covering, leather gloves, and a respirator to filter the air (because who knows what viruses are floating around in there). When you're in a cave, you want to wear a hard hat so that you don’t bang your head and introduce a cut that could lead to infection. It’s completely dark in there. If your headlamp fails, you can't see where you are and you will not find your way out unless you happen also bring a lifeline that you can grab a hold of and follow back out.

It’s pretty clear that most if not all coronaviruses originated in bats. As I mentioned earlier, there have been thousands of viruses that have detected in bats and more than 1000 of those are coronaviruses. There are probably thousands more that we don't know about, and there are 1,200 species of bats in the world. That’s second among mammals only to rodents, which have about 2,200 species. And so as Brian pointed out, we’re really interested in bat simply because of their high density and because bats exhibit peridomestic behavior, which is to say that they don't really have a problem coming into your house or near your house or on your property. When they do, they're usually looking for food. Sometimes they'll build nests. If they have viruses, they'll bring those viruses with them, and that then puts you at exposure risk.

Prior to the last 20 years, the generic coronavirus was really only known for causing mild colds in humans, maybe occasionally serious disease for people who had compromised immunity. Generally speaking, they were rather innocuous infections. Then in 2002, we had the first outbreak of SARS. And it went away within a year. The reason it went away is because it doesn't transmit very efficiently person to person. But more importantly, people show signs of disease before they start shedding the virus and then it's easier to quarantine those people until they get better.

That’s not what happened with Middle East Respiratory Syndrome (MERS), which emerged in 2012. That virus hasn't gone away. What it's done since is a little bit unusual: it's established itself in what we call a secondary reservoir host. Even though it originated in bats, it now circulates in dromedary camels, mainly in the Middle East. Every year we see outbreaks, always coming from camels and into people, not from bats into people, even though the original transmission event was from a bat.

Today, we have COVID-19, which not only efficiently transmits person to person, but there are a number of people who are totally asymptomatic. They get infected and never show signs while still transmitting the virus. And that's makes it very difficult to control, because those people go about their daily lives. If we could get to 95% of people wearing masks, with six foot distancing, and make sure that that we limit the size of groups, we could probably get this virus under control in a couple of months.

So then the question is, when will the next virus emerge? I don’t know. But we've had three human coronaviruses emerge in the last 20 years. I think it's going to be sooner rather than later. And they're all going to require different strategies for control as well as different types of vaccines and drugs to treat them. China is a much more mobile society today in 2020, than it was in 2010. Human mobility increases the chances of spillover events happening in the future. So, I'm certain that there are going to be many more coronavirus spillover events in the future, unless we take really dramatic steps. It’s going to be a continuing process.

I personally don't think COVID-19 began at the Wuhan market; that was probably an amplification site. There were clearly patients who had antibodies to this virus before the big outbreak from the wet market. It wouldn't surprise me if this virus actually originated in southern China before it made its way to Wuhan, which is more centrally located in China were then started transmission.

KU: We’ll go rapid fire through a few viewer questions. Why do most of these illnesses seem to start in animals before humans, and not vice versa?

BF: Because humans are a single species, and there's thousands and thousands and thousands of other species. They all have their own stuff going on that we don’t even know about. We don't know about all the crazy pangolins out there, for instance, and the various species of pangolins or various species of bats and all their particular viruses. It's just a matter of numbers, really.

KU: What are some of the challenges of dealing with animal-based viruses versus human-based ones, particularly the research involved?

TS: We've done a really good job of controlling most infectious diseases through the use of antibiotics or vaccinations. If you go back to the turn of the 20^th century, only about one in five or one in seven children in New York City survived to adulthood because most of them many would die from infectious diseases such as pertussis, whooping cough, measles, etc. We occasionally see outbreaks that tend to occur because of communities that don’t vaccinate. There's also improved sanitation and hygiene practices. So in the history of humanity, this is a very new thing. We've only been doing it pretty well for about 50 to 100 years now. But as Brian said, there are literally millions of species of animals out there. We're just one of them

One of the single biggest drivers of zoonotic spillover is: did animals encroach in human habitat, or did humans encroach on animal habitat? A hundred years ago, you didn't see all these housing developments up in the mountains of Colorado like you do now. If you look at the Nipah outbreak, the first case was at a site where swine were being kept near bat habitat and that brought the swine into contact with the bat. All of these events conspired to make statistically unlikely events become more likely. We haven’t implemented the policies necessary to put these barriers between wildlife and humans in many parts of the world. Consequently, this is going to be an ongoing and persistent threat. If there are any young people out there who are interested in infectious diseases, I think that's a great career to go in because there's going to be a lot of job security for the coming decades.

KU: What is a drastic step that we could use to help alleviate some of the spread of these viruses?

TS: We need to encourage mask use and get 95% of people to wear them while still maintaining that 6 feet of social distancing, and limiting the size of groups. It’s not just about space, it's also about time. I have some of my students come in during the day and others come in during the evening. So we separate them through time, not just physical distance.

BF: It’s a multi-factor process, including the steps Tony mentioned and keeping wild areas wild. That doesn't mean we can’t visit them, because we need to visit them to develop the capacity to understand how beautiful and important sustainable wild places are for human societies. But we need to allow them to grow and develop and not encroach so much. We also probably need to put in some policy changes on some very specific habits. Wet markets are probably not the greatest thing to have, where you're slaughtering a wild animal that's on top of cages of other wild animals. China had already talked about getting rid of them, and they’re common in many other areas. Those probably should be avoided.

And then lastly, we really need to develop modeling and probably surveillance efforts amongst wild and domesticated animals to watch for these spillovers outbreaks so that we can prepare to intervene and stop them before spillover turns into an epidemic. We should certainly continue to develop our public health measures so that we're ready to go with contact tracing and quarantines. The bio bio-pharmaceutical industry can make broad-based vaccines that can target broad classes of coronaviruses that we can quickly pull out of the freezer. Even if they're not perfectly adapted to that one weird coronavirus, they might be good enough to really cut down the spread of the disease.

Lightning Round: Even More Questions from Viewers

Is there any reason to think that humans would eventually evolve to peaceful co-existence with something like COVID-19 (i.e. no pathology, like in bats), or is the evolutionary timeframe far too long on something like that?

BF: Not likely. We have had viruses with us for a VERY long time following their suspected spillover in the ancient past and they still can cause serious disease and death. Measles is hypothesized to have evolved from an ancestor of the Rinderpest virus that spilled over into human from animals between 8,000 and 9,000 years ago, yet measles can still kill.

Are there any particularly encouraging research pathways that could help us manage zoonotic viruses, like biosurveillance?

BF: Biosurveillance is simply the regular sampling and testing the blood/tissues of wild animals in suspected spillover hot spots around the globe regularly, and the blood tissues from domesticated animals and people who live at the interface of wild land (e.g. villages on the outskirts of forests, jungles, or savanna lands).  It is designed to detect and hopefully stop spillovers or localized outbreaks of viruses and other pathogens before they turn into epidemics and pandemics.  It should pair with health information system reports from the same areas to identify what local animals and people are becoming sick from.  This is particularly valuable research pathway that is underfunded, but works. 

One extremely valuable health information system we all use in this field is a surprisingly fast and effective outbreak/disease notification service is called PromedMAIL.org. Physicians, healthworkers and scientists around the globe simply post on suspected outbreaks, whether caused by a known or unknown, pathogen, and scientists discuss these on the post and plan control and research efforts.  One can read the first ever post about COVID-19 outside of China to the scientific world on PromedMAIL. This was machine translated from Chinese of an internet post from the Medical Administration in Wuhan about 4 unexplained pneumonia cases who were connected to the Wuhan South China Seafood market.

Biosurveillance in Wuhan or in Yunnan villages, for example, might allow us to get even earlier detections of spillovers/outbreaks before we hear about them from information services like PromedMAIL. A really cool and less intrusive biosurveillance method we’ve been developing for a while here at CSU is to test the blood meals of captured resting mosquitoes for viruses and other pathogens. We can suck these up from the outdoors or in peoples’ homes, and detect viruses in the blood meal that came from the host which was recently bitten by the mosquito.

Once a virus makes the leap to humans, does the next strain evolve from other humans, from animals, or from both?

TS: Yes, yes and yes (again, depending on the virus, but probably true for coronaviruses).

BF: All three. But the one that we care should most worry about is probably the one evolving from humans, because the spillover events from the animal reservoir are statistically unlikely, but the one evolving in humans is already being circulated among us.