From the bubonic plague to the COVID-19 pandemic, humans are vulnerable to a host of invaders that can jump ship from their original host species. Viruses do so by either acquiring new mutations or swapping genetic material with another virus, which enables them to enter human cells, evade immune surveillance, and cause an infection. With rapid globalization and habitat loss forcing closer human-wildlife interactions, understanding zoonic viral transfer is increasingly pertinent.
Explore this Explainer Article from Drug Discovery News to learn how viruses are transmitted from one species to another.
Bats, pigs, and pangolins – oh my! The COVID-19 pandemic highlighted the consequences of viral spillover from animals, but it is not the first time in history that an animal virus has spurred disease in humans.
BY TIFFANY GARBUTT, PHD, ILLUSTRATIONS BY KRISTYN REID
The ongoing pandemic connected the human race across disparate regions of the world in a unified fight against a common pathological enemy. But the COVID-19 pandemic did more than highlight human similarities. It placed humans in the context of the environment as a species much like any other with biological vulnerabilities to lurking pathogens that can mutate and migrate among many different host systems.
How common is it for viruses to move from animals to humans?
Humans do not exist within a bubble, but coexist with numerous other species, from the largest mammal to the tiniest flea. Interspersed among these large-scale interactions are even smaller, less appreciated run-ins with the pathogens that call each species home. These microscale exchanges result in the spillover of bacteria, viruses, and other microorganisms. Pathogen spillover from one species to another only occasionally results in measurable illness and rarely causes a full-blown pandemic.
The World Health Organization classifies any infection that jumps from animals to humans as a zoonotic disease (1). Various types of animal-borne pathogens cause zoonotic diseases. The bubonic plague that spread across Europe in the 1300s resulted from the transfer of Yersinia pestis bacteria from a flea bite. While the transfer of zoonotic bacteria continues to pose a threat, many modern-day zoonotic diseases result from the transfer of viruses. Mosquito bites can readily transfer Dengue virus, Zika virus, Chikungunya virus, yellow fever, and more. However, even a common dog or cat can transfer rabies or other zoonotic viruses. Researchers estimate that the human immunodeficiency virus (HIV) made its way to humans in the late 1800s when humans hunted chimpanzees for meat and came in contact with contaminated chimpanzee blood (2). Numerous flu strains derive from birds, and the 2009 H1N1 pandemic, commonly known as the swine flu, was caused by the transfer of a novel influenza strain from pigs to humans (3). Lastly, an assortment of pathogens, from the virus that causes the common cold to the novel SARS-CoV-2 virus, which is responsible for the COVID-19 pandemic, originate in bat hosts (4).
With so many examples of zoonosis throughout history, it would seem that the transfer of animal pathogens to humans is a common occurrence. In reality, zoonotic diseases are extraordinarily rare. Experts estimate that mammals and birds house as many as 1.67 million unknown viruses (5). In contrast, scientists estimate that only 219 animal-borne viruses have infected humans throughout history. This suggests that only 0.1% of animal viruses have caused known infections in humans (6).
Do animals carry more viruses than humans?
Despite the rare occurrence of zoonotic viral transfer, some species seem to be a treasure trove of new pathogens. Bats, in particular, have been the source of numerous zoonotic diseases including Ebola virus disease, MERS, SARS-CoV, SARS-CoV-2, and common cold coronaviruses. Researchers estimate that every bat species may host as many as 17 undiscovered pathogens with zoonotic potential. Rodents may host as many as ten undiscovered pathogens with the potential to move into humans per species (7).
A key variable in the ability of some animals to host numerous pathogens is its number of species members. The bat order is so large that approximately one in five mammalian species is a bat (8). The number of different species with overlapping genetic similarities allows more opportunities for viruses to jump from species to species, acquiring new mutations along the way. A wide breadth of species also means that bats may exist in a variety of habitats (7). Rivaling bats are birds, where numerous species live in many different locales. Similar to bats, birds such as ducks, geese, terns, and gulls are a reservoir for every known strain of the influenza virus (9).
For this reason, some scientists argue that bats are no more unique in their ability to host a wide breadth of pathogens than other species-rich animals (10). However, in a study recently published in Nature, researchers analyzed 188 known zoonotic viruses among humans and mammals and found that even after accounting for factors that increase zoonotic viral load, bats indeed host a significantly higher proportion of zoonotic pathogens than other mammals (7).
With all of those viruses, how do bats avoid becoming sick? Bats possess unique immune systems that balance enhanced host defense responses and immune tolerance. They constitutively express type I interferons (IFN) and IFN-stimulated genes. Increased autophagy also helps bats rapidly clear pathogens. These enhanced host defense responses are counterbalanced with suppressed inflammasome pathways that contribute to extraordinary immune plasticity (11).
What makes a virus species-specific?
Pathogens tend to stick within the host animal that they call home. Genetic similarity plays a key role in the transfer of pathogens from one species to the next. Numerous viruses can easily move between different bat species, which share common underlying genetic features. Similarly, viruses in chimpanzees are more likely to spread among other primate species, including humans (12).
The underlying molecular reason for this specificity is that viruses have evolved to preferentially bind to surface molecules on host cells called viral receptors. Most viruses are decorated with surface proteins that preferentially target specific cells within the host species (12). For example, much like SARSCoV-2, influenza is adorned with spike proteins that protrude from the surface of the virus. Influenza uses its own viral spike protein called hemagglutinin (H) to bind to cells in the upper respiratory tract. However, it specifically targets host cells with sialic acid residues — sugar chains attached to the ends of proteins and lipids (9). Different animals possess different sialic acids with different types of linkages that dictate the ability of viruses to infect cells in their respective host species (9).
The host, however, isn’t always an innocent bystander. Host proteases cut and modify parts of viral proteins, altering how the virus binds to host cells. SARS-CoV-2 gains access to host cells via the angiotensin converting enzyme 2 (ACE2) receptor, which would not be possible without the help of two host proteases. The host proteins furin and transmembrane serine protease 2 (TMPRSS2) cut the SARS-CoV-2 spike protein. These cuts alter the amino acid sequence and change the conformation of the SARS-CoV-2 spike protein, making it easier to bind human cells (13, 14). Recent studies suggest that other host-cell mediators may also increase infectivity and aid in SARS-CoV-2 viral entry (15).
How do viruses move between unrelated species?
Selective pressures within a host species lay the groundwork for viruses to acquire new mutations and break free of the genetic confines that limit them to only one animal host. Researchers have long observed a molecular duel between coronaviruses and bats, which serve as the host for many different types of coronaviruses. The original SARS-CoV virus responsible for the 2002 SARS epidemic also originated in bats. Similar to SARS-CoV-2, SARSCoV uses spike proteins to target and bind the ACE2 receptor in host cells. In a recent study, researchers analyzed the interplay between coronaviruses and their bat hosts and found that bats carried many different versions of the ACE2 receptor (16).
Evolutionary pressure from carrying multiple coronaviruses causes the ACE2 receptor in bats to more readily acquire new mutations, resulting in different amino acid combinations that directly affect the binding of spike proteins. In turn, adaptations to the ACE2 receptor in bats place evolutionary pressure on coronaviruses to acquire new spike protein mutations that better facilitate their entry into host cells (16).
While some mutations acquired in initial host species can cause zoonotic diseases, often viral mutations are enhanced by genetic mixing in intermediate host animals. For example, the H1N1 flu virus, commonly called the swine flu, originated in birds. Birds and pigs have the same type of sialic acids on the cells of their tracheae, which allowed the virus to transfer easily from bird hosts to pig hosts. A portion of pig cells also carry a type of sialic acid found in human cells. Thus, pigs served as the ideal mixing vessel for the adaptation of a novel bird-influenza strain to infect human cells (17).
Intermediate animal hosts allow viruses from two different species to interact. In some cases, these viruses may swap segments of genetic material through recombination or reassortment. Both cases produce a new viral strain with the potential to infect cells in a new host species (18). Scientists suspect that SARS-CoV-2 has a similar origin story. Recent studies suggest that SARS-CoV-2 originated in bats and moved into an intermediate animal host, most likely the pangolin, where it acquired new mutations before transferring to humans (19).
What is the immune system’s role in preventing viral jumps?
Entering host cells is only half the battle. Once inside host cells, viruses must traverse a hostile environment where immune defenses lurk behind every corner, ready to eliminate pathogenic threats. The ability of zoonotic viruses to evade host immune responses determines their success in a new host species. Coronaviruses, including SARS-CoV-2, have evolved several strategies for disabling the innate immune response of host cells.
When a virus enters a cell, the host cell temporarily wraps it in an endosome. Viral genomic RNA is then released into the cytoplasm. Both endosomes and naked RNA act as pathogen associated molecular patterns (PAMPs) that signal to host cells that a pathogenic invasion is underway. Recognition pathways activate downstream signaling cascades that stimulate the host’s innate immune system (20).
Coronaviruses, however, have evolved to outsmart the immune system. Upon entry into host cells, coronaviruses immediately interfere with endosome and RNA sensing mechanisms. SARSCoV does this by stimulating the degradation of RNA senor molecules. MERSCoV suppresses RNA sensor molecules via repressive histone modifications (20). In a recent study, researchers discovered that SARS-CoV-2 hijacks a host enzyme and uses it to add methyl groups to SARS-CoV-2 viral RNA to shield it from being recognized by host RNA sensors (21).
Coronaviruses also take a more proactive approach to ensure their successful viral replication. Once they release their genetic material into the cytoplasm, built-in viral machinery immediately translates two large open reading frames that are processed into non-structural proteins (NSPs). These NSPs form a double-membrane complex where the virus can replicate and form double-stranded RNA copies of itself without triggering the host immune response (22).
To further ensure their success, coronaviruses also release viral proteins that obstruct ribosomal messenger RNA (mRNA) entry, block nuclear export and splicing of newly made mRNA, and compromise the export of cellular proteins. Altogether, this hinders the production of newly synthesized immune related mRNAs (20, 22).
Cumulatively, these viral evasion mechanisms delay the immune system just enough to allow the virus to replicate, break free of its host cell, and infect other cells. When the innate immune system of the host finally catches up, it overcompensates by producing excessive amounts of hyperinflammatory neutrophils and macrophages (20). This delayed host immune response and overcompensation contribute to the destructive cytokine storm observed with COVID-19.
How does a zoonotic viral transfer become a pandemic?
Even if a virus acquires just the right mutations and evolves just the right adaptations to evade the innate immune defenses of hosts, it may still not be enough to make the jump from one species to another. For a virus to jump to another species, there has to be an opportunity for cross-species interaction (23).
Humans coexist with numerous other species, from everyday household pets to farm animals to animals hunted and captured as edible delicacies. Although not yet confirmed, researchers suspect that SARS-CoV-2 transferred to humans from an infected pangolin that was captured and housed in a live food market in Wuhan, China (19). In another example, H1N1 (swine flu) likely transferred from pigs to their farmer caretakers. In both cases, pangolins and pigs likely served as intermediate hosts, with SARSCoV-2 originating in bats and H1N1 originating in birds. But how did these viruses physically move from their animal hosts into humans?
SARS-CoV-2 and influenza are viruses that target and infect respiratory cells in hosts. In contrast, other zoonotic viruses require more direct contact. The Ebola virus, which originated in bats, infects a range of cells, including macrophages, dendritic cells, endothelial cells, fibroblasts, and adrenal cells. However, the Ebola virus transfers through interaction with infected blood or other bodily fluids. Similarly, the rabies virus targets nerve cells, but gains access through hosts’ broken skin, which most often occurs from the bite and saliva of a rabid animal.
The medium in which viruses transfer and infect cells plays a significant role in their transmissibility (24). Viruses that rely on direct interaction with blood, feces, saliva, or other bodily fluids are less likely to transfer from species to species or result in a full blown pandemic. However, respiratory viruses like influenza and SARSCoV-2 readily spread via virus-laden respiratory droplets expelled through sneezing, coughing, or simply breathing. This simplifies species to species transfer and facilitates its rapid spread among species members. The recent globalization of the world set the ideal stage for the spread of a pathogenic, respiratory zoonotic virus with just the right evolutionary adaptions.
Predicting the next jump
Despite SARS-CoV-2, pandemiccausing zoonotic viruses are extremely rare. Viruses must first overcome multiple biological hurdles to achieve pandemic potential. That does not mean that another pandemic zoonotic virus is impossible. Scientists are initiating surveillance projects in animals, particularly bats, to uncover viruses with zoonotic potential before they make the jump to a new host species. The Global Virome Project launched in 2018 is an example of one such large-scale viral surveillance effort (5). Other scientists investigate how ecological changes place animals in closer contact with human populations. These efforts, coupled with biological and mechanistic studies into how viruses adapt and evolve within new hosts, will continue to shed light on how viruses move between species and the interconnection between humans, animals, and the microscopic world that surrounds us all.
REFERENCES
1. World Health Organization. Zoonoses. at< https://www.who.int/news-room/fact-sheets/detail/zoonoses>
2. Centers for Disease Control and Prevention. About HIV. at<https://www.cdc.gov/hiv/basics/whatishiv.html>
3. Centers for Disease Control and Prevention. Origin of 2009 H1N1 flu (Swine Flu). at <https://www.cdc.gov/h1n1flu/information_h1n1_virus_qa.htm#d>
4. Lim, Y.X., Ng, Y.L., Tam, J.P., & Liu, D.X. Human coronaviruses: A review of virus–host interactions. Diseases 4(26) (2016).
5. Carroll, D. et al. The Global Virome Project. Science 359(6378), 872-874 (2018).
6. Warren, C.J. & Sawyer, S.L. How host genetics dictates successful viral zoonosis. PLoS Biology 17, e3000217 (2019).
7. Olival, K.J. et al. Host and viral traits predict zoonotic spillover from mammals. Nature 546, 646-650 (2017).
8. Suga, N. Echolocation II: Neurophysiology. Encyclopedia of Neuroscience 801-812 (2009).
9. Chothe, S.K. et al. Avian and human influenza virus compatible sialic acid receptors in little brown bats. Scientific Reports 7, 660 (2017).
10. Mollentze, N. & Streicker, D.G. Viral zoonotic risk is homogenous among taxonomic orders of mammalian and avian reservoir hosts. PNAS 117(17), 9423-9430 (2020).
11. Irving, A.T. et al.Lessons from the host defences of bats, a unique viral reservoir. Nature 589, 363-370 (2021).
12. Haagman, B.L. The application of genomics to emerging zoonotic viral diseases. PLoS Pathogens 5(10), e1000557 (2009).
13. Kumavath, R. et al. The spike of SARS-CoV-2: Uniqueness and applications. Frontiers in Immunology 12, 663912 (2021).
14. Shang, J. et al. Cell entry mechanisms of SARS-CoV-2. PNAS 117(21), 11727-11734 (2020).
15. Kyrou, I., Randeva, H.S., Spandidos, D.A. & Karteris, E. Not only ACE2—the quest for additional host cell mediators of SARSCoV-2 infection: Neuropilin-1 (NRP1) as a novel SARS-CoV-2 host cell entry mediator implicated in COVID-19. Nature 6, 21 (2021).
16. Guo, H. et al. Evolutionary arms race between virus and host drives genetic diversity in bat severe acute respiratory syndromerelated coronavirus spike genes. Journal of Virology 94(20) (2020).
17. Nelli, R.K. et al. Comparative distribution of human and avian type sialic acid influenza receptors in the pig. BMC Veterinary Research 6(4) (2010).
18. Webby, R., Hoffmann, E., & Webster, R. Molecular constraints to interspecies transmission of viral pathogens. Nature Medicine 10, S77-S81 (2004).
19. Wang, Q. et al. Tracing the origins of SARS-CoV-2: lessons learned from the past. Cell Res 31, 1139-1141 (2021).
20. Prompetchara, E., Ketloy, C., & Palaga, T. Immune responses in COVID-19 and potential vaccines:Lessons learned from SARS and MERS epidemic. Asian Pacific Journal of Allergy and Immunology 1, 1-9 (2020).
21. Li, N. et al. METTL3 regulates viral m6A RNA modification and host cell innate immune responses during SARS-CoV-2 infection. Cell Reports 35(6), 109091 (2021).
22. V’kovski, P. et al. Coronavirus biology and replication: implications for SARS-CoV-2. Nature Reviews Microbiology 19, 155-170 (2021).
23. Kreuder, C. et al. Spillover and pandemic properties of zoonotic viruses with high host plasticity. Scientific Reports 5, 14830 (2015).
24. Walker, J.W. et al. Transmissibility of emerging viral zoonoses. PLoS One 13, e0206926 (2018).