by Ziqi Chen
figures by Rebecca Senft

We live in a universe of viruses. It is estimated that there are billions of types of viruses on earth, and ~320,000 types that infect mammals alone. Many viral species exist in our surrounding environment. As we live, breathe, eat, talk, and go about our daily activities, the number of viruses that we come into contact with is virtually infinite. Fortunately, only a relatively small number of viruses are known to infect humans.

The list of human viruses, however, is ever-growing, with 3-4 new species added annually. The vast and diverse pool of animal viruses constitutes the major source from which novel human viral diseases emerge, posing an ever-looming threat to public health. SARS-CoV-2, or the “novel coronavirus”, has announced itself as a new member of the family by causing the COVID-19 pandemic that is now wreaking havoc around the world.

The chain of transmission, both animal-to-human and human-to-human, is front and center to all novel animal-to-human infections. This article provides a general overview of how viruses adapt and change through this chain of transmission, which might be relevant as we seek to better understand and control the current pandemic, as well as prepare for future outbreaks of animal-to-human viruses.

Ongoing Outbreaks: Threats of animal viruses

The process of an animal virus or bacteria infecting humans is termed a “zoonotic shift,” and if humans get sick from the infection, the disease is called a zoonotic disease  or zoonosis. HIV (non-human primate origin), Ebola virus (bat origin), SARS coronavirus (bat origin), and Avian Influenza virus (bird origin) are some famous examples of zoonotic viruses. 

SARS-CoV-2 is the most recent addition to this long list of viruses that have “hopped” onto humans from animals. Studies suggest that this virus likely originated in bats, while other animals in the link to human infection remain unconfirmed (Figure 1). The threat that such a zoonotic shift can pose is exemplified by the current coronavirus outbreak, originating in China, which has now been officially termed a “pandemic” by the World Health Organization (WHO). As of the morning of March 22nd, about 2.5 months after the 1st case report to the WHO country office in China, COVID-19 has had 315,762 confirmed cases worldwide, claimed 13,591 lives, and spread to 188 countries or territories, as well as caused far-reaching medical, social, and economical repercussions. 

Figure 1: Current hypothesis of the chain of transmission for SARS-CoV-2 coronavirus. The virus is thought to have originated in bats (reservoir host) and transmitted to intermediate hosts (not confirmed, though one suspected species is pangolins). The virus likely developed mutations, or changes, that enabled it to transmit from intermediate hosts to humans and afterwards spread through human-to-human transmission.

Overcoming Host Specificity: Requirements for zoonotic shift

What makes an animal virus “hop” onto people? At least two things are required for this process. First, humans need to be exposed to either animals that naturally harbor the virus (reservoir host), or animals that carry the virus transmitted from the reservoir host (intermediate host).

Secondly, the virus needs to be capable of infecting humans. This is not a trivial task for an animal virus, because the virus faces a totally unfamiliar, and often hostile environment. In order to set up camp in the human body, the virus needs to enter our cells, multiply, and avoid destruction by our immune systems. If a virus does successfully colonize one human, it also needs a way to get out of the body and disseminate so that it can infect additional humans and remain viable (Figure 2). Sometimes, the animal virus already possesses one or more of these traits because there are shared features between its animal hosts and humans. However, more commonly the virus needs to undergo genetic changes, or mutations, to acquire these traits, either prior to entering the human population, or during human-to-human transmissions.

The SARS-CoV-2 coronavirus infects humans through a protein on its spikes — crown-like protrusions on the surface of the virus, from which the virus got the name corona (Latin for crown). The protein can interact with a protein on the surface of human cells, thereby enabling the virus to anchor onto and infect cells in our airways. A recent study analyzed two key sites on this spike protein and found that both are different from the bat virus, suggesting that these sites acquired mutations that allowed the virus to successfully infect human cells.

Diverging Paths: Containment versus Co-existence 

What happens when a virus does successfully mutate to allow for infection and spread in humans? In one scenario, if the outbreak is effectively contained and terminated, the virus could be eliminated from the human population.

For COVID-19, social distancing, good hygiene and timely identification / quarantine are currently effective measures for limiting disease spread. These public health measures work by reducing the exposure of uninfected individuals to the virus, and have long been employed to contain infectious outbreaks, such as Ebola, SARS, H1N1, and even the Plague. As we gain more knowledge of SARS-CoV-2 infection and our immune response, development of an effective vaccine might prove to be the final solution for disease containment and hopefully elimination. By imparting immunity, vaccines protect people who are exposed from becoming sick upon infection, and have been very impactful in the fight against many infections, including rabies which is also a zoonotic viral disease. 

Both public health measures and vaccines help reduce new infections, and since the virus can only exist in one person for a few weeks, if it does not get the opportunity to move on to the next person, the chain of transmission is cut and the outbreak will eventually come to a stop. However, another possible outcome is that the virus might circulate and persist in the human population (Figure 2).

Figure 2: Viral transmission and possible outcomes of COVID-19 infection. Animal viruses need to overcome many barriers in order to establish and sustain infection in the human population, including geographic distances, physical barriers (e.g. sanitary precautions) and barriers to transmission (e.g. social distancing), as well as overcome clearance by our immune system. With effective containment, it might be possible to eliminate the virus from the human population. Alternatively, the virus might co-exist with humans long-term.

If SARS-CoV-2 does co-exist with us long-term, over time it might further develop features uniquely adapted to human infection and transmission. This is the case for HIV, where the current human viruses already diverge substantially from their non-human primate origin (SIV). One divergence is in a protein called Gag30, which has a site that differs from SIV to HIV. This change enables HIV to multiply more effectively in human cells. By comparing the genomes of viruses isolated from patients across different dates and geographical locations, researchers can track what and how much genetic change has taken place, and thereby assess how fast the SARS-CoV-2 virus is diversifying  and evolving on both the individual level and population level. Whether or not this evolution will make the virus more virulent (causing severe disease) remains an open question, and currently there is no evidence either way.

Concluding Remarks

Epidemiological studies of viral origin, chain of transmission, and genetic profiles can help inform public health measures to control disease spread (e.g. closing down of animal markets, identifying and limiting contact with intermediate hosts, social distancing, sanitary precautions, timely identification, and quarantine). They can also help track and predict future outcomes (possibility for long-term persistence, or whether a drug intervention or vaccine is likely to be effective). Many questions remain open for the COVID-19 pandemic, as we monitor the speed of disease spread, the effectiveness and persistence of natural immunity, and the changes in the viral genome. By turning an eye to the process and implications of zoonotic shifts, we might derive some insight into how viral evolution and host adaptation has shaped the viral diseases that we know today, and continues to shape the current pandemic. This can provide context, as well as a framework of reference, to the origin and outlook of the ever-changing COVID-19 situation.

Ziqi Chen is a fourth-year Ph.D. student in the Biological and Biomedical Sciences program at Harvard University who studies the gut immune system.

Rebecca Senft is a fifth-year Program in Neuroscience Ph.D. student at Harvard University who studies the circuitry and function of serotonin neurons in the mouse.

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