COVID-19 and the virus that causes it, SARS-CoV-2, have focused the public’s attention on coronaviruses like never before. But medical researchers have more than half a century of experience with this family of viruses — by the time they identified the first human version in 1965, multiple animal coronaviruses were already known to exist. Since then, dozens of additional coronaviruses have been discovered in wildlife, livestock and humans.
We now know of four that cause the common cold: HCoV-OC43, HCoV-229E, HCoV-NL63 and HCoV-HKU1. (HCoV stands for “human coronavirus.” A number of other human strains were also reported in the 1960s, but they were lost and not studied in detail.) Since 2003, we have identified more serious human coronaviruses, which have caused severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS) and now COVID-19.
New papers on SARS-CoV-2 and COVID-19 are coming out at an unprecedented rate, but there’s still a lot we don’t know. Luckily, our extensive history with coronaviruses can help us fill in the gaps. Of course, we must be careful not to overextrapolate. For example, MERS-CoV and SARS-CoV, the viruses that cause MERS and SARS, do not seem to spread easily before the development of symptoms, while SARS-CoV-2 appears to be transmissible at least two days prior. (This may be due to the primary location where the viruses replicate — in the more exposed upper respiratory tract for SARS-CoV-2, versus the lower respiratory tract for the others — but more research is needed to know for sure.)
Still, the hard-won knowledge we’ve gained from decades of studying related viruses can help us answer some of our biggest questions about this pandemic.
Can a coronavirus really cause gastrointestinal symptoms?
While COVID-19 is primarily a respiratory disease, we’ve seen plenty of reports of individuals with gastrointestinal symptoms such as diarrhea and vomiting. Sometimes these symptoms even replace the more typical coughing and fever. This isn’t too surprising, but it does complicate the situation a bit. As testing is currently limited, would an individual with a mild upset stomach even consider themselves a potential COVID-19 case and self-isolate?
Perhaps we should have better anticipated the complexity of the disease. Prior research demonstrated that gastrointestinal symptoms were also an issue with some SARS patients during the 2003 outbreak. And they’re a hallmark of one of the most important coronaviruses in pigs, porcine epidemic diarrhea virus (PEDV). Other coronaviruses cause similar symptoms in cattle, dogs and cats, but the reasons for tissue preference — which determines which organs are most susceptible — aren’t yet clear.
What about even odder symptoms, such losing the senses of smell and taste?
There’s precedent for that too. Some evidence suggests SARS-CoV-2 can target tissue in the central nervous system, leading to temporary loss of some senses, as well as more serious potential consequences, including neurological impairment. In animal models of SARS-CoV and other coronavirus infections, investigators showed that the virus could enter the brain via the olfactory bulb, which processes information about odors. This reflects previous studies that have demonstrated the same process in HCoV-OC43 and mouse hepatitis virus (MHV).
A recent study (not yet peer-reviewed) suggests that the interaction between the virus and smell could be complex, because the cellular receptor in human cells that binds SARS-CoV-2, called angiotensin-converting enzyme 2 (ACE2), does not actually appear directly on the olfactory sensory neurons. It is present on nearby tissue, however, including vascular pericytes (cells that wrap around blood capillaries). Pericyte infection could alter the sense of smell by causing an inflammatory response that alters how the olfactory neurons function, or it might damage cells and alter any signaling from the sensory neurons to the brain.
This has led to suggestions that a coronavirus infection could lead to other neurological diseases, even after the acute infection resolves. We’ve seen no direct evidence of this, but there is reason to be concerned. Patients with multiple sclerosis and other neurological diseases are more likely than healthy controls to have HCoV-OC43 in their brains, and MHV can cause a demyelinating disease similar to MS in rodents and some nonhuman primates. This suggests that we should monitor recovered individuals in the coming years to see if they’re more likely to develop neurological complications akin to MS.
What will it take to stop this pandemic?
Ultimately, we’ll need a vaccine. Once we can prevent new cases from taking hold, the virus will have fewer places to go, making containment possible. Unfortunately, a safe, working vaccine is still months, and likely years, away.
Until then, we can look to PEDV for another possibility. While that disease, which devastates young piglets, now has various working vaccines in place, this wasn’t always the case. At first, farmers had to use an age-old tactic for controlling the spread of the virus: autogenous vaccines. These vaccines are produced on-site rather than by large companies, and they’re based on the particular strain of bacteria or virus that circulates there. Farmers or veterinarians would obtain samples of PEDV from pigs that had succumbed to the infection. They would then feed this tissue, usually taken from the intestine, to sows, who developed immunity to the virus. (They might become ill, but the infection is generally much milder in adult animals.) Antibodies, conferring short-term immunity, would then be passed from the sows to their piglets via the placenta and during nursing, protecting susceptible piglets from the infection.
Clearly, this isn’t a process that humans can easily adapt. But it is similar to a strategy that Sweden is currently attempting: Allow those at lower risk to mingle freely and eventually become infected with the virus; once they recover, a large enough segment of the population should be immune, resulting in herd immunity. In theory, this would protect the most vulnerable (older people and those with certain health conditions) as they self-isolated, while others would become infected and then immune. In practice, however, this strategy, which was rejected in the United Kingdom, is leading to a much higher death rate in Sweden than in other Nordic countries.
Does the amount of virus exposure affect disease severity?
It looks that way.
Many health care workers have become seriously ill with COVID-19, despite being young and healthy. Various reports have suggested it’s because they were exposed to more virus than a typical COVID-19 patient. This is consistent with experimental studies of porcine respiratory coronavirus (PRCV). Scientists found pigs that were inoculated with it developed more severe cases than the pigs that caught the disease naturally. This makes logical sense, since the higher the amount of virus infecting you, the harder it is for your body to control its replication and spread.
This only emphasizes the importance of protective measures — masks, gloves, hand washing — for people who face prolonged exposure to the virus.
Is it possible to get COVID-19 twice? Or are we immune once we get it?
Unfortunately, the news here is not good. While catching and successfully fighting off a virus usually results in a natural immunity to it, coronavirus infections do not seem to result in long-term immunity. Individuals could be reinfected when that immunity wanes.
Volunteers experimentally inoculated with HCoV-229E showed a steep decline in antibody response over time, and the majority could be successfully reinfected a year later. Patients infected with SARS-CoV also showed a decline in antibody titers over time. On the animal side, cattle infected with bovine coronavirus (BCoV) — the ancestor of at least one human coronavirus — are susceptible to reinfection and show no long-term immunity.
And some animal coronaviruses are never resolved at all: They become persistent infections. In cats, for example, infection with feline enteric coronavirus may last for months or longer. When this happens, the virus mutates so much that its very nature seems to change. What starts out as a relatively mild gastrointestinal infection eventually causes serious peritonitis (inflammation of the membrane lining the abdominal wall) in some animals. Examining the virus at this point in the infection, researchers found that the mutations had resulted in the emergence of a related virus, feline infectious peritonitis virus — and this one has a higher fatality rate.
Currently, there is no evidence of particular mutations in SARS-CoV-2 that may alter its virulence. But researchers will certainly be investigating individuals who test positive again after having one or more negative tests to determine if they have truly been reinfected, or if they have a persistent initial infection that only seemed to go away. (It’s also possible the tests may have produced false negatives.)
Could SARS-CoV-2 become endemic among humans and just never go away? What then?
It’s hard to say. There are many potential outcomes here, and they depend on human behavior and ingenuity. If we have a vaccine that significantly reduces the presence and spread of SARS-CoV-2 in the population, it could limit the virus’s ability to evolve. That would probably be the ideal case, even though we’d need to be on the lookout for outbreaks, as we also have to do with measles, mumps and other vaccine-preventable infections. But if we can’t contain the virus and end up constantly exposed to it, we can use our experiences with other coronaviruses to imagine some possibilities.
One outcome: The disease could become milder with time. This may have happened with HCoV-OC43, which appears to have diverged from its ancestral virus BCoV around 1890, when it jumped from cattle to humans. Coincidentally, that was also the year of a nasty influenza epidemic — though it may very well have been a coronavirus outbreak, like today’s.
The increased mildness of HCoV-OC43 may have been facilitated in part by the deletion of 290 base pairs of the virus’s RNA near the spike gene, which allows a virus to penetrate and infect its host’s cells. This deletion likely hindered its ability to bind effectively, making it harder to produce severe infections. Such evolution by deletion is actually a common feature of these viruses. A deletion of part of the spike gene and several other changes in a second gene led to the emergence of PRCV from an ancestral swine gastroenteritis virus. These mutations seem to have changed the virus’s tissue preference, transforming it from a deadly enteric (intestinal) pathogen to a milder respiratory one. Could SARS-CoV-2 undergo a similar change in binding sites in the body that could affect its tissue preferences or lead to a milder presentation? Time will tell, but it does seem to be a habit of coronaviruses.
Another possible outcome if SARS-CoV-2 never goes away: recombination, where the virus mixes and matches its genetic material with those of other circulating coronaviruses. These events are frequent, and they can result in the emergence of entirely new viruses. For example, a novel strain of canine respiratory coronavirus identified in 2017 was likely a recombinant of existing canine and bovine coronaviruses. Recombination of SARS-CoV-2 with the other human coronaviruses, or even animal coronaviruses, may be possible, but the outcome of such an event — good, bad or in between — is almost impossible to predict in advance. We’ll simply have to keep monitoring the virus and trust in our resourcefulness to deal with whatever comes next.
Have your own questions about the coronavirus? Submit them in the comments below, and tune in to a live Q&A with author Tara Smith at 4 p.m. ET on Friday, May 1, on Quanta’s YouTube channel.
This article was reprinted in Spanish at Investigacionyciencia.es.