Image courtesy of nature research.
Coronaviruses are a large group of viruses and one of the two genera belonging to the family Coronaviridae that normally cause mild to moderate upper-respiratory tract illnesses and intestinal infections. Four of the seven known human coronaviruses (229E, NL63, OC43, and HKU1) only cause mild to moderate disease. The other three that emerged in the past 20 years, however, are highly contagious, leading to widespread illness and death worldwide. Coronaviruses were actually not considered highly pathogenic to humans until the severe acute respiratory syndrome (SARS-CoV) outbreak in 2002 and 2003 in Guangdong province, China. Sometimes coronaviruses that infect animals evolve, make humans ill, and become a new human coronavirus. As we all know, the most human outbreak of SARS-CoV-2 that caused COVID-19 has upended our daily lives and changed how we learn, work, and interact as public health measures to prevent the spread have brought virtual existence to our new reality. The pandemic has triggered countless mental and physical health challenges. With that being said, how did human coronaviruses arise and evolve, and are they still evolving?
The Origins of Human Coronaviruses
Bats have been recognized as natural reservoirs of various viruses, but particular attention has been given to bat coronaviruses because it is suggested that the two emerging coronaviruses that have caused unpredictable human disease outbreaks in the 21st century (SARS-CoV and MERS-CoV) originated from bats. These mammals have a vast geographical distribution and flight capability, comprising the second largest group of mammalian species. They have also been documented as natural hosts of a great number of different viruses, including lyssaviruses, paramyxoviruses, and filoviruses. Coronaviruses have four main genera: alphacoronavirus, betacoronavirus, gammacoronavirus, and alphacoronavirus. The first two coronavirus genera mainly affect mammals, and it is suggested that bats are crucial hosts acting as the gene source in the evolution of these two genera.
The origin of SARS-CoV-2, however, has yet to be determined. Its genetic pathway still remains unclear, but what we do know is that the virus had to mutate dramatically in order to survive in a species, like us. It might have obtained a segment of a different coronavirus strain that already lived in its new host and developed into a hybrid that was a better, stronger version of itself. It turns out, though, that coronaviruses and other virus families have been co-evolving with bats for as long as human civilization existed, and perhaps much longer. What scientists do agree is that the disease has an animal origin. “The big question is what led it to jump into humans,” Etienne Simon-Loriere, of the virology department at the Institut Pasteur in Paris, told AFP. It is suspected that SARS-CoV-2 originated from bats as they are major reservoirs for coronaviruses, but there would have likely been an intermediary animal that allowed the virus to jump into humans. The pangolin was identified as a possible carrier early on according to genetic analysis, although the case is not yet settled.
Coronaviruses closely related to the one that causes COVID-19 may have been around for longer than anyone realized. SARS-CoV-2’s closest known relative is a virus isolated from an intermediate horseshoe bat, shown above, in Yunnan Province in China in 2013
(Science Source).
How Did Human Coronaviruses Evolve?
Before a virus can become biologically successful for viral infections, they have to be tightly adapted to their hosts. A molecule on the surface of a coronavirus must match a receptor on the outside of the cell, like a key fitting into a lock, in order to get into a host cell. Once the virus is inside the cell, it has to invade the cell’s immune defenses. Then it instructs the appropriate parts of the host’s biochemistry to go through the process of virus reproduction so that the virus can multiply and spread rapidly. Any, or even all, of these factors are likely to be different on different host species. Therefore, coronaviruses will need to change genetically, or evolve, to have the ability to infect a new species (humans) in order for those viruses to develop into human coronaviruses. Host switching consists of two steps that can overlap. The virus has to be able to invade the host’s cells, which is the minimum requirement in infecting the host. Secondly, the virus has to become infectious, or transmissible between individuals, in its new host to cause epidemics. This is what brings a virus from being an occasional nuisance to the next level and turning it into something that can result in widespread harm.
Diagram of coronavirus virion structure showing spikes that form a "crown" like the solar corona, hence the name (Wikimedia Commons).
To look at the evolution of human coronaviruses, let’s focus on SARS-CoV-2, the virus that caused COVID-19. SARS-CoV-2 demonstrates the two stages of host switching. Both the virus that infects people and a close relative in pangolins have a mutation that changes the shape of the surface “spike protein” when compared with the virus in bats. This mutation is exactly at the spot that binds to host cell receptors to let the virus in, which suggests that the mutation first arose in a specific species and happened to allow the virus to jump over to people as well; however, SARS-CoV-2 carries other changes in the spike protein that may have arisen after it jumped to people. One mutation is in an area known as the polybasic cleavage site, which can lead to other coronaviruses and flu viruses becoming more infectious. Another appears to make the spike protein more strong, and it makes the virus more infectious in lab experiments with cell cultures. The mutation, though, has become more common as the COVID-19 pandemic goes on, which suggests (but does not prove) that it also makes the virus more infectious and spread more easily in the real world.
According to Daniel Streicker, a viral ecologist at the University of Glasgow, “this evolutionary two-step is probably characteristic of most viruses as they shift hosts”, meaning emerging viruses can possibly proceed through this so-called “silent period” immediately after a host shift. The virus will almost be successful when it possesses the mutations needed for an epidemic to flourish.
Streicker sees this in studies of rabies in bats, where he and his colleagues observed decades’ worth of genetic sequence data for rabies viruses that had encountered host shifts. Because larger populations of viruses carry more genetic variants than smaller populations do, measuring genetic diversity in their samples helped determine the approximation of how widespread the virus was at any given time. They discovered that “almost none of the 13 viral strains studied took off immediately after switching to a new bat species.” The viruses actually survived out of marginal existence for years or perhaps decades before they got the mutations that allowed them to bloom in epidemics. The viruses that surfaced the fastest were those that needed the fewest genetic changes to thrive. Before SARS-CoV-2 acquired the crucial adaptations in order to flourish, it probably passed through a similar tenuous phase. A virologist at Cornell University who studies host shifts, Colin Parish, says “by the time the first person in Wuhan had been identified with coronavirus, it had probably been in people for a while” whatever the case might be with the virus’ mutations.
A recent mutation alters the SARS-CoV-2 spike protein to make it less fragile (the altered bits are shown as coloured blobs). This added robustness appears to make the virus more infectious. Three sites are shown because the spike protein is composed of three identical subunits that bind together (Los Alamos National Laboratory).
Why did SARS disappear, but today’s coronavirus keeps on spreading?
SARS-CoV-1 was more aggressive and deadly than SARS-CoV-2, but SARS-CoV-2 spreads faster, sometimes with hidden symptoms, allowing an infected person to infect others. SARS did not go away just because the viruses evolved to cause milder disease, but because it made people sick enough that health workers could contain the disease before it became uncontrollable. SARS has been successfully contained with the use of public health measures, including early case detection and isolation, contact tracing, and social distancing; however, SARS-CoV and SARS-CoV-2 differ in terms of infectious period, transmissibility, clinical severity, and extent of community spread, which means public health measures are not fully able to contain the outbreak of COVID-19. Regardless, they will still be effective in decreasing peak incidence and worldwide deaths. “People who got SARS got very sick, very fast and were easily identified, easily tracked and readily identified and quarantined,” says Mark Cameron, who wired in a Toronto hospital during the height of the SARS outbreak there. This is not the case with COVID-19 though because approximately 80 percent of those infected have a mild illness, and some may even be asymptomatic. People with COVID-19 seem to shed the virus, or release into the environment, earlier in their infectious periods compared with SARS, making it more harder to detect the virus and isolate them before they spread it to others. A study compared the specific area of the viral protein in charge of the binding to the host cell receptor. It observed that the receptor binding site of SARS-CoV-2 binds to the host cell receptor with a higher affinity than that of SARS-CoV, meaning that it spreads more easily than the SARS virus. Furthermore, COVID-19 spreads easily from community to community compared to SARS, which was more commonly spread in healthcare facilities. We have many more global connections that we did in 2003 during the SARS outbreak, so this makes it easier for COVID-19 to spread between countries as well.
Parrish says, “we’re sort of in that 1918 period when the virus is spreading fast in a naive population” with this new coronavirus; however, this may change as more of the world population develops immunity as he says, “there’s no question that once the population is largely immune, the virus will die down.” The real question here is how long that immunity will last for. Will it last for a lifetime, like smallpox, or just a few years, like flu? Some of this will rely on whether the vaccine prompts a permanent or temporary antibody response and if the virus can mutate to evade antibodies made from the vaccine. Although coronaviruses don’t develop mutations as fast as flu viruses, they can still change. For instance, a coronavirus that causes bronchitis in chickens has evolved new variants which were not used in the creation of previous vaccines. Recently, more contagious strains of SARS-CoV-2 have quickly spread to more than 50 countries worldwide, raising matters of concern that they might have already been driving spikes in coronavirus cases in Canada in silence and continuing to threaten to overwhelm the healthcare system more than ever. The UK, South Africa, and Brazil COVID-19 variants are transmitting way more easily than the original strain. It is estimated that the UK variant is at least 56 percent more transmissible.
The Importance of Evolution in Human Coronaviruses
Human coronaviruses have been responsible for three major viral diseases (SARS, MERS, and COVID-19), forcing society to follow public measures in order to slow down viral dissemination at the global scale. In all these diseases, zoonotic transmission, underling, animal reservoirs for the evolution of viral variants with new potentials, and the extreme ease with which coronaviruses can adapt to the human host has resulted in outbreaks at human levels. Having the knowledge of the processes that control the evolution of this sub-family of Coronaviridae (Coronavirus), and which parts of their replication strategy are responsible for their adaptation to the human host is significant for health surveillance and increasing understanding on research areas useful for guiding the antiviral strategies setup in case there are new outbreaks threatening the human population.
Interested in the timeline of human coronavirus discoveries from when human coronaviruses were first discovered to COVID-19 identification? Feel free to take a look at this interactive image!
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Article Author: Tanya Kor
Article Editors: Victoria Huang, Maria Giroux