DOCTORS may be fretting about concurrent outbreaks of flu and covid-19 this winter, but some virologists are worrying about another scenario: a Frankenvirus.
SARS-CoV-2, the virus that causes covid-19, almost certainly originated from the hybridisation of two different coronaviruses. The details remain hazy, but the virus’s genome sequence suggests that this about a decade ago. The bat was simultaneously infected with two closely related coronaviruses, which merged into a new one.
Such recombination isn’t unusual for coronaviruses. “If you look in the family tree of coronavirus, there’s recombination everywhere,” says virologist Samuel DĂaz-Muñoz at the University of California, Davis.
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It occurs for two reasons. First, coronaviruses are tolerant to co-infection. Unlike many other viruses, they allow co-infection of the same cell by other viruses.
Second, the way coronaviruses replicate their genomes makes hybridisation not just possible but likely. They are RNA viruses, which usually have very high rates of mutation – the highest rate of any known biological entity – because the enzymes that copy their RNA don’t have a proofreading function. A high mutation rate can allow a virus to rapidly evolve resistance to the host’s immune response.
Coronaviruses are the exception, because their replicase enzymes do proofread. SARS-CoV-2 has proved very resistant to mutation. According to DĂaz-Muñoz, only six mutants have emerged thus far.
The variability in coronaviruses comes from something else: recombination. Their replicase enzymes frequently jump from one part of the RNA template to another. This makes them adept at remixing their own genomes to create variation, and also allows them to steal genetic material from other closely related coronaviruses. “It is one of the things that facilitates jumping from one species to another. I think there’s no doubt that recombination in a bat was involved in the emergence of SARS-CoV-2,” says DĂaz-Muñoz. The fear is that it could now happen again, inside a human.
Research by Huiguang Yi at the Southern University of Science and Technology in Shenzhen, China, implies that . He has analysed 84 published SARS-CoV-2 genome sequences from human cases and found some that could only have formed through recombination.
There are also many including influenza, rhinovirus, respiratory syncytial virus and the seasonal coronaviruses that cause common colds.
This latter class are especially concerning, because they are quite closely related to SARS-CoV-2 and could potentially hybridise with it.
There are four of these seasonal coronaviruses in general circulation. There is also the original SARS virus, which caused an epidemic from 2002 to 2004. It is no longer in general circulation but virologists . Finally, there is the MERS coronavirus, which emerged in 2012 and still circulates at low levels. The fear is that a human co-infected with SARS-CoV-2 and a second coronavirus could be a crucible for the creation of a new virus, and even another pandemic.
A caveat is needed, however. In medical circles, co-infection means simultaneous infection of an individual host by two or more pathogens, not necessarily of the same cell within that host. We don’t yet know whether cellular co-infection occurs with SARS-CoV-2, says DĂaz-Muñoz. But from what is known about coronaviruses, it is likely that it does.
“We worry about flu, but we should be paying more attention to the seasonal coronaviruses,” says DĂaz-Muñoz. “They are flying under the radar. Looking at what is going to happen with seasonal corona is one of the most important questions right now.”
It isn’t known whether SARS-CoV-2 could recombine with a common coronavirus, but we can’t rule it out. “To effectively combine the genomic material of two viruses is more complicated if the viruses are very different,” says Raúl Rabadán at Columbia University in New York. “If there is a co-infection between a common coronavirus and SARS-CoV-2 it is unlikely, although not impossible, that the potential recombinants will be viable.”
“We worry about flu, but we should be paying more attention to the seasonal coronaviruses”
Yi told żěè¶ĚĘÓƵ that he isn’t especially worried about a recombination event between SARS-CoV-2 and a cold-causing seasonal coronavirus, because their genomes aren’t closely related enough. However, the SARS and MERS viruses, or as yet unknown closely related coronaviruses, are a different story. SARS is the most genomically similar and hence the most dangerous, he says.
That sounds worrying, but a hybrid virus wouldn’t necessarily be worse than SARS-CoV-2, says DĂaz-Muñoz. It could combine less virulent features of the two parent viruses, and become a mild respiratory virus like the common cold. “That may be evolutionarily advantageous to the virus. If people are no longer sheltering in place, it could spread more easily.”
Even if a mash-up is unlikely, recombination in SARS-CoV-2 is still a huge concern, says Yi. It generates genetic variation that could make the virus more virulent, drug-resistant or better able to evade our immune system. It could also render diagnostics based on RNA assays useless. Doctors and disease control specialists should be concerned about these possibilities, he says.
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