Covid-19 Origin: Why There Might Be No Intermediate Host

Shin

We have to think beyond the bat cave in Yunnan.

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The search for an intermediate host of SARS-CoV-2, the coronavirus that causes Covid-19, has been disappointing. Animals like dogs, snakes, and turtles were suspected initially but were soon disproven. Then pangolins became the next suspect and remained unconfirmed to this day.

But what if there was no intermediate host involved all along? What if an intermediate host isn’t necessary for the evolution of SARS-CoV-2?

Coronavirus intermediate host in brief

When we discovered that a coronavirus, namely SARS-CoV-2, causes the pneumonia outbreak in Wuhan (a city in China) in December 2019, we also know that it most likely came from bats. Bats are well-known carriers of coronaviruses — including SARS and MERS — and other zoonotic pathogens that have jumped into humans.

In fact, the closest known relative of SARS-CoV-2 is the RaTG13 coronavirus — with 96.2% genomic identity — found in horseshoe bats in Yunnan, China. But 4% genomic mismatch is still substantial, equating to about 50 years of evolutionary gap, which led to scientists believing that an intermediate host facilitating viral evolution is involved.

Besides, the coronaviruses that caused serious outbreaks in the past—namely, the 2003 SARS-1 and 2012 MERS — involved an intermediate host mediating the spillover from bats to humans, so it’s likely the same for SARS-CoV-2.

Specifically, scientists identified the SARS-CoV-1 and MERS-CoV progenitors sharing >99% genomic identity in palm civets and dromedary camels, respectively, confirming their participation as intermediate hosts.

For Covid-19, the closest hint we’ve got is the pangolin coronavirus that is about 90% genetically identical to SARS-CoV-2. Interestingly, the receptor-binding domain (RBD) of the pangolin coronavirus and SARS-CoV-2 is 97.4% identical at the genetic level — suggesting that SARS-CoV-2 might have gotten its RBD from the pangolin coronavirus. But 3% genomic difference is still big, especially when it comes to the crucial RBD that binds to the ACE2 receptor on the cell surface to initiate infection.

Moreover, the pangolins had severe respiratory diseases at sampling, which disfavors its involvement as an intermediate host. “An ideal intermediate reservoir host does not develop severe disease on infection with a virus, a key feature that allows a virus to multiply and seek alternative hosts without killing its evolutionary host,” argued a 2020 research review.

Plus, the RaTG13 coronavirus — the closest relative of SARS-CoV-2 — can’t infect cells expressing the pangolin ACE2 receptor, questioning the notion that RaTG13 evolved into SARS-CoV-2 in pangolins. Another bioinformatics study published in Nature Microbiology also doesn’t support pangolins as the intermediate host of Covid-19, stating that “there is no evidence that pangolin infection is a requirement for bat viruses to cross into humans.”

So, we still don’t know which animal is the intermediate host mediating the Covid-19 spillover from bats to humans.

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Why intermediate host may not be essential for SARS-CoV-2 evolution

Back to the questions: But what if there was no intermediate host involved all along? Specifically, what if an intermediate host isn’t necessary for the evolution of SARS-CoV-2?

A study published in PLOS Biology in March 2021— titled “Natural selection in the evolution of SARS-CoV-2 in bats created a generalist virus and highly capable human pathogen,” from the University of Glasgow Centre for Virus Research in the U.K. and Temple University’s Institute for Genomics and Evolutionary Medicine in Philadelphia — suggests that this might be the case.

The study found that, among the SARS-CoV-2 genomes sampled 11 months since the outbreak began in December 2019, only a few important mutations have occurred — consistent with earlier reports.

This is strange because viral evolution usually accelerates in a new host as it adapts to its new biological system. “What’s been so surprising is just how transmissible SARS-CoV-2 has been from the outset,” said one of the co-authors. “Usually viruses that jump to a new host species take some time to acquire adaptations to be as capable as SARS-CoV-2 at spreading, and most never make it past that stage, resulting in dead-end spillovers or localised outbreaks.”

“These results suggest that the majority of adaptive changes which generated SARS-CoV-2 took place prior to its emergence in the human population,” the study authors wrote, presumably in bats, intermediate hosts, or humans.

The authors think that the answer is bats, based on their subsequent analyses.

First, they admit that drastic genetic changes might have occurred before countries started isolating and sequencing SARS-CoV-2 genomes. Others have also raised the possibility of SARS-CoV-2 circulating silently in humans for some time before the outbreak in December 2019.

However, “we fail to find evidence of diversifying selection on the terminal branch leading up to the emergence of SARS-CoV-2 in humans,” the authors stated. This “indicates that the adaptations that created a generalist [SARS-CoV-2] capable of efficient replication in humans and other mammals, probably did not occur in the unsampled SARS-CoV-2 lineage.”

Diversifying selection refers to mutations that greatly change the biological function of a protein, which often drives speciation — i.e., the emergence of diverse or new species.

In fact, the study revealed that such diversifying mutations occurred in the deeper (earlier) bat coronavirus lineages, not in the terminal (late) lineages — as depicted in the figure below.

“Our analysis finds that diversifying selection left its imprints primarily in the deepest branches of the nCoV clade or lineage leading to it, with no evidence of selection in the terminal branch leading to SARS-CoV-2,” the authors explained. “This is consistent with the nonhuman progenitor of SARS-CoV-2 requiring little or no novel adaptation to successfully infect humans.”

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* Source: Figure shows the important genes in coronaviruses’ genomes, such as the S (spike protein), nucleocapsid (N), and open reading frame (ORF) genes. Note that the deeper (earlier) branches or lineages have a higher rate of genetic changes driving diversifying selection (denoted by increasing red color intensity) than the terminal (late or ending) branches.

In a word, the study shows that SARS-CoV-2 most likely jumped from bats to humans with little genetic changes — explaining why SARS-CoV-2 genomes have been stable since the pneumonia outbreak began in December 2019. And it also explains why there may be no need for an intermediate host to facilitate viral evolution.

More context and remaining questions

The study I’ve discussed is directed by David L. Robertson, a professor and head of Viral Genomics and Bioinformatics at the University of Glasgow Centre for Virus Research, who was also very kind in responding to my email inquiries about this topic.

1. A conduit vs. reservoir intermediate host

One of the points the professor clarified is that an intermediate host could mean an active reservoir or simply a conduit for viral transmission.

“With SARS, the Civet cats were really only a conduit for the transmission of the virus from bats to humans,” Prof. Robertson wrote, so “bats are the true reservoir species and the civets not necessary for transmission to humans.” For MERS, on the other hand, the camels serve as reservoir species, where camel-to-human spillover can occur repeatedly. This is unlike SARS-CoV-1, where civets are not reservoirs, so they only carry the coronavirus briefly to humans.

“With SARS-CoV-2, given that the virus that has emerged is a generalist (able to infect pangolins, minks, cats, and other animals), it’s probably not necessary that there’s an intermediate species but we can’t discount this was the route to humans,” Prof. Robertson stated. “Our study can’t really address this but what I think we can be confident about is the virus that emerged in humans probably didn’t require much adaptation, if any, to be so successful.”

In a word, to repeat a point, an intermediate host isn’t compulsory for SARS-CoV-2 evolution. But whether there’s an intermediate host conduit bringing the SARS-CoV-2 progenitor from bats to humans is unknown.

2. The missing SARS-CoV-2 progenitor in Yunnan

Still, all things considered, everything isn’t 100% confirmed. Bioinformatics studies such as the one Prof. Robertson directed only suggest the most sensible scenario.

Whether SARS-CoV-2 or its progenitor really jumped directly from bats to humans is still missing a piece of critical evidence — the isolation of a coronavirus with ~99% genomic identity to SARS-CoV-2 in a bat species.

So, the step toward solving the origin of SARS-CoV-2 is to conduct further sampling and research on the bat coronaviruses residing in Yunnan, the prime geographical suspect where the spillover occurred.

This is because RaTG13, the closest coronavirus relative of SARS-CoV-2, and RmYN02, a coronavirus with an S1/S2 cleavage site similar to SARS-CoV-2, are both isolated from bats in Yunnan.

(Scientists believe that RmYN02 holds a clue to the mysterious origin of the furin cleavage site of SARS-CoV-2, which endows it with a spike protein that binds so efficiently to the human ACE2 receptor. But this topic is highly debated and complex, which I’m not covering here.)

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3. Is it really Yunnan?

In a highly relevant preprint released recently, researchers in China collected 283 fecal samples, 109 oral swabs, and 19 urine samples from various bat species in Yunnan between May 2019 to November 2020.

From these samples, “we assembled 24 novel coronavirus genomes from different bat species, including four SARS-CoV-2 like coronaviruses,” the preprint authors wrote. “Further PCR based tests revealed that these four viruses tested positive in nine individual samples collected in Yunnan province between May and July 2020.”

This is a crucial finding, showing that bat coronaviruses similar to SARS-CoV-2 could jump to humans directly without an intermediate host. So, it’s reasonable to think that the SARS-CoV-2 progenitor could do the same.

But another way of looking at this preprint is that the SARS-CoV-2 progenitor was not present in Yunnan, at least not among the samples sampled.

The preprint authors, however, mentioned that “these results clearly demonstrate that SARS-CoV-2 related viruses continue to circulate in bat populations…” So, it’s still possible that the SARS-CoV-2 progenitor was simply not present among the bat samples the researchers collected.

All in all, whether the SARS-CoV-2 progenitor — a coronavirus sharing about 99% genomic identity with SARS-CoV-2 — is present in bats in Yunnan or not still requires further arduous investigations.

If the SARS-CoV-2 progenitor is really not among the bats in Yunnan, then it means the progenitor might evolve in:

4. Beyond Yunnan

Prof. Robertson further pointed me to a preprint his team authored. Using bioinformatics tools to analyze coronaviruses’ genomes, the preprint found that a horseshoe bat species called Rhinolophus affinis is the most probable reservoir of SARS-CoV-2 progenitor. R. affinis is also the bat species that harbors RaTG13, the closest relative of SARS-CoV-2.

Importantly, R. affinis has a broad geographical distribution across China and Southeast Asia, including Thailand and Cambodia. To make matters more complicated, “Having presented evidence in support for R. affinis’s importance,” the authors wrote, “it should be noted at least 20 different Rhinolophus species are distributed across China…leaving many species for which the viruses are unknown.”

The preprint has also generated a map showing that several Rhinolophus species co-inhabit overlapping geographical regions, providing ample opportunities for bat coronaviruses to co-infect and recombine in various bat species. In fact, this is exactly how SARS-1 has most likely evolved.

So, Yunnan isn’t the only place where the spillover can happen. It could occur anywhere in China or even other parts of Southeast Asia where R. affinis could reside. Finding the SARS-CoV-2 progenitor will prove to be an arduous task that may be accomplishable anytime soon.

As the preprint of Prof. Robertson concluded, “The only way, however, of finding the animal progenitor of SARS-CoV-2 as well as the whereabouts of its close relatives, very likely capable of posing a similar threat of emergence in the human population and other animals, will be by (carefully) increasing the intensity of our sampling” of bat coronaviruses.

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MSc Biology student | 5x first-author academic papers | 100+ articles on coronavirus | Freelance medical writer

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