Evolution of SARS-CoV-2 from Bat to Human Pathogen – JD Supra

A recent COVID post elicited the comment that we were just a "ray of sunshine." Following in this tradition, this post concerns a recent report, in PLOS Biology, that the evolution of the SARS-CoV-2 virus (which causes COVID-19) evinced the development of a "highly efficient human pathogen" (to quote Billie Eilish, "Duh!").

The paper, entitled "Natural selection in the evolution of SARS-CoV-2 in bats created a generalist virus and highly capable human pathogen," was reported by an international team* of researchers. It was known prior to this work that SARS-CoV-2 and the virus that caused the SARS outbreak in 2002-2003 (which these authors term "SARS-CoV-1" to avoid confusion) arose in bats, and that SARS-CoV-2 is particularly infective in humans, inter alia, for having a furin protease cleavage site (Arg-X-X-Arg/ Arg-X-Arg/Lys-Arg) in its Spike protein, which facilitates protease-related binding to human angiotensin-converting enzyme 2 (ACE2) because furin is expressed in human lung tissue. The interesting conclusions drawn by these authors is that mutational adaptations that facilitate human infection by the virus occurred prior to the jump from bats to humans, which accounts (at least in part) for the rapid dissemination/infectivity in the pandemic because the virus did not require long-term incubation to achieve the species switch typical of other zoonotic viruses. Specifically, the authors report:

[U]nlike most other RNA viruses which acquire adaptations after switching to a new host species for efficient replication and spreading as successfully as exhibited by SARS-CoV-2, the Sarbecoviruses [a closely related bat viral species]which already transmit frequently among bat speciescan exploit the generalist properties of their ACE2 binding ability, facilitating successful infection of non-bat species, including humans.

The paper reports these researchers' comparison between signs of positive selection during the pandemic with historic selection in related bat viruses. They assessed 133,741 SARS-CoV-2 virus samples collected in the first 11 months of the pandemic with 69 samples of related (Sarbecovirus) virus genomes for the frequencies of nonsynonymous (dN) mutations (which result in amino acid sequence differences that can be subject to selective pressures) with synonymous (dS) mutations (which change at the nucleic acid but not amino acid sequence). Nonsynonymous mutations were expected to arise (i.e., be detected) more slowly in the viral population, because while both synonymous and nonsynonymous changes arise "randomly" there is no basis for selection of synonymous ones. As expected, dN mutations arose at 4% the rate of dS when comparing SARS-CoV-2 with related bat Sarbecovirus RaTG13. The authors further report that "[t]he vast majority of 20,687 observed mutations occur at very low frequency, with 79% of mutations observed in 10 or fewer of the 133,741 SARS-CoV-2 genome sequences analysed." They conclude from these data that "SARS-CoV-2 is evolving relatively slowly with no dramatic increases in selective pressures occurring over the sampling period [from] December 2019 to October 2020."

Perhaps surprisingly, the D614G mutation, putatively associated with higher rates of infection (see "The D614G mutation in the SARS-CoV-2 spike protein reduces S1 shedding and increases infectivity"), was detected in samples collected early in the pandemic, whereas other mutated sites occurred later, suggesting that the D614G variant has a higher capacity for positive selection in unvaccinated/uninfected populations because it has had a longer time to spread through the virus populations. In addition, these researchers found that most of the other mutations were only transiently present in the viral population.

In comparisons with other bat viruses, "diversifying" selection, associated with the ability of the virus to "jump" species, was found in the earliest branches of virus evolution from the bat virus. These researchers further report that there was "no evidence of selection in the terminal branch leading to SARS-CoV-2[, c]onsistent with the nonhuman progenitor of SARS-CoV-2 requiring little or no novel adaptation to successfully infect humans" (although they also caution that "no model can detect all signatures of historic genomic adaptation, and mutations which may enable SARS-CoV-2 to infect humans could have arisen by genetic drift in the reservoir host before human exposure").

Also found was evidence of a related bat virus, RmYN02, that has a sequence in comparison with SARS-CoV-2 that indicates recombination with prototype of SARS-CoV-2 as early as 1976, evidence of how long this virus was "brewing" in bat populations over time and consistent with "direct" bat-to-human transmission; indeed, the researchers found no evidence that related viruses are found in pangolins.

Further (and having the character of improvident destiny or the propensity for God to play dice contrary to Einstein's preferences), the sequence comparisons with bat viruses are consistent not with sequence changes related to a change in host species (from bat to human) but more consistent with a history of sequence changes related to the bat host(s) (such as immune avoidance or tissue preferences) having arisen that "preselected" the virus for effective human infection. As these authors write: "[t]hese results suggest that the majority of adaptive changes which generated SARS-CoV-2 took place prior to its emergence in the human population."

Exceptions are the mutations related to UK (B.1.1.7) or South African (B.1.351) mutations, which seem associated with "host immunity due to previous exposure and/or chronic infections of probably immunocompromised individuals," i.e., mutations more in line with conventional stories of how zoonotic viruses show sequence changes related to adaptation to a new host.

There has been evidence supporting these conclusions (outside the depth of the genetic analyses presented here; see "Sequence Comparisons Illustrate Susceptibility to Coronavirus Infection") regarding the biology of the observed ease of transmission to other hosts due to evolution of a "generalist" virus that arose in bats. In this regard, the authors state "[t]he apparent 'success' of these bat viruses to transmit to multiple other mammals and spread with few to no significant genomic changes further supports the hypothesis that the SARS-CoV-2 progenitor is from a viral lineage with a relatively generalist nature." This is consistent with a mechanism wherein this "generalist" virus arose in bat populations over the past ~100 years as a function of host switching or tissue tropism within bat species, perhaps due to resistance in bats (see "How Bats Are Different").

Finally, and consistent with these ideas, the authors present a histogram of the various related coronavirus species showing the genetic distance between SARS-CoV-1 and SARS-CoV-2 and illustrating that the genetic changes characterizing the increased human infectivity of SARS-CoV-2 arose late in the evolution of this species.

The authors conclude with a cautionary note:

An overarching point stemming from these observations is the lack of sampling and knowledge of the diversity in this viral subgenus. In particular, the closest known bat viruses to SARS-CoV-2 are relatively divergent in time[], and the apparent generalist nature of these viruses suggests that there are species of wild mammals, yet to be sampled, infected with nCoV-like viruses. Serological studies of communities in China that come into contact with bats indicate that incidental and dead-end spillover of SARS-like viruses into humans do occur[]. Due to the high diversity and generalist nature of these Sarbecoviruses, a future spillover, potentially coupled with a recombination event with SARS-CoV-2, is possible, and such a "SARS-CoV-3" emergence could be sufficiently divergent to evade either natural or vaccine-acquired immunity, as demonstrated for SARS-CoV-1 versus SARS-CoV-2. We must therefore dramatically ramp up surveillance for Sarbecovirusesat the humananimal interface and monitor carefully for future SARS-CoV emergence in the human population.

* MRC-University of Glasgow Centre for Virus Research, Glasgow, United Kingdom; Temple University, Institute for Genomics and Evolutionary Medicine, Philadelphia, Pennsylvania; Center for Infectious Disease Dynamics, Department of Biology, Pennsylvania State University, University Park, Pennsylvania; Department of Microbiology, Immunology and Transplantation, Rega Institute, KU Leuven, Leuven, Belgium

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Evolution of SARS-CoV-2 from Bat to Human Pathogen - JD Supra