The proximal origin of HCoV-19 (also called SARS-CoV-2)

These GEITP pages have (mostly) stayed away from articles about “allergy” and “infectious disease” — simply because the topic of gene-environment interactions is already enormous, without going into those areas. ☹ However, given the extreme minute-by-minute interest by all of us regarding the current global pandemic, we believe this Letter-to-the-Editor (see attached, from Nature Med) is appropriate to share quickly. 😊 Since the first reports of a distinct type of pneumonia (COVID-19) in Wuhan, China, there has been considerable speculation on the origin of the causative virus SARS-CoV-2 (also referred to as HCoV-19). Infections with SARS-CoV-2 are exploding, worldwide: as of 11 March 2020 when this Letter was written — there were 121,564 confirmed cases in more than 110 countries, with 4,373 deaths; as of this moment writing this GEITP email (13 days later), there are 407,485 confirmed cases worldwide, 18,226 deaths, and a startling 1,815 deaths during the past 24 hours.

If we can understand in detail — how an animal virus jumped species boundaries — to infect humans so efficiently and productively, this might help us in preventing future zoonotic events (e.g. if SARS-CoV-2 ‘pre-adapted itself’ in another animal species, then there is the risk of future re-emergence events; in contrast, if the adaptive process occurred in humans, then, even if repeated zoonotic transfers occur, they are unlikely to flare-up, without coincidentally ‘having the same series of mutations’). Moreover, identifying the closest viral relatives of SARS-CoV-2 — which are currently circulating in animals — might greatly help studies of viral function. In fact, availability of the RaTG13 bat viral sequence helped reveal key receptor-binding domain (RBD) mutations, as well as the polybasic cleavage site (PCS).

What allowed this virus to “jump” from an animal origin to humans? The answer lies in the mutation of one or several nucleotides in the RBD as well as the PCS. The RNA sequence of the animal-based form is unable to function in humans because it does not carry “the information” to encode the “required” RBD and PCS. Viruses, just like every living thing, are mutating during every generation; it’s a natural result of evolution. Just by chance (or dumb luck), this virus mutated — either between two animal species before jumping to humans or after jumping into humans. Following this chance mutational event(s), the virus was then able to enter human white cells, causing an enormous cytokine storm in some (but not most; remember we all exhibit MANY genetic differences 😊) people that leads to lung fluid accumulation, pulmonary fibrosis, and subsequent serious heart inflammation.

The genomic features [there are 29,903 bases of positive-sense-single-stranded RNA; (+)ssRNA] discussed in this Letter [see attached] may help to explain, in part, the efficiency of the infectiousness and transmissibility of SARS-CoV-2 in humans. Although the evidence shows that SARS-CoV-2 is not a purposefully (i.e. lab-manipulated) manufactured virus, it is currently impossible to prove or disprove the other theories of its origin detailed in this Letter. However, because the authors identified all notable SARS-CoV-2 features — including the optimized RBD and polybasic cleavage site — in related “naturally-occurring” coronaviruses, they are convinced that no type of laboratory-based scenario is plausible.

More scientific data could swing the balance of evidence to favor one hypothesis over another (i.e. adaptation in a second animal strain before it jumped to humans — versus adaptation AFTER it jumped into humans). Obtaining related viral sequences from animal sources will be the most definitive way of revealing viral origins [e.g. future discovery of an intermediate or fully-formed polybasic cleavage site in a SARS-CoV-2 -like virus from animals would lend further support to the former (pre-adaptation in animals) hypothesis]. It will also be helpful to obtain more genetic and functional data about SARS-CoV-2, including animal studies; identification of a potential intermediate host of SARS-CoV-2 — as well as sequencing the viral single-stranded RNA from very early clinical cases — would similarly be highly informative. Irrespective of the exact mechanisms by which SARS-CoV-2 originated via natural selection, the ongoing surveillance (i.e. nucleotide-sequencing) of any new pneumonia in humans, and other animals, is clearly of utmost importance. 😊

DwN

Nature Med [submitted 11 Mar 2020] published online 24 Mar 2020

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