Friday, November 20, 2020

Preprint: Recurrent Mutations in SARS-CoV-2 Genomes Isolated from Mink Point to Rapid Host-Adaptation


#15,571

Yesterday, in EID Journal: SARS-CoV-2 Transmission between Mink (Neovison vison) and Humans, Denmark, we looked at study from researchers at the University of Copenhagen, Copenhagen, Denmark and the Statens Serum Institut, that described the recent zoonotic spread of a mutated COVID-19 virus from mink to humans in Denmark.

This variant COVID-19 strain had mutated after being introduced to a mink farm by a human carrier, and then adapting as it passaged through hundreds, perhaps thousands of mink. Essentially mimicking the classic serial passage experiment illustrated above. 

The process (see graphic above) is fairly simple; You inoculate a naive host with a strain of a virus, let it replicate for awhile, then take the virus from the first host and inoculate a second, and then repeat the process five, ten, fifteen times or more.

All viruses mutate over time, but RNA viruses are notorious for making minor replication errors in their genome.  Most are benign, or even detrimental to the virus.  While these mutations are random, those  that favor survival in the new host tend to dominate or even supplant less efficient iterations. 
 
Over time, a better `adapted' virus often emerges. 

This simulates in the laboratory - in a controlled way - pretty much what goes on in the `wild' all the time. The advantage is you can compare the original virus to the downstream `adapted' virus at specific intervals to find out what genetic changes have occurred and document any behavioral changes.

Today we've a new (preprint) study from researchers at University College London, that examines hundreds of published SARS-CoV-2 genomes isolated from minks for the presence of recurrent mutations that are infrequently seen in SARS-CoV-2 genomes isolated from humans. 

I've only reproduced the abstract, and a small excerpt from the discussion.  Follow the link to download and read the full 27-page PDF File.  

Recurrent mutations in SARS-CoV-2 genomes isolated from mink point to rapid host-adaptation
Lucy van Dorp, Cedric CS Tan, Su Datt Lam, Damien Richard, Christopher Owen, Dorothea Berchtold, Christine Orengo, Fran├žois Balloux
doi: https://doi.org/10.1101/2020.11.16.384743

This article is a preprint and has not been certified by peer review [what does this mean?].
Abstract
Severe acute respiratory coronavirus 2 (SARS-CoV-2), the agent of the ongoing COVID-19 pandemic, jumped into humans from an unknown animal reservoir in late 2019. In line with other coronaviruses, SARS-CoV-2 has the potential to infect a broad range of hosts.
SARS-CoV-2 genomes have now been isolated from cats, dogs, lions, tigers and minks. SARS-CoV-2 seems to transmit particularly well in mink farms with outbreaks reported in Spain, Sweden, the Netherlands, Italy, the USA and Denmark.
Genomic data from SARS-CoV-2 isolated from infected minks provides a natural case study of a secondary host jump of the virus, in this case from humans to animals, and occasionally back again. We screened published SARS-CoV-2 genomes isolated from minks for the presence of recurrent mutations common in mink but infrequent in SARS-CoV-2 genomes isolated from human infections.
We identify 23 recurrent mutations including three nonsynonymous mutations in the Receptor Binding Domain of the SARS-CoV-2 spike protein that independently emerged at least four times but are only rarely observed in human lineages. The repeat emergence of mutations across phylogenetically distinct lineages of the virus isolated from minks points to ongoing adaptation of SARS-CoV-2 to a new host.
The rapid acquisition and spread of SARS-CoV-2 mutations in minks suggests that if a similar phenomenon of host adaptation had occurred upon its jump into humans, those human-specific mutations would likely have reached fixation already before the first SARS-CoV-2 genomes were generated.

(SNIP)

The secondary transmissions of SARS-CoV-2 from humans into minks provides a set of ‘natural experiments’ to identify mutations involved in the adaptation of the virus to a novel host. By analysing SARS-CoV-2 isolated from minks, we recovered 23 mutations having independently emerged multiple times.

By restricting this set to the nonsynonymous mutations that have appeared at least three times in mink, we identify seven variants that are strong candidates for host adaptation to minks (Figure 2, Table S4). These seven candidates comprise a recurrent change in nsp9 of Orf1ab, a region involved in mediating viral replication84, as well as the repeat emergence of three mutations in Orf3a, a protein thought to play an important role in triggering host inflammatory response85,86 . 

         (Continue . . . )


Because a mink farm can house thousands of mink in close quarters, the ability of a novel virus like SARS-CoV-2 to spread like wildfire - and accrue mutations - is far greater than what might occur with other susceptible hosts - like companion animals (i.e. dog & cats) or Mustelids (ferrets, mink, weasels, etc.) in the wild.

Other farmed animals (poultry, swine, cattle, etc.) appear far less susceptible to the virus, making them unlikely intermediate hosts, or non-human reservoirs for the virus (see Susceptibility of Ferrets, Cats, Dogs & Other Domestic Animals to SARS-CoV-2).

The $64 question is whether a mink (or other intermediate host) adapted COVID-19 virus - if reintroduced back in to the human population - could become more virulent in humans, evade current vaccine candidates, or otherwise exacerbate our current pandemic. 

And the answer is, we don't know.  

So far, the mink-adapted viruses that have been detected in humans don't appear to be any more pathogenic than their progenitor strains, and a week ago Denmark's Serum Statens Institute issued a fairly upbeat update, indicating they had not detected their problematic `5th cluster strain' in humans since mid-September, and may have contained (or eradicated) the threat.

But of course, Nature's laboratory is open 24/7.

Meaning there will be many more rolls of the genetic dice ahead, making more opportunities for surprises along the way.