As with all previous outbreaks of new virus infections, we are being warned of impending doom concerning the new coronavirus, 2019-nCoV that is now spreading globally. China€™s National Health Commission Vice Minister Li Bin recently warned that ‘there is the possibility of viral mutation€™. Perhaps Mr. Li is unaware that viral genomes sustain mutations during every replication cycle. More importantly, the implication of his message is that with mutation, bad things will happen. But outbreak-associated mutations do not have to increase viral replication or virulence.
As a new virus circulates in humans, mutations in the genomes occur, and some are fixed – that is, they remain as virus transmission continues. SARS-CoV, which emerged in humans in China in 2003 after transmission from open meat markets, is an example of what can be learned from the study of such changes. During the middle and late phase of the epidemic, a 29 nucleotide deletion occurred in the viral genome, in a region called Orf8, which encodes a small polypeptide. Viruses with this deletion were present in most isolates from humans during this phase of the epidemic.
It was subsequently suggested that the 29 nucleotide deletion was somehow involved in adaptation of SARS-CoV to humans. Some evidence for this hypothesis included the observation that virus replication increased in cells that over produce the protein encoded in Orf8. Furthermore, the results of some studies suggested that the Orf8 protein antagonizes the antiviral activities of interferon.
Results of a subsequent study show that the 29 nucleotide deletion decreases viral replication in a number of different cell types, including human airway epithelial cell cultures. In other words, this virus is debilitated, compared with a virus containing a full Orf8.
Normally a mutation that leads to a loss of viral fitness will disappear from the population, because viral lineages with the mutation cannot compete with more fit viruses circulating in humans. Surprisingly, during the SARS outbreak, a less fit virus remained. The authors suggest that this unusual event occurred because there was no competition – SARS-CoV had just spilled over from bats and was unique to humans. It didn€™t matter that the virus was somewhat wimpy – there were no other similar viruses to outcompete it.
The 29 nucleotide deletion likely arose randomly (the deletion is not found in coronaviruses from Asian bats) and remained. It has nothing to do with adaptation to humans. In retrospect, the SARS outbreak might have been more severe had the deletion not taken place. Perhaps it is one reason why it was possible to extinguish the outbreak.
Mutations have been identified in the genomes of other zoonotic viruses, including MERS-CoV, that might also reduce virulence of the virus for humans. A single amino acid change in the ebolavirus glycoprotein has been suggested to increase replication and therefore transmission in humans. However subsequent studies showed that the change reduces virulence in animal models. It is interesting to consider that in all these cases, the selection for mutations that reduce virulence might prolong survival time of the host to allow transmission to others. Such a scenario is consistent with the fact that the strongest selection force on a viral genome is transmission to another host.
The current outbreak by a new coronavirus, 2019-nCoV, appears to have started in an open market in Wuhan, China. It seems likely that the original host was a bat, but that remains to be proven. The genome sequence of 2019-CoV shows that Orf8 is intact. If it is not lost during subsequent virus circulation in humans, the outbreak could be more severe.
10 thoughts on “A lesson from SARS-CoV for 2019-nCoV”
One of the biggest questions for me is why are corona viruses causing so much disease now. Before the SARS outbreak I was aware the corona viruses cause flu like symptoms but I donâ€™t remember them being linked to significant disease outbreaks. If this is right, have these viruses always been around and globalisation and better analysis have led to their spread and identification, or is there another reason for their spread and increased virulence?
Thanks for this insightful article !
I have always wondered why the 2003 SARS outbreak could be contained relatively easily, given the fact that it already spread globally and that obvious sustained human-to-human transmission was happening not only in hospital settings but also in the general community ( For example the super spreader event in the Hongkong Metropole Hotel early in the epidemic or the large outbreak in the Amoy Garden private housing complex ).
As far as I know it is epidemiologically impossible to ‘contain’ any respiratory virus that has the ability for effective,sustained human-to-human transmission in the general community (R0>1). What can be done is to only *delay* the spread in certain areas.
But in the end it is only the growing herd immunity (lack of further host to infect, also due to mortality ) of the population of the community that will eventually stop the epidemic.
Another explanation for the extinction of the SARS epidemic, then, would be as suggested in the article: that virus transmissibility becomes less efficient with increasing numbers of generations in the human host.
However, there is one sentence in the article I do not quite understand:
“It didnâ€™t matter that the virus was somewhat wimpy â€“ there were no other similar viruses to outcompete it.”
But what about the obvious competition with all the other much more numerous and more virulent viruses that do not have that “virulence-attenuating” mutation ?
Thanks for this special article that let me learn about some different information about 2019-nCov !
Looking forward to your next article about 2019-nCoV !
Iâ€™m not a virologist but In regards to the question about viral competition he is referring to competition with another strain of the same virus. Think of all the influenza viruses as competing with one another. One particularly hot strain, say the 1918 flu, would burn out OR hybridized with a less aggressive strain. The goal is survival and transmission to another host. It would benefit a virus to balance R0 with case fatality for its own survival. Flu is a good example but I also think about syphillis and varicella evolution as being similar. But again, Iâ€™m just a nurse and not a virologist. Great article.
CDC have published the full genome of the Ncov 2019. According to some articles viral partical has not been undergone a mutations. If so cann’t we use the genetic sequence to produce antibodies against this virus.
I think the interpretation and information of the 29-nucleotide deletion from the human SARS CoV is wrong based on the research that we published in 2007 in Journal of Infectious Disease (featured article of the issue). https://www.ncbi.nlm.nih.gov/pubmed/17597455/
I think the deletion of 29 nucleotides makes the human SARS CoV more pathogenic and fitter than its ancestor virus.
I attached the abstract of our publication as follows:
Open reading frame 8a of the human severe acute respiratory syndrome coronavirus not only promotes viral replication but also induces apoptosis.
Chen CY, et al. J Infect Dis. 2007.
BACKGROUND: A unique genomic difference between human and civet severe acute respiratory syndrome coronaviruses (SARS-CoVs) is that the former has a deletion of 29 nucleotides from open reading frame (orf) 8a’ that results in the generation of orf8a and orf8b. The objectives of the present study were to analyze antibody reactivity to ORF8a in patients with SARS and to elucidate the function of ORF8a.
METHODS: Western-blot and immunofluorescent antibody assays were used to detect anti-ORF8a antibody. SARS-CoV HKU39849 was used to infect stable clones expressing ORF8a and cells transfected with small interfering RNA (siRNA). The virus loads (VLs) and cytopathic effects (CPEs) were recorded. Confocal microscopy and several mitochondria-related tests were used to study the function of ORF8a.
RESULTS: Two (5.4%) of 37 patients with SARS had anti-ORF8a antibodies. The VLs in the stable clones expressing ORF8a were significantly higher than those in control subjects 5 days after infection. siRNA against orf8a significantly reduced VLs and interrupted the CPE. ORF8a was found to be localized in mitochondria, and overexpression resulted in increases in mitochondrial transmembrane potential, reactive oxygen species production, caspase 3 activity, and cellular apoptosis.
CONCLUSIONS: ORF8a not only enhances viral replication but also induces apoptosis through a mitochondria-dependent pathway.
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Two sentences peaked my interest.
“The 29 nucleotide deletion likely arose randomly (the deletion is not found in coronaviruses from Asian bats) and remained. It has nothing to do with adaptation to humans. ”
What interested me was 1) the use of the words “likely arose randomly” and 2) “nothing to do with adaptation to humans.”
What, then, are the unlikely, non-random possibilities for the deletion/recombination within the spike glycoprotein; and, if not for adaptation, what might be the cause behind the seemingly haphazard deletion/recombination detected on various sub-strain spikes?
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I agree with William’s belief that the “weaker” virus thrived because it does not kill the host before the infection can be spread to new hosts. An extremely virulent virus that kills the host before the infection can spread would have a competitive disadvantage.
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