February 3, 2020

expert reaction to two Nature papers looking at the genome sequence and characteristics of the novel coronavirus

Two studies, published in the journal Nature, report on the the genome sequence and characteristics of the novel coronavirus.

Prof Ian Jones, Professor of Virology, University of Reading, said:

“These two scientific papers provide the formal evidence for what is already widely known.  2019-nCoV is a bat virus, and SARS-CoV, which caused an epidemic in 2002/3, is the closest relative seen previously in people.  In essence, it’s a version of SARS that spreads more easily but causes less damage.  The virus also uses the same receptor, the door used to get into human cells, which explains transmission and why it causes pneumonia.  Most encouragingly though, this indicates that treatments and vaccines developed for SARS should work for the Wuhan virus.”

Dr Michael Skinner, Reader in Virology, Imperial College London, said:

“The Wu paper is the first publication by those who published the first full genome sequence (https://www.ncbi.nlm.nih.gov/nuccore/MN908947) of what they refer to as WHCV (WH Human 1 coronavirus), now officially called 2019-nCoV, as isolated from an intensive care patient who worked at the local seafood market.  The sequence was hotly awaited and its prompt, early release pre-publication has been rightly and widely applauded.

“Their analysis showed that WHCV was fairly closely related to SARS and some known SARS-like viruses found previously in bats.  It was most closely related to bat virus ZC45.  Viruses like ZC45, though SARS-like, are unable to infect humans as their ‘spike’ protein is unable to bind the human protein ACE-2 used as a receptor by SARS.  SARS is believed to have evolved from bat SARS-like viruses after acquisition (by recombination, or sequence exchange) of human ACE2-binding sequence from another bat virus (which was not otherwise SARS-like).  The sequence from WHCV, however, notably differs from ZC45 in the region needed to bind human ACE2.  It also actually differs significantly from SARS in that region.

“The manuscript by Zhou et al. has been widely read, and commented on, as a BiorXiv preprint.  They identified nCoV in 7 patients (6 of whom sold at or delivered from the fish market), and sequenced virus from one of them.  They too observed close similarity of nCoV to ZC45, except in the receptor-binding domain.  However, they had access to the sequence of another bat SARS-like virus, TG13, found in a Rhinolophus affinus bat from Yunnan Province.  TG13 was even more closely related than ZC45 to nCoV and, remarkably, that similarity spanned the receptor-binding sequence.  However, TG13 and nCoV are not 100% identical (the figure is 96.2% overall); the early release of the sequences and the preprint means that others are also looking at their evolutionary relationship but, following this discovery, all now agree that recombination has not played a role in recent evolution of nCoV.  The analysis is difficult because there is evidence of multiple ancestral recombination events affecting different genes of this large RNA virus, this being typical of the evolution of coronaviruses from livestock and companion animal species, due to the peculiarities of their replication cycle.

“The discovery definitely places the origin of nCoV in bats in China.  We still do not know whether another species served as an intermediate host to amplify the virus (and possibly even to bring it to the market), nor what species that host might have been, but the high level of sequence similarity between nCoV and TG13 is not really compatible with some of the more exotic hosts that were considered earlier in the epidemic.  Crucially, Zhou et al. also showed that nCoV can bind ACE2 from horseshoe bats and humans, as well as those from civets and pigs (making them possible intermediates – among many others), but not mice (ruling them out).  They also showed it does not bind the MERS virus receptor DPP4 nor APN, that of the “older” mild human respiratory viruses.

“The now recognised (but as yet unquantified) spread of nCoV from infected humans before they become symptomatic was surprising as it is a feature more of influenza (which uses as receptor a molecule called sialic acid (SA), found in the upper airways) than SARS, where the ACE2 receptor is found deep in the lungs in the alveoli.  The long known but mild human coronaviruses (e.g. OC43) also bind SA (as well as APN), allowing them to cause common colds, and their ‘spike’ differs from that of SARS at one end of the protein.  Wu et al. point out that this region of WHCV is more like SARS than OC43 but Zhou et al. speculate whether short insertions in this region in nCoV (and TG13) might allow it to bind SA as well as ACE2.

“Together, these papers describe the first steps in understanding the evolutionary and epidemiological origins of WHCV/2019-nCoV.  The speed of their appearance attests to the rapid pace and extent of scientific and technological progress, globally – but not least in China, since the SARS epidemic in 2002-3.  They confirm some of the early suspicions, discount others and, typically, raise even more questions that many are already trying to answer – but those answers need more information, which may not be forthcoming for several years.”

Paper 1: ‘A pneumonia outbreak associated with a new coronavirus of probable bat origin’ by Peng Zhou et al. was published in Nature on Monday 3 February 2020 (last author Shi).

DOI: 10.1038/s41586-020-2012-7

Paper 2: ‘A new coronavirus associated with human respiratory disease in China’ by Fan Wu et al. was published in Nature on Monday 3 February 2020(last author Zhang).

DOI: 10.1038/s41586-020-2008-3

All our previous output on coronavirus can be seen at this weblink:

http://www.sciencemediacentre.org/tag/wuhan-coronavirus/

Declared interests

Dr Michael Skinner: “Dr Mike Skinner is a [semi-retired] Reader in Virology at Imperial College London.  His introduction to virology was with mouse coronaviruses at the hands of Stuart Siddell working in Germany long before SARS emerged.  He’s since worked on poliovirus vaccines, HIV and avian viruses (including viruses that have emerged to threaten global poultry production).  He takes avid interest in emerging viruses and vaccines.  He still works on projects led by others and funded by the BBSRC.  He no longer has any direct or indirect current interest in coronaviruses.”

None others received.