Researchers have identified microscopic features that may make this pathogen more infectious than the SARS Virus and can serve as drug targets.
With nearly 100,000 people infected with SARS-CoV-2 worldwide, researchers are racing to understand what makes it so easy to spread.
Several genetic and structural analyses have identified a key feature of this virus—a Protein on the surface—which may explain why it is so susceptible to infect human cells.
Other groups are studying how SARS-CoV-2 enters human tissue. Both cellular receptors and viral proteins provide potential targets for drugs to block pathogens, but researchers say they are not yet certain.
“Understanding the spread of the virus is key to control and future prevention,” says David Veesler, a structural virologist at the University of Washington in Seattle, who released his team’s findings on viral proteins on the biomedical preprint server bioRxiv on February 20.
The SARS-CoV-2 spreads much easier than the virus that causes severe acute respiratory syndrome (SARS), also a coronavirus, and infects more than ten times as many people as SARS.
Stinging intruder
To infect cells, coronaviruses use a “spike” protein (S protein) to bind to the cell membrane, and the process is activated by specific cellular enzymes. Genomic analysis of this novel coronavirus showed that its peak protein was different from those of close relatives and showed that there was a site on this protein that was activated by a host cell enzyme called flynase.
Li Hua, a structural biologist at Huazhong University of Science and Technology, said it was significant because Flynn proteases are present in a large number of human tissues, including the lung, liver, and small intestine, which means that the virus has the potential to attack multiple organs. Li said the findings could explain some of the symptoms observed in patients with SARS-CoV-2 infection, such as liver failure. On Feb. 23, Li and others collaborated on a viral genetic analysis report, which was released on ChinaXiv’s preprinted server. He said SARS and other coronaviruses, which belong to the same family as the new virus, do not have Flynn protease activation sites.
Gary Whittaker, a virologist at Cornell University in New York, said the Flynn protease activation site makes the virus enter cells in a very different way than SARS and may affect the stability of the virus and thus affect transmission. His team published another structural analysis of coronavirus peak proteins on bioRxiv on February 18.
Several other groups have also identified this activation site and believe that it may enable the virus to spread effectively between humans. They point out that these sites are also present in other viruses that are easily transmitted from person to person, including severe influenza virus strains. On these viruses, the activation site is on a protein called hemagglutinin, not on spike proteins.
Calls for caution
But some researchers are cautious about the role of exaggerated activation sites in helping coronaviruses spread more easily. “We don’t know if this will be a big question,” says Jason McLellan, a structural biologist at the University of Texas at Austin. He and others co-authored another structural analysis of coronaviruses, which was published in the February 20 issue of Science.
Other scientists are cautious about comparing the activation site of influenza viruses with that of SARS-CoV-2. Peter White, a virologist at the University of New South Wales in Sydney, Australia, says the hemagglutinin protein on the surface of the influenza virus is neither similar nor related to the peak protein of the coronavirus.
Rong Lijun, a virologist at the University of Illinois in Chicago, said the influenza virus that caused the deadliest influenza pandemic on record (the 1918 Spanish influenza pandemic) did not even have a Flynase activation site.
Whittaker says studies in cells or animal models are needed to test the function of the activation site. “Coronaviruses are unpredictable, and good assumptions often prove wrong,” he said. His team is currently testing how removing or modifying this site affects the function of the S protein.
Drug Target
Li’s team is also studying molecules that can prevent flynase, which may be a possible treatment. But their progress was slow due to the outbreak. Li lives on campus and is currently the only member with access to the team laboratory.
McLellan’s team in Texas discovered another feature that could explain why SARS-CoV-2 was so successful in infecting human cells. Their experiments showed that this S protein binds to a receptor on human cells, angiotensin-converting enzyme 2 (ACE2), at least ten times more tightly than the S protein in the SARS virus. This was also found by Veesler’s team, suggesting that the recipient is another potential target for vaccines or therapies. For example, a drug that blocks the receptor may make it harder for coronaviruses to enter cells.
Reference
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