This week in Covid 19 Science: Snakes? Pangolins, Transmission & Reproduction

Pools of data, information and research are being shared across borders as an international quest drives our species in a fight for survival.  While the focus of our news is on the slowing down of the spread, painstaking hours have gone into dissecting the data of the various stages of the disease to understand how to defeat it.

The genetic quest to understand COVID-19

Unlocking the genetic code of the novel coronavirus will help us prevent other diseases.

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It drives the quest in understanding how the virus made the leap from animals to humans – a puzzle that scientists are trying to solve as humanity comes to grip with the deadly pandemic sweeping the globe.

At the frontline of this scientific work is Professor Edward Holmes, an evolutionary virologist who holds a joint position with the School of Life and Environmental Sciences and the School of Medical Sciences at the University of Sydney.

He has been working closely with scientists in China and around the world to unlock the genetic code of SARS-CoV-2, which is the virus that causes COVID-19, to understand its origins and assist in the race other scientists are engaged in to find an effective vaccine.  Their work will also help in the monitoring and prevention of other viruses that could potentially transfer from wildlife into humans, causing what are known as zoonotic diseases.  Already this year, Professor Holmes has co-authored four papers on the novel coronavirus.  This past week publishing two more.

The first paper identifies a similar coronavirus to the one now infecting humans in the Malayan pangolin population of southern China.

Understanding the evolutionary pathway by which this novel coronavirus has transferred to humans will help us not only combat the current pandemic but assist in identifying future threats from other coronaviruses in other species.

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Native in Asia and Sub-Saharan Africa, could Pangolins (anteaters) hold the key to unlocking our problems?  

“The role that pangolins play in the emergence of SARS-CoV-2 (the cause of COVID-19) is still unclear.  However, it is striking is that the pangolin viruses contain some genomic regions that are very closely related to the human virus.: explains Holmes. :The most important of these is the receptor binding domain that dictates how the virus is able to attach and infect human cells.”

The paper identifies pangolins as possible intermediate hosts for the novel human virus that has emerged.  The authors call for these animals and others to be removed from wet markets in order to prevent zoonotic transmission to humans.

“It is clear that wildlife contains many coronaviruses that could potentially emerge in humans in the future.  A crucial lesson from this pandemic to help prevent the next one is that humans must reduce their exposure to wildlife, for example by banning ‘wet markets’ and the trade in wildlife.” continued Holmes.

The paper in last week’s Nature Medicine co-authored with scientists from Scripps Research Institute in La Jolla California, the University of Edinburgh, Colombia University in New York and Tulane University in New Orleans, has dispelled the fanciful idea that the novel coronavirus was a manufactured biological agent.

And this week Holmes published commentary in Cell with colleague, Professor Yong-Zhen Zhang from the Shanghai Public Health Clinical Centre and the School of Life Science at Fudan University, Shanghai –  outlining our current knowledge of what the genomic data reveals about the emergence of SARS-CoV-2 virus and discuss the gaps in our knowledge.

This includes taking samples from the Wuhan wet market where it is believed the virus originated.  The paper says that “genome sequences of ‘environmental samples’ — likely surfaces — from the market have now been obtained and phylogenetic analysis reveals that they are very closely related to viruses sampled from the earliest Wuhan patients.”

However, Professor Holmes and Professor Zhang are quick to point out that as “not all of the early [COVID-19] cases were market associated, it is possible that the emergence story is more complicated than first suspected.”

The paper says that the SARS-CoV-2 virus is likely to become the fifth endemic coronavirus in the human population.  It concludes that “coronaviruses clearly have the capacity to jump species boundaries and adapt to new hosts, making it straightforward to predict that more will emerge in the future.”

How we respond to that will require more research to assist develop public health policy. They point to policy and other measures to help prevent other coronaviruses becoming a health danger to humans.

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These include:

Surveillance of animal coronaviruses in a variety of mammalian species. It is known that bats carry many coronaviruses, we know little about what other species carry these viruses and which has the potential to emerge in humans.

Increase action against the illegal wildlife trade of exotic animals

Removal of mammalian and perhaps avian wildlife from wet markets

When they figured out it was from Pangolins, not snakes:

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The recent study that analysed the new virus’ genome suggested snakes as this host, despite the fact that coronaviruses are only known to infect mammals and birds. Meanwhile, an unrelated study compared the sequence of the spike protein — a key protein responsible for getting the virus into mammalian cells — of the new coronavirus to that of HIV-1, noting unexpected similarities.   Although the authors withdrew this preprint manuscript after scientific criticism, it spawned rumors and conspiracy theories that the new coronavirus could have been engineered in a lab.  Yang Zhang and colleagues wanted to conduct a more careful and complete analysis of SARS-CoV-2 DNA and protein sequences to resolve these issues.

Compared to the previous studies, the researchers used larger data sets and newer, more accurate bioinformatics methods and databases to analyze the SARS-CoV-2 genome. They found that, in contrast to the claim that four regions of the spike protein were uniquely shared between SARS-CoV-2 and HIV-1, the four sequence segments could be found in other viruses, including bat coronavirus.

After uncovering an error in the analysis that suggested snakes as an intermediate host, the team searched DNA and protein sequences isolated from pangolin tissues for ones similar to SARS-CoV-2.  The researchers identified protein sequences in sick animals’ lungs that were 91% identical to the human virus’ proteins.  Moreover, the receptor binding domain of the spike protein from the pangolin coronavirus had only five amino acid differences from SARS-CoV-2, compared with 19 differences between the human and bat viral proteins.  This evidence points to the pangolin as the most likely intermediate host for the new coronavirus, but additional intermediate hosts could be possible, the researchers say.

How to identify factors affecting COVID-19 transmission

Much remains unknown about how SARS-CoV-2, the virus that causes COVID-19, spreads through the environment.   A major reason for this is that the behaviors and traits of viruses are highly variable — some spread more easily through water, others through air; some are wrapped in layers of fatty molecules that help them avoid their host’s immune system, while others are “naked.”

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This makes it urgent for environmental engineers and scientists to collaborate on pinpointing viral and environmental characteristics that affect transmission via surfaces, the air and fecal matter, according to Alexandria Boehm, a Stanford professor of civil and environmental engineering, and Krista Wigginton, the Shimizu Visiting Professor in Stanford’s department of civil and environmental engineering and an associate professor at the University of Michigan.

Their article in Environmental Science & Technology called for a broader, long-term and more quantitative approach to understanding viruses, such as SARS-CoV-2, that are spread through the environment.  They are also principal investigators on a recently announced National Science Foundation-funded project to study the transfer of coronaviruses between skin and other materials, the effect of UV and sunlight on the coronaviruses, and the connection between disease outbreaks and virus concentrations in wastewater.

“When a new virus emerges and poses a risk to human health, we don’t have a good way of predicting how it will behave in the environment,” Boehm said.  “There has been much more work on the fate of non-enveloped or naked viruses because most intestinal pathogens in excrement are nonenveloped viruses — like norovirus and rotavirus,” said Wigginton.

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In their paper, Boem and Wigginton address potential threats that viruses such as SARS-CoV-2 pose to water sources.   We usually only worry about viruses in water if they are excreted by humans in their feces and urine.  Most enveloped viruses aren’t excreted in feces or urine, so they aren’t usually on our minds when it comes to our water sources.  There is increasing evidence that the SARS-CoV-2 viruses, or at least their genomes, are excreted in feces.  If infective viruses are excreted, then fecal exposure could be a route of transmission, according to Boehm, who added, “It’s unlikely this could be a major transmission route, but a person could potentially be exposed by interacting with water contaminated with untreated fecal matter.”

Drinking water treatment systems have numerous treatment barriers to remove the most prevalent viruses and the most difficult-to-remove viruses, according to the engineers. Research on viruses similar to the SARS-CoV-2 virus suggests they are susceptible to these treatments. “In terms of virus concentration and persistence, this isn’t a worst-case scenario,” Wigginton said.

Broadly, Wigginton and Boehm write, we tend to study viruses very intensely when there is an outbreak, but the results from one virus aren’t easy to extrapolate to other viruses that emerge years later. “If we took a broader approach to studying many kinds of viruses, we could better understand the characteristics driving their environmental fate,” Wigginton said.

A possible treatment for COVID-19 and an approach for developing others

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SARS-CoV-2, the virus that causes COVID-19 disease is more transmissible, but has a lower mortality rate than its sibling, SARS-CoV, according to a review article published this week in Antimicrobial Agents and Chemotherapy, a journal of the American Society for Microbiology.

In humans, coronaviruses cause mainly respiratory infections.  Individuals with SARS-CoV-2 may remain asymptomatic for 2 to 14 days post-infection and some individuals likely transmit the virus without developing disease symptoms.

So far, the most promising compound for treating COVID-19 is the antiviral, remdesivir. It is currently in clinical trials for treating Ebola virus infections.

Remdesivir was recently tested in a non-human primate model of MERS-CoV infection. Prophylactic treatment 24 hours prior to inoculation prevented MERS-CoV from causing clinical disease and inhibited viral replication in lung tissues, preventing formation of lung lesions.  Initiation of treatment 12 hours after virus inoculation was similarly effective.

Remdesivir has also shown effectiveness against a wide range of coronaviruses. It has already undergone safety testing in clinical trials for Ebola, thereby reducing the time that would be necessary for conducting clinical trials for SARS-CoV-2.

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In early tests, Coronavirus has been manipulated into incorporating the active form of the drug into its genome, stifling its ability to reproduce itself.

Nonetheless, much work needs to be done to gain a better understanding of the mechanics of SARS-CoV-2. For example, understanding how SARS-CoV-2 interacts with the host ACE2 receptor — by which SARS-CoV-2 gains entry into the host (whether human or animal) — might reveal how this virus overcame the species barrier between animals and humans. This could also lead to design of new antivirals.

Although coronaviruses are common in bats, no direct animal source of the epidemic has been identified to date, according to the report. “It is critical to identify the intermediate species to stop the current spread and to prevent future human SARS-related coronavirus epidemics,” the researchers write

Research: Sydney University, Stanford University, American Chemical Society, American Society for Microbiology  | Photography:  Amar Shrestha, Travel Faery / Getty Images

 


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