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Coronaviruses that Spillover

In the Family

Coronaviruses cause diseases in humans ranging from mild colds that annoy the sufferer to MERS that kills 37% of those infected. Seven types affect humans so far, but thousands exist. Most come from bats, and some come from rats.

Even in the Severe acute respiratory syndrome-related coronavirus, variations come from different spillover events. The variations cause many diseases if they spill over at all.

Humans are all related, living all over the planet with different lifestyles and appearances. We can know only so much about humanity from one individual. But we can learn about a family from an individual member.

For the current pandemic, we can study the “individual” causing it by comparing it to its older, 96% identical sibling.

SARS coronavirus, or SARS-CoV, first spilled over in 2002. Most of our knowledge from it over the years applies to SARS coronavirus-2 or SARS-CoV-2.

The World Health Organization abandoned systematic, clinical naming for this particular outbreak. Scientists have ignored this change. They have kept the old rules, which means that COVID-19 is also SARS-2.

“We are scientists. We want clarity, not obfuscation. We will use this name because it is accurate and informative, revealing the high similarity between these two pathogens. This name thus reminds us that we can infer a lot about SARS-CoV-2 from existing data on SARS-CoV.”

Michael Lin, biologist, Stanford University
Novel Coronavirus SARS-CoV-2
National Institute of Allergy and Infectious Diseases slideshow of SARS-CoV-2.

Lock and Key

The similarity scientists look at is the lock and key mechanism. On their surface, coronaviruses have club-shaped keys that stick out. They meet chemical locks on the surface of animal cells.

Locks are unique to every strain of the virus, and key mechanisms are unique to every animal species. Because viruses mutate so fast, a virus jumping between host species is still the same virus. But the key changed.

SARS-CoV and SAR-CoV-2 have six critical points on their keys to infect cells.

If the virus stays in one host species for a short time, the keys fail to adjust. If the virus jumps again, it still will have some points for the previous host and some for the new host. If a virus stays in one species for a long time, it will optimize. From there, it may continue to mutate into different strains.

The shape and chemistry of the lock and key show a history of the virus.

Researchers traced SARS-CoV to wild civets through locks and keys. And then, from genome sequencing, they traced the virus to bats. That’s why some researchers suspect SARS-CoV-2 emerged in pangolins from bats.

It’s also why primates, pigs, and cats receive the same spillovers from bats: we all have similar locks.

Pigs even suffered from an outbreak in 2016 in the same region as the first SARS. A virus 98% identical to a virus found in horseshoe bats in Yunnan province caused swine acute diarrhea syndrome (SADS). It killed 25,000 pigs.

Asian palm civet (photo courtesy of Bernard Dupont), Chinese pangolin (photo courtesy of Flickr user verdammelt), pigs at finishing farm (photo courtesy of Pork Checkoff).

Detective Work in Epidemiology

Scientists struggle to see if the disease—not the virus—started in pangolins or humans. Did the disease emerge in pangolins and then jumped with the virus into people? Or did the virus jump into people and mutated and transmitted until it “learned” how to cause the disease?

The latter would explain why a third of China’s first official cases had no associations with the Huanan Seafood Wholesale Market. It would also explain why the first official case preceded the others by a week.

“That’s a big number, 13, with no link.”

Daniel Lucey, infectious disease specialist, Georgetown University

“If the new data are accurate, the first human infections must have occurred in November 2019—if not earlier—because there is an incubation time between infection and symptoms surfacing. If so, the virus possibly spread silently between people in Wuhan—and perhaps elsewhere—before the cluster of cases from the city’s now-infamous Huanan Seafood Wholesale Market was discovered in late December.”

Kat Eschner, writer, Popular Science

“The virus came into that marketplace before it came out of that marketplace.”

Daniel Lucey, infectious disease specialist, Georgetown University

Virologists can also create infectious chimeric viruses, though some countries ban the practice. They engineer the keys from civet strain SARS-CoVs with the “backbone” or core body from other viruses. Then researchers study what increases or decreases infectiousness.

Despite the knowledge from this research, SARS-CoV-2 shows ingenuity. It has optimized for humans at the most critical key point in a way that scientists have never seen. It also has a unique backbone.

But many laboratories grow natural bat coronaviruses that sometimes escape. So “engineered” and “laboratory-released” don’t mean the same. Even a laboratory-released SARS-CoV-2 source would need to mutate its way through the ecosystem to have the genetic story it has so far told us.

Chimeric viruses also happen in nature, and they likely apply to SARS-CoV-2.

The virus has almost identical keys for pangolins and humans. It also has a near-identical genome to a virus retrieved from horseshoe bats in Yunnan province in 2013. Yet, neither of these relations directly precede SARS-CoV-2. In a sense, it’s an orphan.

Many viruses clone themselves in cells and evolve through mutations. But not coronaviruses or even HIV.

If two capable viruses meet in a cell, they can mix or recombine their genes and emerge unique from the cell. Scientists link recombination with a broader host geographical range, more disease severity, better avoidance of the host’s immune system, and resistance to antivirals.

The keys and genome sequencing are also how we can trace three types of human SARS-CoV-2 and subtypes in different countries.

The pandemic traces to a first-generation from China. A second generation came out of the free exchange of genetics across the world. Everyone has these two types. Then Europe got the third generation from non-Chinese second-generation types.

Go to Nextstrain and play the animation that follows the SARS-CoV-2’s genetic changes and geographic paths.

Scientists have studied the SARS-CoV genome enough that they know if one specific gene mutated, it may make the virus much more infectious. This gene is the same in SARS-CoV-2, and so medical researchers can track that gene.

Knowing whether the disease-causing part of the virus developed in pangolins or humans would tell scientists how to predict new outbreaks of SARS-CoV-2.

If it emerged in pangolins, then the disease will likely spillover in the future. If it emerged in humans, then transmission of the virus from animals is harmless, and the random series of mutations that cause the disease are unlikely to repeat.


References

Lin, Michael. “Coronavirus and COVID-19: The basic biology behind the epidemic.” MIT CSAIL talk (20 March 2020) https://www.youtube.com/watch?v=qOF5a3I7puQ&t=43s, accessed 14 April 2020.

Gorbalenya, AE et al. “The species Severe acute respiratory syndrome-related coronavirus: classifying 2019-nCoV and naming it SARS-CoV-2.” Nature Microbiology, vol. 5 (2 March 2020): 536-544. DOI: 10.1038/s41564-020-0695-z, acessed 15 April 2020.

Sheahan, Timothy et al. “Mechanisms of zoonotic Severe Acute Respiratory Syndrome Coronavirus host range expansion in human airway epithelium.” Journal of Virology, 82, 5 (February 2008):2274-2285. DOI: 10.1128/JVI.02041-07, accessed 17 April 2020.

Wan, Yushun et al. “Receptor recognition by the novel coronavirus from Wuhan: an analysis based on decade-long structural studies of SARS Coronavirus.” Journal of Virology, vol. 94, 7 (March 2020). DOI: 10.1128/JVI.00127-20, accessed 15 April 2020.

Andersen, Kristian G et al. “The proximal origin of SARS-CoV-2.” Nature Medicine, vol. 26 (17 March 2020): 450-2. DOI: 10.1038/s41591-020-0820-9, accessed 15 April 2020.

Eschner, Kat. “We’re still not sure where the Wuhan coronavirus really came from.” Popular Science (28 January 2020). https://www.popsci.com/story/health/wuhan-coronavirus-china-wet-market-wild-animal/, accessed 17 April 2020.

Huang, Chaolin et al. “Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China.” The Lancet, vol. 395, 10223 (15 February 2020): 479-506. DOI:10.1016/S0140-6736(20)30183-5, accessed 15 April 2020.

Hassanin, Alexandre. “Coronavirus origins: genome analysis suggests two viruses may have combined.” The Conversation (18 March 2020). https://theconversation.com/coronavirus-origins-genome-analysis-suggests-two-viruses-may-have-combined-134059, accessed 15 April 2020.

Simon-Loriere, Etienne and Holmes, Edward C. “Why do RNA viruses recombine?” Nature Reviews Microbiology, vol. 9, 8 (4 July 2011): 617-626. DOI: 10.1038/nrmicro2614, accessed 15 April 2020.

Qui, Jane. “How China’s ‘Bat Woman’ Hunted Down Viruses from SARS to the New Coronavirus.” Scientific American (1 March 2020). https://www.scientificamerican.com/article/how-chinas-bat-woman-hunted-down-viruses-from-sars-to-the-new-coronavirus1/, accessed 11 April 2020.

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