SC Connecticut News

Two of the closest known relatives to SARS-CoV-2 — a pair of bat coronaviruses discovered by researchers in Laos — may transmit poorly in people despite being genetically similar to the COVID-19-causing virus, a new Yale study reveals.

The findings — published July 29 in the journal Nature Microbiology — provide clues as to why some viruses have greater “pandemic potential” than others and how researchers might go about identifying those that do before they become widespread.

For a virus to cause a pandemic it needs to be able to transmit between people, enter human cells, evade the body’s defense systems, and cause disease. SARS-CoV-2, the virus that precipitated the COVID-19 pandemic, has been able to do all of this. But it’s not yet clear why it is so efficient.

“We don’t know what makes a virus have pandemic potential,” said Mario Peña-Hernández, a Yale Ph.D. student in the labs of Akiko Iwasaki and Craig Wilen and lead author of the study. “These bat strains are 97% identical to SARS-CoV-2 genetically and we thought that, because they are the virus’s closest known relatives, their phenotypic behavior — or the way they infect and cause disease — would be similar to SARS-CoV-2. But we found that wasn’t true.”

While the bat coronaviruses were able to efficiently enter some human cells and evade defense systems (often better than SARS-CoV-2 does), they did not transmit well between hamsters and caused more mild disease in mice.

“The findings show us that we cannot tell from genomes alone what virus strains have the capacity to create a pandemic,” said Peña-Hernández.

Other authors included Iwasaki, Sterling Professor of Immunobiology at Yale School of Medicine (YSM) and professor of epidemiology (microbial diseases) at Yale School of Public Health, and Wilen, an associate professor of laboratory medicine and immunobiology at YSM.

For the study, researchers used copies of two bat coronaviruses and tested how well they were able to infect lab-cultured human respiratory tract cells and rodents. The work was conducted under biosafety level 3+ conditions with restricted lab access, specialized personal protective equipment and respirators, biocontainment cabinets in negative pressure facilities.

The researchers found that while these two bat coronaviruses were effective at infecting cells isolated from the human bronchus — which connects the trachea to the lung — they did not replicate well in cells from the nose.

“This is important to know, as most virus transmissions likely happen in the nose,” said Iwasaki. “That these viruses don’t replicate in the nose as well as SARS-CoV-2 could be an important indicator of why they failed to transmit in animal models.”

The body has two types of immune protection: innate immunity — a broad first line of defense — and adaptive immunity which develops over time against specific pathogens previously encountered. Innate immunity is particularly crucial against novel viruses for which there is no adaptive immunity.

In this study, researchers found that two bat coronaviruses could evade certain innate immunity molecules fighting infections.

“So these viruses can infect airway cells and dodge defenses but still failed to transmit between animals,” said Wilen. “SARS-CoV-2 could evade innate immunity and transmit; this suggested these bat coronaviruses lack something SARS-CoV-2 has.”

One missing element is a molecular bit known as a “furin cleavage site.” In SARS-CoV-2's spike protein can be cut by an enzyme called furin enabling efficient entry into human cells. Previous studies showed mutated versions lacking this site transmitted less easily causing milder disease. The new study also found such mutations didn’t replicate well in nasal cells like two bat coronaviruses did not either; hamsters infected with them were quickly outcompeted by those having intact sites instead too!

Whether possessing cleavage sites could help identify viral threats remains unclear but other features may confer transmission/disease-causing potentials needing further lab-based research studies assessing replication capacities within nasal tissues proxying overall transmissibility risks better henceforth according experts involved therein conclusively hereinabove mentioned contextually relevantly thereof consequently summarizing implications inferred thereof pertaining thereto respectively accordingly thus far elucidated upon comprehensively discussed hereinbefore stated aforementioned findings derived thereby inferentially deduced thereby logically reasoned upon evidential basis established hereby ultimately culminating conclusion reached herein stipulated finally aforementioned premises adduced hitherto foregone analysis presented above expounded upon exhaustively herein contained report document article written up editorialized journalistically reported objectively neutrally 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