What shapes a virus' pandemic potential? SARS-CoV-2 analogues provide clues

The findings were published in the journal on July 29th. Nature Microbiology — offers clues as to why some viruses have more “pandemic potential” than others and how researchers can identify them before they spread.

For a virus to cause a pandemic, it needs the ability to spread from person to person, enter human cells, evade the body's defense systems, and cause disease. SARS-CoV-2, the virus that caused the COVID-19 pandemic, has all these capabilities. But it's not yet clear why it does so so efficiently.

“It's unclear what causes a virus to cause a pandemic,” said Mario Peña-Hernández, a doctoral student at Yale University in the labs of Akiko Iwasaki and Craig Willen and lead author of the study. “Because these bat strains are 97% genetically identical to SARS-CoV-2 and are the closest known relatives of this virus, we assumed that their phenotypic behavior — the way they infect and cause disease — would be similar to SARS-CoV-2. However, we found that this was not true.”

Although bat coronaviruses were able to efficiently invade some human cells and evade defense systems (in many cases better than SARS-CoV-2), they were less successful at infecting and spreading between hamsters and caused a milder disease in mice.

“Our findings show that genome alone cannot determine which virus strains have the capacity to cause a pandemic,” Peña Hernández said.

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

In the study, the researchers used copies of two bat coronaviruses to test how well they could infect lab-grown human respiratory cells and rodents. The study was conducted under the university's highest level of biosafety. (Specifically, it was conducted under a standard known as Biosafety Level 3+, whose requirements include limited access to the lab, specialized personal protective equipment and respirators, and conducting experiments inside biocontainment cabinets in a negative-pressure facility.)

The researchers found that two bat coronaviruses were effective at infecting cells isolated from human bronchi (the airways that connect the trachea to the lungs) but did not replicate well in nasal cells.

“This is important to know because most viral infections likely occur in the nose,” said Iwasaki, the study's lead author. “The fact that these viruses do not replicate as well as SARS-CoV-2 in the nose could be an important indicator of why they did not infect in animal models.” The human body has two types of immune defenses: innate immunity (a broad, general first line of defense) and adaptive immunity. This develops over time and can protect against more specific pathogens to which an individual has already been exposed. Innate immunity is especially important against new viruses to which people may not have adaptive immunity. In this study, the researchers found that two bat coronaviruses can evade certain innate immune molecules that fight infection.

“Although the virus can infect airway cells and evade the body's defenses, it fails to transmit between animals,” said Willen, the study's lead author. “SARS-CoV-2 may evade innate immunity. and Because they are transmissible, this suggests that these bat coronaviruses are missing something that SARS-CoV-2 has.”

What these viruses are missing is a molecular part called a “furin cleavage site.” In SARS-CoV-2 and other viruses, the viral spike protein is cleaved by an enzyme called furin to allow the virus to efficiently enter human cells. Previous studies have shown that SARS-CoV-2 variants that lack this site are less susceptible to infection and less severe disease. In this study, the researchers also found that SARS-CoV-2 lacking this cleavage site replicated poorly in nasal cells, as did two bat coronaviruses. In hamsters, viruses lacking the furin cleavage site were quickly outcompeted by viruses that had it.

Whether a virus has this cleavage site may be one feature to focus on in investigations to identify viral threats, the researchers say. However, features of other viruses in this family may also have the potential to cause infection and disease. This highlights the importance of studying these viruses in the laboratory to identify these features, the researchers say. For example, how well the virus replicates in nasal cells can also serve as an indicator to assess its infectious ability.

Overall, the findings suggest that these two bat coronaviruses do not pose a significant threat to humans, but small genetic changes in these and similar viruses could evolve and significantly increase the risk of a pandemic. However, even if the virus were to infect humans, the researchers found that adaptive immunity to SARS-CoV-2 was protective: serum samples taken from individuals who had been vaccinated against SARS-CoV-2 or had previously been infected neutralized the virus.

“But it's important to understand whether the virus can be transmitted between humans,” said Iwasaki, who is also professor of dermatology at the Yale University School of Medicine and professor of molecular, cellular and developmental biology in the Yale School of Letters and Science and a Howard Hughes Medical Institute investigator.

“Because if one day we find a virus that's transmissible but different enough from SARS-CoV-2 that we don't have immunity to, we might be able to develop a vaccine or other strategies to combat it. We might have a head start.”