Two bat coronaviruses found in Laos, which are among the closest known relatives to SARS-CoV-2, seem to have limited transmission capabilities in humans, even though they share a significant genetic similarity with the virus responsible for COVID-19, according to a new Yale study.
Recent research from Yale indicates that two bat coronaviruses closely related to SARS-CoV-2, discovered in Laos, might transmit poorly among humans despite their genetic resemblance to the COVID-19 virus.
Published on July 29 in the journal Nature Microbiology, the study sheds light on why certain viruses exhibit a higher potential for causing pandemics compared to others, helping researchers identify potential threats before they spread widely.
For a virus to trigger a pandemic, it must effectively spread among humans, infiltrate human cells, evade the immune system, and lead to illness. SARS-CoV-2 accomplished all of this, but the reasons for its efficiency are still not fully understood.
“We’re still determining what factors contribute to a virus’s pandemic potential,” said Mario Peña-Hernández, a Yale Ph.D. candidate and lead author of the study. “Although these bat strains are 97% genetically identical to SARS-CoV-2, we assumed their behavior in terms of infection and disease would mirror that of SARS-CoV-2; however, our research showed that this was not the case.”
While these bat coronaviruses could enter some human cells efficiently and evade immune defenses (often more successfully than SARS-CoV-2), they were not effective at spreading between hamsters and caused milder illness in mice.
“This indicates that genomic data alone cannot predict a virus’s pandemic potential,” Peña-Hernández explained.
Other contributors included Akiko Iwasaki, Yale’s Sterling Professor of Immunobiology and professor of epidemiology (microbial diseases), and Craig Wilen, an associate professor of laboratory medicine and immunobiology.
For their study, the researchers examined the two bat coronaviruses to see how well they infected lab-grown human respiratory cells and rodents, all conducted under strict biosafety protocols (biosafety level 3+), which involved limited lab access and stringent protective measures.
They discovered that, while the bat coronaviruses effectively infected cells from the human bronchus—which connects the trachea to the lungs—they did not replicate well in nasal cells.
“This is critical to understand, as most virus transmissions likely occur in the nose,” said Iwasaki, one of the senior authors. “Their poor replication in nasal cells compared to SARS-CoV-2 might explain why they did not transmit well in the animal studies.” The immune system has two levels of defense: innate immunity, which provides a general response, and adaptive immunity, which takes time to develop and targets specific pathogens. The study revealed that the bat coronaviruses could evade certain innate immune responses.
“So, while these viruses can infect airway cells and avoid some immune defenses, they still struggled to transmit between animals,” noted Wilen, another senior author. “In contrast, SARS-CoV-2 could evade innate immunity and spread, indicating that these bat coronaviruses lack some critical factor present in SARS-CoV-2.”
One distinguishing feature of these viruses is the absence of a “furin cleavage site.” In SARS-CoV-2 and some other viruses, this site allows the spike protein to be cleaved by the enzyme furin, facilitating entry into human cells. Prior studies indicated that SARS-CoV-2 strains without this site transmit less effectively and cause milder disease. The current research also found that strains of SARS-CoV-2 lacking this cleavage site replicated poorly in nasal cells, similar to the bat coronaviruses. In hamsters, viruses missing the furin cleavage site were outcompeted by those possessing it.
The presence of such a cleavage site could help researchers identify viral threats, but other characteristics of these viruses could also influence their transmission potential. The researchers emphasized the importance of laboratory studies for pinpointing these traits. For instance, the replication efficiency in nasal cells might be indicative of a virus’s ability to spread.
Overall, the study suggests that these bat coronaviruses may pose a limited risk to humans, although genetic changes could potentially enhance their pandemic threat. Furthermore, the research found that blood samples from people vaccinated against or previously infected by SARS-CoV-2 could neutralize the studied bat coronaviruses.
“However, it’s essential to understand which viruses can transmit between humans,” said Iwasaki, who holds multiple positions at Yale and is also an investigator at the Howard Hughes Medical Institute.
“If we ever encounter a new virus that can spread and is sufficiently different from SARS-CoV-2—against which we lack immunity—we could develop vaccines and other strategies in advance. This would give us an edge.”