By Marie Rosenthal, MS

Apparently, it takes teamwork to adapt to coronaviruses. A University of Saskatchewan (USask) research team demonstrated that cells from an insect-eating brown bat can be persistently infected with Middle East respiratory syndrome (MERS) coronavirus, due to adaptations made by both the bat and virus working together (Sci Rep 2020;10[1]:7257. doi: 10.1038/s41598-020-64264-1).

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Bats appear to be the vector for the coronaviruses that cause MERS, severe acute respiratory syndrome (SARS), and for SARS-CoV-2, the cause of COVID-19. However, for reasons not well understood, bats serve only as reservoirs and do not become ill, whereas the viruses cause severe morbidity and mortality in humans.

The human body responds to coronavirus (CoV) exposure by producing inflammation-causing proteins to fight the virus, but bats maintain a natural antiviral response, a function that shuts down in other species. Simultaneously, the MERS virus adapts to the bat host cells by very rapidly mutating one specific gene, according to Vikram Misra, PhD, a professor in the Department of Veterinary Microbiology at USask, in Saskatoon.

Big brown bat Credit: ©Dennis Donohue / stock.adobe.com

Operating together, these adaptations result in a delicate equilibrium that allows the virus to remain long-term in the bat. When that equilibrium is upset, the virus multiplies quickly and jumps to another host.

The research was carried out at USask's Vaccine and Infectious Disease Organization-International Vaccine Centre (VIDO-InterVac), one of the world's largest containment level 3 research facilities, by a team of researchers from USask's Western College of Veterinary Medicine and VIDO-InterVac.

The researchers established a long-term MERS-CoV infection in brown bat cells and maintained them for 126 days or longer, regularly measuring viral particles, proteins and transcripts. They found that the bat cells selected for viral variants of the MERS-CoV, which enabled the virus to enter and reside in the bat without causing infection. (While camels are the known intermediate hosts for MERS-CoV, bats are suspected to be the ancestral host, according to the report.)

“By sequencing the whole genome of MERS-CoV from persistently infected bat cells, we identified that bat cells repeatedly selected for viral variants that contained mutations in the viral open reading frame 5 (ORF5) protein. Furthermore, bat cells that were persistently infected with ΔORF5 MERS-CoV were resistant to superinfection by wildtype virus, likely due to reduced levels of the virus receptor, dipeptidyl peptidase 4 (DPP4) and higher basal levels of interferon in these cells. In summary, our study provides evidence for a model of coronavirus persistence in bats, along with the establishment of a unique persistently infected cell culture model to study MERS-CoV?bat interactions,” the researchers wrote.

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“Instead of killing bat cells as the virus does with human cells, the MERS coronavirus enters a long-term relationship with the host, maintained by the bat’s unique ‘super’ immune system," said Dr. Misra, the corresponding author on the paper. “SARS-CoV-2 is thought to operate in the same way.”However, the delicate balance is upset by stress. The team’s work suggests that stresses on bats—such as wet markets, other diseases and possibly habitat loss—may have a role in coronavirus spilling over to other species, according to Dr. Misra.

“When a bat experiences stress to its immune system, it disrupts this immune system?virus balance and allows the virus to multiply," he said. Coronaviruses rapidly adapt to the new species they infect, he added.

“We see that the MERS coronavirus can very quickly adapt itself to a particular niche, and although we do not completely understand what is going on, this demonstrates how coronaviruses are able to jump from species to species so effortlessly,” said VIDO-InterVac scientist Darryl Falzarano, who co-led the bat study, developed the first potential treatment for MERS-CoV infection, and is leading VIDO-InterVac's efforts to develop a vaccine against COVID-19.
Next, the team will turn its focus to understanding how the bat-borne MERS virus adapts to infection and replication in camelid and human cells.

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“This information may be critical for predicting the next bat virus that will cause a pandemic,” Dr. Misra said.Lead researchers on the paper were Dr. Misra's former PhD students Arinjay Banerjee and Sonu Subudhi, who are now at McMaster University, in Toronto, and Massachusetts General Hospital, in Boston, respectively. Other team members included researchers Noreen Rapin and Jocelyne Lew, as well as summer student Richa Jain.

So far, the SARS-CoV-2 virus has infected more than 5 million people worldwide and killed 7% of those infected. In contrast, the MERS virus infected nearly 2,500 people in 2012, but killed one in every three people infected. There is no vaccine against SARS-CoV-2 or for MERS.