‘Immune cop’: La Jolla scientists identify the lungs’ sensor that detects virus that causes COVID-19

Sumit Chanda of the Sanford Burnham Prebys Medical Discovery Institute
Sumit Chanda of the Sanford Burnham Prebys Medical Discovery Institute led a study that found the sensor in human lungs that detects SARS-CoV-2, the virus that causes COVID-19.

Scientists at the Sanford Burnham Prebys Medical Discovery Institute in La Jolla say they have identified the sensor in human lungs that detects SARS-CoV-2, the virus that causes COVID-19, and signals the body to mount an antiviral response. The discovery may lead to improved treatment for those diagnosed with the disease.

The sensor in the lungs, called MDA-5, was found to be “the immune cop that’s tasked to keep an eye out for SARS-CoV-2 and call for backup,” said Sumit Chanda, director of the immunity and pathogenesis program at SBP and senior author of the study.

“MDA-5 recognizes replicating viruses in lung cells and activates interferon,” Chanda said. Interferon, a signaling protein released by cells in the immune system, is “the body’s own frontline defender against viral invasion,” he said.

Once activated, interferon “provides a broad alarm to cells in our body to reposition themselves into an antiviral state to better stave off infection of SARS-CoV-2 and primes the immune system to mount a vigorous response to viral infection,” Chanda said.

“Without a proper interferon response, viral infections can lead to deadly, out-of-control inflammatory reactions,” he said.

Before the study, it was known that activating interferon is key to a coordinated immune response to the virus, but the sentinel switch that controls the process, now revealed as MDA-5, was unknown.

Chanda’s study was published Jan. 12 in Cell Reports. It was co-authored by Xin Yin of SBP and the Chinese Academy of Agricultural Sciences; Paul De Jesus, Kristina Herbert, Laura Martin-Sancho, Yuan Pu, Laura Riva, Chih-Cheng Yang and Sunny Yoh of SBP; Jun Kanamune, Shimpei Gotoh and Yuki Yamamoto of Kyoto University; Kouji Sakai of the National Institute of Infectious Diseases in Tokyo; Judd Hultquist of Northwestern University; and Lisa Miorin and Adolfo Garcia-Sastre of the Icahn School of Medicine at Mount Sinai in New York.

The study surveyed 16 viral RNA binding proteins in human lung epithelial cells and identified MDA-5 as the predominant sensor responsible for activating interferon. MDA-5 detects double-stranded viral RNA — a form the SARS-CoV-2 virus takes when it replicates to spread the infection.

“SARS-CoV-2 appears to disable the innate immune arm of our surveillance system,” Chanda said, “which in the case of SARS-CoV-2 is controlled by MDA-5 and prevents the activation of interferon. … Data suggests that we need this activity to control early stages of viral infection and avoid the worst outcomes of COVID-19.”

“Whether our bodies can defeat the virus’s offensive tactics and activate interferon greatly influences the severity of disease,” he said. “Past studies have shown that interferon responses are higher in patients with mild to moderate cases, compared to reduced levels in critically ill patients.”

Even as COVID-19 vaccine programs roll out across the globe, Chanda said “there is still a tremendous need to develop effective therapies for COVID-19 and to prepare for future outbreaks.”

“It’s possible that patients who become critically ill are deficient in the interferon signaling pathway,” he said. “From a therapy standpoint, finding ways to reinforce this response can lead to therapeutics that can help control early infection of SARS-CoV-2. This research opens new avenues toward therapies that enhance the MDA-5 signaling to boost interferon levels early in infection to prevent severe disease.”

The discovery also will “pave the way for even better and possibly longer-lasting vaccine protection through the development of what are called vaccine adjuvants,” which are added to a vaccine to boost immune response, he said. “The better a vaccine can model the events that occur during natural infection, the better the vaccines can be.”

The research has implications beyond COVID-19, Chanda said, because “several coronaviruses now appear to trigger this MDA-5 response.”

“Finding new therapeutics and vaccine adjuvants can help us battle future coronavirus outbreaks,” he said. ◆