LA JOLLA, CALIF. - Jan 12, 2021 - Scientists at Sanford Burnham Prebys Medical Discovery Institute have identified the sensor in human lungs that detects SARS-CoV-2 and signals that it's time to mount an antiviral response. The study, published today in Cell Reports, provides insights into the molecular basis of severe disease and may enable new strategies for the treatment and prevention of COVID-19.
"Our research has shown that MDA-5 is the immune cop that's tasked to keep an eye out for SARS-CoV-2 and call for back-up," says Sumit Chanda, Ph.D., director of the Immunity and Pathogenesis Program at Sanford Burnham Prebys and senior author of the study. "MDA-5 recognizes replicating viruses in lung cells and activates interferon, the body's own frontline defender against viral invasion. Without a proper interferon response, viral infections can lead to deadly, out-of-control inflammatory reactions."
The new 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 that the SARS-CoV-2 virus takes when it replicates to spread the infection. Prior to this research, it was known that activating interferon is key to a coordinated immune response to the virus, but the sentinel switch that controls the process was unknown.
"Understanding the biology of a virus and how it is detected is paramount to controlling infection and disease spread," says Chanda. "SARS-CoV-2 appears to disable the innate immune arm of our surveillance system, which, in the case of SARS-CoV-2 is controlled by MDA-5, and prevents the activation of interferon. It's the interferon response that drives the subsequent activation of many genes that exert antiviral activities--and 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. Past studies have shown that interferon responses are higher in patients with mild-to-moderate cases compared to reduced levels in critically ill patients," adds Chanda.
According to the World Health Organization, as of January 2021 there have been nearly 87 million confirmed cases of COVID-19, including nearly 1.9 million deaths. Although remdesivir and two antibody treatments have received emergency use authorization by the FDA, cases continue to rise. Newly approved vaccines are rapidly being deployed worldwide to end the crisis, however a handful of people are experiencing severe allergic reactions to the shots.
"There is still a tremendous need to develop effective therapies for COVID-19 and to prepare for future outbreaks," says Chanda. "It's possible that patients who become critically ill are deficient in the interferon signaling pathway. This research opens new avenues toward therapies that enhance the MDA-5 signaling to boost interferon levels early in infection to prevent severe disease.
"It also creates opportunities to develop COVID-19 vaccines that include an adjuvant(s) to enhance MDA-5 signaling. These would be formulations that use less 'vaccine' to minimize toxicity and side effects," adds Chanda.
The first author of the study is Xin Yin, Ph.D., of Sanford Burnham Prebys and the Chinese Academy of Agricultural Sciences. Additional study authors include Paul D. De Jesus, Kristina Herbert, Laura Martin-Sancho, Yuan Pu, Laura Riva, Chih-Cheng Yang and Sunny Yoh of Sanford Burnham Prebys; Jun Kanamune, Shimpei Gotoh and Yuki Yamamoto of Kyoto University; Kouji Sakai of the National Institute of Infectious Diseases (Tokyo); Judd F. Hultquist of Northwestern University; and Lisa Miorin and Adolfo Garcia-Sastre of the Icahn School of Medicine at Mount Sinai.
The study's DOI is 10.1016/j.celrep.2020.108628.
This work was supported by the following grants to the Sanford Burnham Prebys Medical Discovery Institute: DoD: W81XWH-20-1-0270; DHIPC: U19 AI118610; Fluomics/NOSI: U19 AI135972; R01 AI127302-01A1, as well as generous philanthropic donations from Dinah Ruch and Susan & James Blair. This work was additionally supported by the following grants to Northwestern University Feinberg School of Medicine: a CTSA supplement to NCATS: UL1 TR002389; a CTSA supplement to NUCATS with the generous support of the Dixon family: UL1 TR001422; and a Cancer Center supplement: P30 CA060553. This work was also partly supported by CRIP (Center for Research for Influenza Pathogenesis), an NIAID-supported Center of Excellence for Influenza Research and Surveillance (CEIRS, contract # HHSN272201400008C), by NIAID grant U19AI142733, by NCI grant U54CA260560, by supplements to NIAID grant U19AI135972 and DoD grant W81XWH-20-1-0270, by the Defense Advanced Research Projects Agency (HR0011-19-2-0020), and by the generous support of the JPB Foundation, the Open Philanthropy Project (research grants 2020-215611 and 2020-218415) and anonymous donors to Adolfo Garcia-Satre. Development and implementation of iPSC technology for production of airway epithelial cells was supported by the Incubation Program from the Office of Society-Academia Collaboration for Innovation, Kyoto University.
About Sanford Burnham Prebys Medical Discovery Institute
Sanford Burnham Prebys is a preeminent, independent biomedical research institute dedicated to understanding human biology and disease and advancing scientific discoveries to profoundly impact human health. For more than 40 years, our research has produced breakthroughs in cancer, neuroscience, immunology and children's diseases, and is anchored by our NCI-designated Cancer Center and advanced drug discovery capabilities. For more information, visit us at SBPdiscovery.org or on Facebook at facebook.com/SBPdiscovery and on Twitter @SBPdiscovery.