News – LA JOLLA, CALIF. – January 12, 2020 – Scientists at the Sanford Burnham Prebys Medical Detectives Institute have identified the sensor in human lungs that detects SARS-CoV-2 and indicates that it is time to set up an antiviral response. The study, published today in Cell reports, provides insights into the molecular basis of severe disease and may be able to devise new strategies for the treatment and prevention of COVID-19.
“Our research has shown that MDA-5 is the protective foam that has a duty to monitor for SARS-CoV-2 and a call for backup,” said Sumit Chanda, Ph.D., director of the Immunity and Pathogenesis Program at Sanford Burnham Prebys and senior author of the study. “MDA-5 recognizes replica viruses in lung cells and activates interferon, the body’s own immune defender against viral attack. Without a proper response from interferon, viral infections can lead to a fatal, uncontrolled reaction. ”
The new study examined 16 viral RNA binding proteins in human lung epithelial cells and identified MDA-5 as the primary sensitizer responsible for interferon activation. MDA-5 detects double-stranded viral RNA – a form that the SARS-CoV-2 virus takes over when it reproduces to spread the disease. Prior to this research, interferon activity was known to be crucial in a coordinated immune response to the virus, but it was not known which sentinel variant controls the process.
“Understanding the biology of a virus and how to detect it is crucial to controlling the spread of disease and infections,” says Chanda. “SARS-CoV-2 appears to disable the tissue protective arm of our monitoring system, which, in the case of SARS-CoV-2 is controlled by MDA-5, and inhibits interferon activation . It is the interferon response that directs the activity of many genes involved in antiviral activities – and data show that we need this activity to control early stages of viral infection and the avoid the worst results of COVID-19.
“Whether or not our bodies can be affected by the offensive mechanisms of the virus and the activation of interferon can have a profound effect on the severity of the disease. Previous studies have shown that interferon responses are higher in patients with moderate to severe cases compared to lower levels in severe patients, ”says Chanda.
According to the World Health Organization, as of January 2020 there are nearly 87 million confirmed cases of COVID-19, including nearly 1.9 million deaths. Although remdesivir and two antibody treatments have received emergency use approval from the FDA, cases are still arising. Newly approved vaccines are being used quickly around the world to end the crisis, but a handful of people are suffering a severe allergic reaction to the blows.
“There is an urgent need to develop effective treatments for COVID-19 and prepare for future outbreaks,” says Chanda. “It is possible that patients who have become seriously ill are in the interferon signaling pathway. This research opens new avenues toward therapies that increase MDA-5 signaling to stimulate interferon levels early in infection to prevent serious infection.
“It will also create opportunities to develop COVID-19 vaccines that contain adjuvant (s) to enhance MDA-5 signaling. These are formulas that use less ‘vaccines’ to reduce poisoning and side effects, ”adds Chanda.
The first author of the study is Xin Yin, Ph.D., of Sanford Burnham Prebys and China 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 from the National Institute of Infectious Diseases (Tokyo); Judd F. Hultquist of Northwestern University; and Lisa Miorin and Adolfo Garcia-Sastre from Icahn School of Medicine at Mount Sinai.
The DOI of the study is 10.1016 / j.celrep.2020.108628.
This work was supported by the following grants to the Sanford Burnham Prebys Medical Tracking 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 further supported by the following grants to Northwestern University’s Feinberg School of Medicine: CTSA development on NCATS: UL1 TR002389; CTSA addition to NUCATS with generous support of the Dixon family: UL1 TR001422; and Cancer Center development: P30 CA060553. This work was also partly supported by CRIP (Center for Research for Influenza Pathogenesis), a Center of Excellence supported by NIAID for Influenza Research and Analysis (CEIRS, contract # HHSN272201400008C), with NIAID U19AI142733 grant, with grants NCI U54CA260560, with NIAID U19AI135972 Grant support materials and DoD W81XWH-20-1-0270 grant, with Defense Advanced Research Projects Agency (HR0011-19-2-0020), and with generous support from the JPB Foundation, the Philanthropy Project Open (2020-2611 and 2020-218415 research grants) and anonymous donors to Adolfo Garcia-Satre. The development and implementation of iPSC technology for airway epithelial cell production was supported by the Stimulation Program from the Office of the Society-Academia Society for Innovation, Kyoto University.
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About Sanford Burnham Prebys Medical Discovery Institute
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