UMass Medical School Scientist Katherine A. Fitzgerald, PhD; Fiachra Humphries, PhD; and Liraz Galia, PhD, in collaboration with the British pharmaceutical company GlaxoSmithKline, have identified a novel molecule that can stimulate the innate immune system against the SARS-CoV-2 virus. As a trigger for the STING pathway (stimulator of interferon genes), the compound diamidobenzimidazole (diABZI-4) protected animal models and human cells in the laboratory from SARS-CoV-2 infection. Published in Science immunology, these results show that diABZI-4 has the potential to be an effective antiviral prophylaxis against COVID-19.
“The identification of antiviral therapies for SARS-CoV-2 is still urgently needed as vaccines continue to roll out worldwide,” said Dr. Fitzgerald, the Worcester Foundation for Biomedical Research Chair, Professor of Medicine, Assistant Professor of Research in the Faculty of Medicine and Director of the Innate Immunity Program. “An approach like this with a STING agonist could be used to protect those at greatest risk in this pandemic and future pandemics before we have drugs that target the virus itself.” Galia, a postdoctoral fellow in the Fitzgerald laboratory, are the authors of the paper.
Dr. Humphries, professor of medicine and first author of the study, added, “Not everyone can get a vaccine. For people with immunodeficiency or allergies, this treatment, which could be administered through an inhaler, can be a viable alternative to strengthening the immune response. “
Vaccines work by stimulating the adaptive immune system, which makes antibodies against disease and viruses. By removing a small piece of a virus that does not cause infection, in the case of SARS-CoV-2, a portion of the spike protein that attaches to and infects epithelial cells, scientists can train the adaptive immune system to recognize certain viral invaders . Once the adaptive immune system is trained, it can respond more quickly to subsequent encounters by producing antibodies that fight off the virus. This prevents serious illnesses like COVID-19 and in some cases blocks infection completely.
However, the innate immune system is more of a generalist, explained Humphries. The innate immune system identifies all pathogens it can encounter – regardless of whether they are bacteria, viruses or fungi. One of its main functions is the production of cytokines that serve as first line of defense, antiviral responders. It also alerts the immune system to the presence of the intruder and triggers the adaptive immune system to wake up.
The intracellular protein STING is like an early warning system for the immune system. Once activated, it triggers the production of the cytokine interferon. This activity stimulates the adaptive immune system to fight off the infection. A STING agonist like diABZI-4 could potentially wake up the immune system and give it a boost to fight off pathogens before they become established.
Humphries and colleagues believed that diABZI-4’s immune-stimulating properties could also serve as an antiviral drug. It is already being tested as an immunotherapy against cancer.
By administering diABZI-4 directly to the site of infection in mice intranasally, Humphries demonstrated that it can activate the immune system and clear viral infections such as SARS-CoV-2.
“It was kind of amazing,” said Humphries. “A single dose could protect 100 percent of the mice from serious diseases. After taking diABZI-4, the mice were completely protected from infection. “
Subsequent cell studies showed that diABZI-4 was able to stimulate the innate immune response by activating the STING signaling pathway that produces interferon I.
What makes SARS-CoV-2 so effective in part is its ability to bypass the innate immune system’s antiviral response, Fitzgerald said. “But what we’re showing is that we can use a STING agonist to violate antiviral immunity and be effective.”
The use of diABZI-4, which is stable at room temperature and relatively easily manufactured, can be an important adjuvant for current vaccine treatments against COVID-19. “You could see that this is important for breakthrough infections and new varieties,” said Humphries. “You could potentially take this shortly after potential exposure, or even prophylactically through an inhaler, before entering a high-risk environment like an airplane, and you’d have a short-lived antiviral boost to your immune system that would clear any virus before infection is set.” “
Fitzgerald and Humphries also showed that this antiviral response went beyond SARS-CoV-2. It also protected against influenza and herpes simplex virus. “Ultimately, this could have very broad antiviral uses,” said Humphries.
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