A new drug developed to treat severe influenza works in a unique way, unlike what a drug would expect, to treat lung disease and infection.
Inventing a new drug to treat influenza!
A new drug to treat severe flu successfully keeps patients at the right level of lung inflammation to protect against lung damage while still allowing the immune system to fight infection. This drug has been effective in mice even a few days after infection.
According to New Atlas, if you’ve ever had the flu, you’ve most likely contracted the influenza A virus (IAV). Compared to influenza B virus, infection with type A often causes more severe symptoms. But, while many of us have experienced the fever and chills, headache and muscle aches, fatigue, sore throat, and cough of the common flu, severe infection with the animal IAV strain is different and potentially life-threatening.
Severe infection of this type of influenza causes a special type of cell death called necroptosis in infected cells. While this is a natural process designed to limit viral spread by actively eliminating infected cells and mobilizing the immune system to respond, necroptosis can activate a hyperinflammatory response and cause collateral lung damage that is potentially fatal. Is. Other than managing its symptoms, there are few treatment options for treating severe influenza.
In a new study, researchers from Tufts University School of Medicine, St. Jude Children’s Research Hospital, the University of Houston, and Fox Chase Cancer Center collaborated to test a drug called UH15-38 that could prevent this flu-related lung damage in mice. It prevents and allows the immune system to fight the virus.
“Our drug significantly increased survival and reduced symptoms of influenza virus infection,” said Paul Thomas, co-author of the study. The new drug reduced dangerous inflammation and even seemed to improve the adaptive response to the virus.
Achieving the Goldilocks effect, or the effect of the right amount of the drug on inflammation, required researchers to use clever chemistry along with a thorough understanding of the underlying mechanisms of necroptosis.
Receptor-interacting protein kinase 3 (RIPK3) is an essential part of the necroptosis cell death pathway, but it also controls another cell death pathway called apoptosis. Both types of cell death trigger opposing immune responses. Apoptotic death usually results in muted immunological responses, while necroptosis releases molecules that cause inflammation. UH15-38 was designed to prevent the stimulation of the necroptosis pathway by RIPK3, while still allowing cell death and removing infected cells in a less inflammatory manner.
Alexei Degterev, an associate professor of developmental, molecular, and chemical biology at Tufts University School of Medicine and one of the authors of the paper, says: “If you eliminate necroptosis, you will still limit virus replication without severe damage to the lungs.” Necroptosis does not appear to be necessary to limit viral activity, so if we can block it, we can protect the host by reducing inflammation in the lungs.
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The researchers tested the drug UH15-38 in mouse models and found that high doses of the drug provided protection against the usually fatal IAV influenza. At low doses, the UH15-38 drug protected mice against similar amounts of influenza that humans experience. Notably, the mice were protected even if they received the drug several days after being infected with the disease.
“This drug can do something we haven’t seen before,” says Thomas. We can start five days after the initial infection and still see benefits. Completely removing the RIPK3 protein is not a great choice because then the immune system cannot clear the virus. When we removed only the necroptosis, the animals did better because they still had apoptosis and could still get rid of the infectious cells, but their condition was not as severely inflammatory.
UH15-38 improved survival by preventing collateral necroptosis damage to type 1 alveolar epithelial cells, a special type of cell in the lungs that facilitates gas exchange. Damage to these cells can make it difficult for oxygen to enter the blood and carbon dioxide from it, and cause symptoms such as shortness of breath, wheezing, and chest tightness. The drug also reduced the number of immune cells associated with inflammation, such as neutrophils, in the mice.
Often, the worst part of the flu happens after the virus is under control when inflammation destroys lung cells, Thomas says. UH15-38 can reduce influenza-induced inflammation while leaving viral clearance and other functions of tissue and immune responses intact. This makes the drug a promising option to move towards clinical use.
The next step is clinical and human trials safely. Researchers are testing whether UH15-38 is effective in treating other respiratory diseases.
While the worst of COVID-19 may be upon us, another pandemic is expected, and we need something that protects the host regardless of how it is infected, Degtref says. This study demonstrates the possibility of achieving such a goal and renews interest in how cell death occurs against infections.
This study was published in the journal Nature.