Researchers develop new drug that can prevent lung damage caused by influenza

Infection with influenza viruses causes lung damage through hyperactivation of inflammation that causes collateral damage to cells needed for breathing. Such damage can be life-threatening, but scientists have developed new preventive treatments. A team from St. Jude Children's Research Hospital, the University of Houston, Tufts University School of Medicine, and Fox Chase Cancer Center has developed a drug that can prevent lung damage caused by influenza. In mouse models, the drug achieved a new balance between stopping inflammation running wild and allowing the immune system to thwart the virus. The survey results are announced today. Nature.

Our drug significantly increased survival rates and reduced symptoms of influenza virus infection. It appears to reduce dangerous inflammation and improve adaptive responses to viruses. ”

Dr. Paul Thomas, co-corresponding author, St. Jude Host-Microbe Interactions Division

In a series of experiments, a drug called UH15-38 was able to protect against deadly influenza. The results showed that even at low doses, the drug protected mouse models from influenza doses similar to those experienced by humans. Additionally, the team found that high doses of the drug could completely prevent infection by significant amounts of the virus that would normally be fatal. The model was protected even when given days after infection, a difficult feat for influenza drugs.

“This drug could also enable things we've never seen before,” Thomas said. “We were able to show that we could start five days after the initial infection and still provide some benefit.”

Healthcare workers must administer modern antiviral drugs within the first few days of infection to be effective. This study suggests that UH15-38 may fill a currently unmet need, as critically ill patients are often infected for several days before seeking medical attention. This breakthrough comes from understanding how influenza and the immune system interact to cause lung damage.

Send influenza-infected cells to the correct route

“Infected lung cells cause inflammation, which alerts the immune system that there is a problem, but when they occur in excess, out-of-control inflammation can occur and cause serious problems,” Thomas said. “We have to strike a delicate balance between keeping these processes well-maintained to clear the virus, but not causing out-of-control inflammation.”

The collaborating scientists used clever chemistry to achieve Goldilocks levels of inflammation. Their new drug inhibited a portion of receptor-interacting protein kinase 3 (RIPK3), a key inflammatory protein in immune cells. RIPK3 controls two cell death pathways in response to infection: apoptosis and necroptosis. Necroptosis is highly inflammatory, whereas apoptosis is not. Both pathways are used in antiviral responses. UH15-38 was designed to prevent RIPK3-induced initiation of necroptosis while preserving the pro-apoptotic properties of RIPK3.

“Knocking out RIPK3 completely is not a good idea because the immune system will not be able to eliminate the virus,” Thomas said. “When we knocked out just necroptosis, the animals performed better because they still had apoptosis and were able to get rid of infected cells, but they were less inflammatory.”

Stop lung inflammation and damage

“We also showed that the improved survival was a direct result of reduced local inflammation and improved lung cell survival,” Thomas said.

In a series of previous studies, the Thomas lab discovered that a specific set of cells in the lungs are collateral damage to an out-of-control inflammatory response. These cells, type 1 alveolar epithelial cells, handle gas exchange, taking in oxygen and expelling carbon dioxide. When these cells are lost, the body is unable to breathe. The study demonstrated that this literally breathtaking group of cells survived even in the presence of the drug. Furthermore, inflammation-related immune cells, such as neutrophils, were much reduced in the lungs of treated animals.

“Often the worst part of the flu happens after the virus is brought under control, when runaway inflammation destroys lung cells,” Thomas says. “UH15-38 is able to attenuate the inflammation caused by influenza while leaving virus clearance and other immune and tissue response functions intact, making it a promising candidate to advance toward the clinic. I am.”

Authors and funders

The study's co-lead author is Avishek Gautam of Fox Chase Cancer Center. David Boyd, St. Jude. and Sameer Nikal of the University of Houston. The study's other corresponding author is Gregory Cuny of the University of Houston. Alexei Degterev of Tufts University School of Medicine; Siddharth Balachandran of Fox Chase Cancer Center.

Other authors of the study are Ting Zhang, Bikash Thapa, Kathy Cai, Chaolan Ying, Carly DeAntoneo, Riley Williams, Maria Shubina and Mark Andrake of Fox Chase Cancer Center. Ioannis Siokas and Dingqiang Zhang of Tufts University School of Medicine; Daniel Schnepf, Julius Beer, Martin Schwemle, University of Freiburg. Seungheon Lee, Raghavender Boda, Anantha Duddupudi, University of Houston. Christian Roch, reaction biology. Lee-Anne Van de Velde, Jessica Gebert, Victoria Meliopoulos, Diego Rodriguez, Brandi Livingston, Jeremy Chase Crawford, Peter Vogel, Lawrence Fritz, Stacey Schultz-Cherry, Douglas Green , St. Jude.

This research was supported by grants from the National Institutes of Health (AI135025, AI168087, AI144400, AI161624, AI164003, HL170121, R01AI144828, R35CA231620 and P30CA006927) and the Collaborative Influenza Vaccine Innovation Center (75N93019C0005). 2), Health and Human Services (75N93021C00016) to St. Jude's Influenza Research and Surveillance Center and (75N93021C00018) Influenza Disease and Emergency Response Center, Deutsche Forschungsgemeinschaft (SFB1160), Fox Chase Cancer Center (S10OD030332), and St.・ALSAC, Jude's fundraising and awareness organization.