Researchers create novel drug that can prevent flu-induced lung injury

Infection with the influenza virus leads to lung injury through inflammation over-activation that causes collateral damage to cells required for breathing. Such damage can be life-threatening, but scientists have a new preventative treatment. A team from St. Jude Children's Research Hospital, University of Houston, Tufts University School of Medicine and Fox Chase Cancer Center created a drug that can prevent flu-induced lung injury. In a mouse model, the drug achieves a novel balance between shutting down runaway inflammation and allowing the immune system to stop the virus. The findings were published today in Nature.

Our drug significantly increased survival and lowered symptoms of influenza virus infection. It dampened dangerous inflammation and even seemed to improve the adaptive response against the virus."

Paul Thomas, PhD, co-corresponding author, St. Jude Department of Host-Microbe Interactions

In a series of experiments, the drug UH15-38 protected against lethal influenza. Results showed that the drug protected mouse models from similar amounts of influenza that humans experience, even at low doses. Additionally, the team found that a high drug dose could fully protect against an infection with a substantial amount of virus, which would usually be deadly. The models were protected even if they received the dose days after infection, a difficult achievement for an influenza therapeutic.

"This drug can also do something we've never seen before," Thomas said. "We're able to start five days after the initial infection and show that we're still providing some benefit."

Providers 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 patients with severe disease have often been infected for several days by the time they get to a doctor. The breakthrough results from understanding how influenza and the immune system interact to cause lung injury.

Sending influenza-infected cells down the right path

"Infected lung cells create inflammation that alerts the immune system that there's a problem, but too much of it generates runaway inflammation that can cause major problems," Thomas said. "We need to strike a delicate balance between maintaining enough of these processes to get rid of the virus, but not so much that you're getting this runaway inflammation."

The collaborating scientists achieved a Goldilocks amount of inflammation using clever chemistry. Their new drug inhibited one part of a major inflammation protein in immune cells: Receptor-Interacting Protein Kinase 3 (RIPK3). RIPK3 controls two cell death pathways in response to infection: apoptosis and necroptosis. Necroptosis is highly inflammatory, but apoptosis is not. Both pathways are used in the antiviral response. UH15-38 was designed to prevent RIPK3 from starting necroptosis while maintaining its pro-apoptotic properties.

"Knocking out RIPK3 entirely is not great because then the immune system can't clear the virus," Thomas said. "When we knocked out just necroptosis, the animals did better because they still had apoptosis and could still get rid of infected cells, but it wasn't as inflammatory."

Stopping lung inflammation and injury

"We also showed that the improved survival was the direct result of the reduction in local inflammation and improved lung cell survival," Thomas said.

In a series of prior studies, the Thomas lab found that a specific set of cells in the lung are collateral damage in the runaway inflammatory response. These cells, Type 1 alveolar epithelial cells, handle gas exchange, letting oxygen in and carbon dioxide out. Loss of these cells leads to an inability to breathe. The current study demonstrated that this group of literal breath-taking cells was spared in the presence of the drug. Additionally, inflammation-related immune cells, such as neutrophils, were far less prevalent in the lungs of treated animals.

"Often the worst part of influenza illness happens after the virus is controlled when runaway inflammation destroys lung cells," Thomas said. "UH15-38 can dampen that influenza-caused inflammation while leaving viral clearance and the other functions of the immune and tissue responses intact. That makes it a promising candidate to move forward toward the clinic."

Authors and funding

The study's co-first authors are Avishekh Gautam, Fox Chase Cancer Center; David Boyd, St. Jude; and Sameer Nikhar, University of Houston. The study's other corresponding authors are Gregory Cuny, University of Houston; Alexei Degterev, Tufts University School of Medicine; and Siddharth Balachandran, Fox Chase Cancer Center.

The study's other authors are Ting Zhang, Bikash Thapa, Kathy Cai, Chaoran Yin, Carly DeAntoneo, Riley Williams, Maria Shubina and Mark Andrake, Fox Chase Cancer Center; Ioannis Siokas and Dingqiang Zhang, Tufts University School of Medicine; Daniel Schnepf, Julius Beer and Martin Schwemmle, University of Freiburg; Seungheon Lee, Raghavender Boda and Anantha Duddupudi, University of Houston; Christian Loch, Reaction Biology; Lee-Ann Van de Velde, Jessica Gaevert, Victoria Meliopoulos, Diego Rodriguez, Brandi Livingston, Jeremy Chase Crawford, Peter Vogel, Lawrence Fritz, Stacey Schultz-Cherry and Douglas Green, St. Jude.

The study was supported by grants from the National Institutes of Health (AI135025, AI168087, AI144400, AI161624, AI164003, HL170121, R01AI144828, R35CA231620 and P30CA006927), Collaborative Influenza Vaccine Innovation Centers (75N93019C00052), Health and Human Services (75N93021C00016) to the St. Jude Center of Excellence for Influenza Research and Surveillance and (75N93021C00018) Center for Influenza Disease and Emergence Response, Deutsche Forschungsgemeinschaft (SFB1160), Fox Chase Cancer Center (S10OD030332) and ALSAC, the fundraising and awareness organization of St. Jude.