As lung cells are killed by the influenza virus, they burst open, releasing molecular signals that trigger the immune cells that can combat the infection. This strategy can be an important red flag that something is wrong; however, if one cell death response, called necroptosis, continues unchecked, it can cause life-threatening injury to lung tissue.
Now, a team of researchers from multiple institutions has developed a compound capable of reversing the course of infection in mice by blocking necroptosis. The researchers say the compound not only fills a currently unmet need by addressing the most severe flu infections, but it could also work with other viruses that trigger severe respiratory symptoms.
“While the worst of COVID-19 may be behind us, the credible expectation is that there will be another pandemic that’s going to happen and we need something that is going to protect the host independent of how the host is infected,” said co-corresponding author Alexei Degterev, associate professor of developmental, molecular and chemical biology at Tufts University School of Medicine. “This work highlights the possibility of achieving such a goal and renews interest in how cell death shapes infection.”
In a paper published in Nature, the researchers showed that the drug UH15-38 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.
“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,” said co-corresponding author Paul Thomas, St. Jude Department of Host-Microbe Interactions. “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 scientists achieved this Goldilocks amount of inflammation using clever chemistry. UH15-38 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.”
The researchers found that the mice were protected even if they received a dose days after infection, a difficult achievement for an influenza therapeutic. Typically, patients with severe disease have 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.
The collaborators are now pursuing the second generation of inhibitors. They are also continuing to test how UH15-38 and related compounds can protect against other respiratory diseases.
“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.”