The research shows that a newly developed drug has the ability to stop excessive inflammation while still allowing the immune system to fight the virus, even when administered late in the infection. Infection with the flu virus can lead to lung damage due to the over-activation of inflammation, which can harm the cells necessary for breathing. This damage can be very dangerous, but a new treatment has been developed by a team of scientists from St. Jude Children’s Research Hospital, University of Houston, Tufts University School of Medicine, and Fox Chase Cancer Center. Their drug has the ability to prevent lung damage caused by the flu in mice.In a study published in Nature, researchers found that a new drug, UH15-38, effectively balanced the shutting down of excessive inflammation while still allowing the immune system to combat the virus. Co-corresponding author Paul Thomas, PhD, from the St. Jude Department of Host-Microbe Interactions, stated, “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.” The drug was shown to protect against lethal influenza in a series of experiments conducted on mouse models.Animals experience similar levels of illness from influenza as humans, even with low doses. The research team also discovered that a high dosage of the drug could fully prevent an infection from a large amount of virus, which would typically be fatal. The models remained protected even when receiving the dose several days after being infected, which is a significant accomplishment for an influenza treatment. “This drug also has an unprecedented effect,” Thomas explained. “We can start treatment five days after the initial infection and still see some benefits.” Healthcare providers need to administer the latest antiviral medications within the first few days of an outbreak.In order for the infection to be effective, UH15-38 may fill a current gap by addressing the needs of patients who have been infected for several days by the time they seek medical attention. The breakthrough in understanding the interaction between influenza and the immune system may potentially prevent lung injury.
Guiding influenza-infected cells in the right direction
“The inflammation created by infected lung cells serves as a signal to the immune system, indicating a problem. However, excessive inflammation can lead to serious complications,” Thomas explained. “It is essential to maintain a delicate balance between generating enough inflammation to alert the immune system and avoiding excessive inflammation that can cause harm.”
Researchers found a balance in the amount of inflammation needed to fight off the virus without causing excessive inflammation. The scientists used innovative chemistry to develop a new drug that targeted a specific part of a key inflammation protein in immune cells called Receptor-Interacting Protein Kinase 3 (RIPK3). RIPK3 is responsible for regulating two cell death pathways in response to infection: apoptosis and necroptosis. Necroptosis is highly inflammatory, while apoptosis is not. Both pathways play a role in the body’s defense against viruses. The drug UH15-38 was created to block RIPK3 from initiating necroptosis while still allowing it to maintain its pro-apoptotic properties.
“Eliminating RIPK3 completely isn’t ideal because then the immune system won’t be able to eliminate the virus,” Thomas explained. “When we only eliminated necroptosis, the animals fared better because they still had apoptosis and could still remove infected cells, but it wasn’t as inflammatory.”
Preventing lung inflammation and damage
“We also demonstrated that the increased survival was directly linked to the decrease in local inflammation and improved survival of lung cells,” Thomas noted.
In a series of previous studies, the Thomas lab discovered that a specific group of cells in the lung are Collateral damage occurs in the uncontrollable inflammatory response. Type 1 alveolar epithelial cells, responsible for gas exchange, are affected, resulting in difficulty breathing. The study showed that these crucial cells were not harmed by the drug. Furthermore, inflammation-related immune cells, like neutrophils, were much lower in the treated animals’ lungs. “The most severe consequences of influenza occur after the virus is under control, when inflammation destroys lung cells,” Thomas explained. “UH15-38 can reduce this influenza-caused inflammation.”The study found that the drug reduced inflammation but did not interfere with the body’s ability to fight off viruses or other immune responses. This makes it a promising candidate for further development and potential use in medical clinics.
