(This article has been updated to include the contribution of Scripps Research scientist Hugh Rosen to the study).
Scientists at The Scripps Research Institute have identified a cause of a deadly immune system reaction to flu infection. Moreover, they have identified how a class of drugs tested in animals stops this “cytokine storm,” which can be more damaging than the flu itself.
The study was published Wednesday in the Proceedings of the National Academy of Sciences. It was led by Michael Oldstone, Hugh Rosen and John Teijaro, all of Scripps.
The work builds on a 2011 study led by Oldstone and Rosen finding that cytokine storms can kill flu patients. They also discovered a compound that inhibits this out-of-control immune reaction.
The new study charts the molecular paths affected by the compound, called CYM 5442, helping to explain why it’s effective. This knowledge can help guide development of new drugs to reduce flu mortality. Scientists who read the study said it may lead to new therapies for other infectious diseases characterized by immune overreaction.
“We show that with this type of drug, we can quiet the storm enough to interfere with the virus-induced disease and lung injury, while still allowing the infected host to mount a sufficient immune response to eliminate the virus,” Teijaro said in a Scripps press release.
Cytokine storms are believed to have caused the unusually heavy mortality of the 1918 flu, which killed an estimated 50 million to 100 million people. Most of those killed were young adults, who presumably had strong immune systems.
A version of this compound has been licensed to San Diego biotech Receptos, which is now in Phase 3 testing to treat multiple sclerosis, an autoimmune disease. The compound was developed in Rosen's lab.
The compound targets a receptor, or cell surface molecule, called S1P1. Receptors trigger reactions inside cells once activated. The S1P1 receptor is found in endothelial cells, which line blood vessels. These cells initiate the cytokine storm released in H1N1 flu infection. This cascade of chemicals is accompanied by infiltration of immune system cells into the lungs that can cause further damage. Activating the S1P1 receptor reduced the cytokine storm.
The scientists bred mice engineered to lack certain receptors that sense influenza infection and trigger an immune response. Elimination of any individual receptor produced a modest reduction in cytokine production and immune cell infiltration into the lungs. Compounds that activated S1P1 produced a much stronger reduction.
“What this shows is that our drug is working not through one selective pathway but much more broadly,” Teijara said in the release. “Many different cytokines are induced in this reaction, so just blocking one is surely not enough to reduce lung disease.”
The study results are “exciting,” scientists at Sanford-Burnham Medical Research Institute and the La Jolla Institute for Allergy & Immunology said by email.
“What is unknown is whether this drug is effective in humans at times late during infection when a drug like Tamiflu is not effective,” said Carl Ware, of Sanford-Burnham. “My take on John’s exciting results is a bit broader in that this class of drug may be effective in stopping damage in the lung caused by the immune system due to other infections or a virus infection in other sensitive organs, e.g., the brain.”
Sujan Shresta of the La Jolla Institute also said the drug could help other diseases beside the flu.
“In a cytokine storm, you have this massive immune activation and elevation of various types of cytokines and chemokines, both pro and anti-inflammatory, which are believed to be important in a number of viral diseases, including Ebola hemorrhagic fever and dengue hemorrhagic fever/dengue shock syndrome,” Shresta said.
Shresta is an expert in dengue virus, which infects up to 400 million people per year worldwide, according to the U.S. Centers for Disease Control and Prevention.
“The possibility that this research may benefit sufferers of a variety of potentially deadly diseases makes it even more noteworthy,” Shresta said.