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One of the most threatening complications of influenza stems not from the virus itself, but from the overreaction of the immune system. This overreaction can cause persistent lung inflammation that lasts long after the virus has been quelled.
The group, led by Thirumala-Devi Kanneganti, PhD, Immunology, is exploring the immunological machinery that triggers this inflammation. In their latest work, the researchers have uncovered new clues to the machinery that could lead to drugs to suppress influenza-triggered inflammation. The scientists reported the findings in the April 17 issue of the journal Immunity.
A key target of exploration is a protein called cryopyrin, which is a trigger molecule in the body’s innate immune system. This immune system is the rapid general responder to disease, springing into action to protect the body against infection while the powerful-but-slower adaptive immune system marshals its more targeted defense.
Cryopyrin is a type of receptor molecule that nestles in the interior of immune cells. When cryopyrin latches onto a foreign molecule that is part of an invading virus or bacterium, it activates other components of the innate immune response.
Kanneganti’s earlier research had found specifically that cryopyrin—a member of a family called NOD-like receptors—switches on the enzyme called caspase-1, which in turn activates still other proteins called cytokines that launch the innate immune response. Her initial in vitro studies also revealed that influenza can activate cryopyrin.
In the latest study, Kanneganti, in collaboration with Paul Thomas, PhD, and Peter Doherty, PhD, both of Immunology, and their colleagues explored further the in vivo role of the cryopyrin/caspase-1 machinery during influenza virus infection.
The investigators found that mice engineered to lack either cryopyrin or caspase-1 were, indeed, more susceptible to influenza infection—demonstrating the proteins’ key protective role in influenza. Furthermore, these knockout mice also showed deficient production of two cytokines, IL-1 beta and IL-18. The knockout mice also displayed a reduced level of immune cells known to be responsible for inflammation during influenza infection and a greater level of lung damage when infected.
The researchers discovered clues to how cryopyrin detects that the influenza virus has invaded an immune cell. They found that exposing mice to the virus’ genetic material was enough to activate cryopyrin and caspase-1 in their immune cells.
“Our findings about the role of cryopyrin and caspase-1 show that these molecules could be important targets for drugs or vaccines to treat the complications of influenza,” said Kanneganti, the study’s senior author.
The findings about the cryopyrin machinery also have implications beyond influenza. Malfunction of the machinery underlies such autoinflammatory disorders as rheumatoid arthritis and Crohn’s disease, in which the immune system attacks the body’s own tissues.
“We are focusing on dissecting the role of these internal defense molecules, the NOD-like receptors, with the hope that our research could lead to better treatment for inflammatory and autoimmune diseases, and in designing better vaccines for infectious diseases,” Kanneganti said.
Other authors are Pradyot Dash, PhD, of Immunology; Jerry Aldridge Jr., PhD, Ali Ellebedy and Richard Webby, PhD, all of Infectious Diseases; William Martin and Amy Funk, DVM, both of the Animal Resources Center; and Cory Reynolds and Kelli Boyd, formerly of St. Jude.
The research was supported in part by the National Institutes of Health (NIH), the NIH’s National Institute of Allergy and Infectious Diseases and ALSAC.