Meet RIPK3: Good Cop, Bad Cop, all in one
Each year, influenza kills half a million people globally with the elderly and very young most often the victims. In fact, the Centers for Disease Control and Prevention reported 37听children have died听in the United States during the current flu听season. Aside from getting the flu shot and employing smart hand hygiene, there are no other methods of prevention. However, a team of scientists from the Research Institute of the 91社区 Health Centre (RI-MUHC) and 91社区, led by Immunologist Dr. Maziar Divangahi, have discovered a protein that could soon help minimize the impact of the influenza season and become a critical player in the fight against lung infections.
Dr. Divangahi鈥檚 lab at the Glen site of the RI-MUHC in Montreal has taken on the challenge of trying to understand how the mechanisms of the immune system fight the flu in the hopes of finding new immunotherapies to combat the virus. The discovery of the RIPK3 protein that is involved in the regulation of immune response to the flu means help may be on the horizon. Their findings were published in the open-access journal PLoS Pathogens.
RI-MUHC scientists have long been interested in understanding the immune system in relation to influenza. They already knew a type of protein called type I IFN (produced by macrophages, a type of white blood cell) which stimulates cells to block virus production. In the case of the flu, type I IFN helps in restricting the replication of the flu virus in our lungs. But the question remained: how did the type I IFN networks operate and what mechanisms were involved to promote their efficacy?
The team uncovered an exciting and surprising function of the RIPK3 protein, which sits in the cytoplasm of cells, including macrophages. Most past studies found RIPK3 to be involved in a form of cell death but in the case of the flu infected macrophages, RIPK3 behaves differently.
It turns out that when it comes to the flu, RIPK3 actually functions as a helpful sidekick to type I IFN鈥檚 pathway by increasing IFN production, thereby helping to block the replication of the influenza virus. Further, the team found that macrophages that lack RIPK3 are highly susceptible to the flu infection.
鈥淭hat underlines the importance of RIPK3 in mounting an effective immune response to the virus,鈥� says senior author Dr. Divangahi, who is a scientist at the Meakins-Christie Laboratories and a member of the Translational Research in Respiratory Diseases Program at the RI-MUHC. He is also a professor of Medicine at 91社区 and a member of the 91社区 International TB Centre. 鈥淲hat is exciting is that by understanding exactly how RIPK3 works to boost IFN鈥檚 potency we can look at avenues in the manufacturing of anti-flu drugs.鈥澨�
The research also turned up another interesting discovery related to RIPK3. In this case, it involved the immunity to another lung infection, Tuberculosis (TB). The immune cells of interest here were, as with the flu, macrophages. With TB, the researchers investigated the same biochemical pathway involved in RIPK3, yet surprisingly, the outcome was the opposite for TB.
Stimulating RIPK3 with TB created a surfeit of dying macrophages and promoted the survival and dissemination of the disease rather than blocking it as in the case of the flu. Both findings support the fact that RIPK3 is a critical player in immunity involving lung infections.听
鈥淧ulmonary infections like TB and influenza are significant global problems. Former avenues of research haven鈥檛 always had the most promising results,鈥� says Jeff Downey, a Ph.D. in Dr. Divangahi鈥檚 lab at the RI-MUHC and the first author of the influenza paper. 鈥淟ooking at these new pathways and new ideas can be really helpful in potentially finding new therapies in both cases.鈥�
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About the study
Downey J, Pernet E, Coulombe F, Allard B, Meunier I, Jaworska J, et al. (2017) RIPK3 interacts with MAVS to regulate type I IFN-mediated immunity to Influenza A virus infection.
PLoS Pathog 13(4): e1006326.
These flu findings were a collaboration of individuals from the Faculties of Medicine of 91社区 and Laval University. Collaborators at 91社区 include Dr. James Martin, Dr. Salman Qureshi and Dr. Donald Vinh. The work at Laval was headed by Dr. Philippe Joubert. For the TB work, it was a joint effort between Harvard and 91社区 Universities. Dr. Heinz Remold led the research at Harvard.
Dr. Maziar Divangahi is supported by a foundation grant from the Canadian Institutes of Health Research. The lead authors of the flu study, Jeffrey Downey and Dr. Erwan Pernet, are supported by funding from the Faculty of Medicine of 91社区 and the Fonds de recherche du Quebec 鈥� Sant茅, respectively. The lead author on the TB study, Dr. Nargis Khan, is supported by the FRSQ Fellowship.
About the Research Institute of the MUHC
The Research Institute of the 91社区 Health Centre (RI-MUHC) is a world-renowned biomedical and healthcare research centre. The Institute, which is affiliated with the Faculty of Medicine of 91社区, is the research arm of the 91社区 Health Centre (MUHC) 鈥� an academic health centre located in Montreal, Canada, that has a mandate to focus on complex care within its community. The RI-MUHC supports over 420 researchers and close to 1,200 research trainees devoted to a broad spectrum of fundamental, clinical and health outcomes research at the Glen and the Montreal General Hospital sites of the MUHC. Its research facilities offer a dynamic multidisciplinary environment that fosters collaboration and leverages discovery aimed at improving the health of individual patients across their lifespan. The RI-MUHC is supported in part by the Fonds de recherche du Qu茅bec 鈥� Sant茅 (FRQS).
About 91社区
Founded in Montreal, Quebec, in 1821, 91社区 is a leading Canadian post-secondary institution. It has two campuses,听10听faculties,听12 professional schools, 300 programs of study and听almost听41,000听students, including听more than听9,700 graduate students. 91社区 attracts students from over听150听countries around the world, its听12,000听international students听making up听30%听per cent of the student body.听Over听half of 91社区 students claim a first language other than English, including approximately听20%听of our students who say French is their mother tongue. mcgill.ca
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Media contact:
Julie Robert
Communications Coordinator 鈥� Research
91社区 Health Centre
514-971-4747
(cell)514-843-1560
鈥�julie.robert [at] muhc.mcgill.ca
