Therapeutic targeting of the NLRP3 inflammasome may protect against lethal influenza infection.

Lead researcher

Associate Professor Ashley Mansell

Main finding

We found that the PB1-F2 protein from the H7N9 avian influenza A virus strain induces activation of the NLRP3 inflammasome leading to excessive production of the pro-inflammatory cytokine interleukin-1β (IL-1β). We further found that temporal administration of the NLRP3 small molecular inhibitor, MCC950, ameliorates PB1F2-induced inflammation. This identifies H7N9 PB1-F2 as a major virulence factor and key mediator of excessive inflammation and infection. Importantly, it also suggests that targeting the NLRP3 inflammasome with a small molecule inhibitor such as MCC950 may be a therapeutic option to treat the ‘cytokine storm’ associated with these infections.

Centre

Centre for Innate Immunity & Infectious Diseases

Research group

Pattern Recognition Receptors and Inflammation

Co-authors

Anita Pinar, Jennifer K Dowling, Avril B Robertson, Eicke Latz, Cameron R Stewart, Grant Drummond, Matthew A Cooper, Julie L McAuley, Michelle D Tate and Ashley Mansell

Journal and article title

Most surprising

A major question is ‘why do these avian influenza strains cause such catastrophic infections in people and induce the cytokine storm’? Currently, over 800 people have been infected with H7N9 IAV and approx. 40% of those infected die. Identifying PB1-F2 as a potential cause of this excessive inflammatory response compared to circulating seasonal IAV infections identifies an important ‘motif’ to look for in emerging, potentially pandemic, strains. Importantly, we could reduce this excessive inflammation caused by PB1-F2 by inhibiting the inflammasome. Currently there are no real effective treatments for patients who present at hospital with avian influenza- this offers hope that maybe we could target the inflammasome to treat these infections.

Future implications

Potential anti-inflammatory therapeutic to protect against pandemic avian influenza infections such as the current H7N9 strain.

Disease/health impact

Pandemic avian influenza infections

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