Inhibition of the NOD-Like Receptor Protein 3 Inflammasome Is Protective in Juvenile Influenza A Virus Infection

Abstract

Influenza A virus (IAV) is a significant cause of life-threatening lower respiratory tract infections in children. Antiviral therapy is the mainstay of treatment, but its effectiveness in this age group has been questioned. In addition, damage inflicted on the lungs by the immune response to the virus may be as important to the development of severe lung injury during IAV infection as the cytotoxic effects of the virus itself. A crucial step in the immune response to IAV is activation of the NOD-like receptor protein 3 (NLRP3) inflammasome and the subsequent secretion of the inflammatory cytokines, interleukin-1β (IL-1β), and interleukin-18 (IL-18). The IAV matrix 2 proton channel (M2) has been shown to be an important activator of the NLRP3 inflammasome during IAV infection. We sought to interrupt this ion channel-mediated activation of the NLRP3 inflammasome through inhibition of NLRP3 or the cytokine downstream from its activation, IL-1β. Using our juvenile mouse model of IAV infection, we show that inhibition of the NLRP3 inflammasome with the small molecule inhibitor, MCC950, beginning 3 days after infection with IAV, improves survival in juvenile mice. Treatment with MCC950 reduces NLRP3 levels in lung homogenates, decreases IL-18 secretion into the alveolar space, and inhibits NLRP3 inflammasome activation in alveolar macrophages. Importantly, inhibition of the NLRP3 inflammasome with MCC950 does not impair viral clearance. In contrast, inhibition of IL-1β signaling with the IL-1 receptor antagonist, anakinra, is insufficient to protect juvenile mice from IAV. Our findings suggest that targeting the NLRP3 inflammasome in juvenile IAV infection may improve disease outcomes in this age group.

NLRP3 Inflammasome—A Key Player in Antiviral Responses

“…Modulating the NLRP3 inflammasome activity can prove to be a promising strategy for the intervention of viral diseases. In a juvenile mouse model of IAV infection, MCC950, a specific inhibitor of the NLRP3 inflammasome, ameliorates severe NLRP3 inflammasome-mediated lung injury without impairing viral clearance (76).…”

The inflammasome potentiates influenza/Staphylococcus aureus superinfection in mice

“…Studies have shown that both NLRP3 and AIM2 are required for inflammation during influenza infection through the use of mice lacking components of NLRP3 and AIM2 (15,16). However, temporal inhibition of NLRP3 during influenza infection through the use of a small-molecule inhibitor of NLRP3 results in decreased disease and lung inflammation if used later in the course of infection (17,18). To investigate the individual component AIM2, we challenged WT and AIM2 -/mice with A/ PR/8/34 for 6 days followed by MSSA and saw enhanced bacterial clearance in the superinfected AIM2 -/mice compared with superinfected WT mice ( Figure 5A).…”

Rhein Suppresses Lung Inflammatory Injury Induced by Human Respiratory Syncytial Virus Through Inhibiting NLRP3 Inflammasome Activation via NF-κB Pathway in Mice

“…In the academic sector of anti-inflammatory and anti-viral pharmacology, the NLRP3 inflammasome and NF-kB signaling both play essential role in the excessive inflammatory response stimulated by various types of viruses, including RSV, and are closely related to the viral-induced lung injury (Xu et al, 2015;Tate et al, 2016;Chen et al, 2017;Coates et al, 2017;Pinar et al, 2017;Ren et al, 2017;Sarvestani and McAuley, 2017). As for the application of effective treatment strategies against inflammatory response caused by RSV invasion, there has been no research paradigm until now.…”