Hero turned villain: NLRP3 inflammasome-induced inflammation during influenza A virus infection.

The severity of influenza A virus (IAV) infection can range from asymptotic to mild to severe. Infections, such as those seen following outbreaks of avian IAV, are associated with hyperinflammatory responses and the development of fatal disease. There is a continual threat that a novel or pandemic IAV will circulate in humans with high rates of mortality. The neuronal apoptosis inhibitor protein, class 2 transcription activator of the MHC, heterokaryon incompatibility, telomerase-associated protein 1, leucine-rich repeat, and pyrin domain-containing protein 3 (NLRP3) inflammasome is an innate immune sensor that has been shown to be critical for the secretion of the potent proinflammatory cytokines, IL-1ß and IL-18, as well as chemokine production and cellular inflammation in vivo following IAV infection. Initial studies illustrated a protective role of NLRP3 during severe IAV infection in mice. However, the NLRP3 inflammasome may be a hero that turns villain in the later stages of severe IAV infection via the promotion of a hyperinflammatory state. Current treatments for patients who present to hospitals with a severe IAV infection are limited. The understanding of the mechanisms involved in the induction of NLRP3-dependent inflammation during severe IAV infections may provide new therapeutic targets that reduce human mortality.

Reassessing the role of the NLRP3 inflammasome during pathogenic influenza A virus infection via temporal inhibition.

The inflammasome NLRP3 is activated by pathogen associated molecular patterns (PAMPs) during infection, including RNA and proteins from influenza A virus (IAV). However, chronic activation by danger associated molecular patterns (DAMPs) can be deleterious to the host. We show that blocking NLRP3 activation can be either protective or detrimental at different stages of lethal influenza A virus (IAV). Administration of the specific NLRP3 inhibitor MCC950 to mice from one day following IAV challenge resulted in hypersusceptibility to lethality. In contrast, delaying treatment with MCC950 until the height of disease (a more likely clinical scenario) significantly protected mice from severe and highly virulent IAV-induced disease. These findings identify for the first time that NLRP3 plays a detrimental role later in infection, contributing to IAV pathogenesis through increased cytokine production and lung cellular infiltrates. These studies also provide the first evidence identifying NLRP3 inhibition as a novel therapeutic target to reduce IAV disease severity.