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

Michelle D Tate,James D H Ong,Paul J Hertzog,Julie L Mcauley,Grant R Drummond,Eicke Latz,Ashley Mansell,Avril B Robertson,Jennifer K Dowling,Matthew A Cooper

doi:10.1038/srep27912

Abstract

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.

Highlights

(M2) ion channel have been shown to activate the NLRP3 inflammasome[4,5], which is important in the development of adaptive immune responses to IAV6
This study identifies for the first time that activation of the inflammasome in the later stages of influenza A virus (IAV) disease detrimentally contributes to pathogenesis and suggests that targeting the inflammasome may be a therapeutic option to treat pathogenic IAV infections
Using MCC950, we examined the temporal role of NLRP3-induced inflammation during mild (102 PFU; Fig. 1a,d) and severe (105 PFU; Fig. 1b,c,e and f) IAV infection

Summary

Introduction

(M2) ion channel have been shown to activate the NLRP3 inflammasome[4,5], which is important in the development of adaptive immune responses to IAV6. Studies utilising mice lacking components of the NLRP3 inflammasome have demonstrated its importance in eliciting an early, protective immune response when challenged with the mouse-adapted A/Puerto Rico/8/34 strain (PR8, H1N1)[5,7]. In these studies, inflammasome-deficient mice were highly susceptible to both low and high inoculum doses of PR8 and the NLRP3 inflammasome was shown to be required for production of pyrogenic IL-1βand IL-18 in the airways, cellular infiltration and lung immunopathology. This study identifies for the first time that activation of the inflammasome in the later stages of IAV disease detrimentally contributes to pathogenesis and suggests that targeting the inflammasome may be a therapeutic option to treat pathogenic IAV infections

Methods

Results

Conclusion