Research Article: Human metapneumovirus activates NOD-like receptor protein 3 inflammasome via its small hydrophobic protein which plays a detrimental role during infection in mice

Date Published: April 9, 2019

Publisher: Public Library of Science

Author(s): Vuong B. Lê, Julia Dubois, Christian Couture, Marie-Hélène Cavanagh, Olus Uyar, Andres Pizzorno, Manuel Rosa-Calatrava, Marie-Ève Hamelin, Guy Boivin, Matthias Johannes Schnell.

http://doi.org/10.1371/journal.ppat.1007689

Abstract

NOD-like receptor protein 3 (NLRP3) inflammasome activation triggers caspase-1 activation-induced maturation of interleukin (IL)-1β and IL-18 and therefore is important for the development of the host defense against various RNA viral diseases. However, the implication of this protein complex in human metapneumovirus (HMPV) disease has not been fully studied. Herein, we report that NLRP3 inflammasome plays a detrimental role during HMPV infection because NLRP3 inflammasome inhibition protected mice from mortality and reduced weight loss and inflammation without impacting viral replication. We also demonstrate that NLRP3 inflammasome exerts its deleterious effect via IL-1β production since we observed reduced mortality, weight loss and inflammation in IL-1β-deficient (IL-1β-/-) mice, as compared to wild-type animals during HMPV infection. Moreover, the effect on these evaluated parameters was not different in IL-1β-/- and wild-type mice treated with an NLRP3 inflammasome inhibitor. The production of IL-1β was also abrogated in bone marrow derived macrophages deficient for NLRP3. Finally, we show that small hydrophobic protein-deleted recombinant HMPV (HMPV ΔSH) failed to activate caspase-1, which is responsible for IL-1β cleavage and maturation. Furthermore, HMPV ΔSH-infected mice had less weight loss, showed no mortality and reduced inflammation, as compared to wild-type HMPV-infected mice. Thus, NLRP3 inflammasome activation seems to be triggered by HMPV SH protein in HMPV disease. In summary, once activated by the HMPV SH protein, NLRP3 inflammasome promotes the maturation of IL-1β, which exacerbates HMPV-induced inflammation. Therefore, the blockade of IL-1β production by using NLRP3 inflammasome inhibitors might be a novel potential strategy for the therapy and prevention of HMPV infection.

Partial Text

The inflammasomes are cytosolic multiprotein complexes responsible for caspase-1 activation [1]. Once activated, caspase-1 proteolytically cleaves interleukin (IL)-1β and IL-18 precursors (pro-IL-1β and pro-IL-18), leading to the release of mature forms [2, 3]. Among identified inflammasomes, the NOD-like receptor protein 3 (NLRP3) inflammasome containing NLRP3, adapter protein apoptosis-associated speck-like protein (ASC) and pro-caspase-1 is the most fully studied [4]. NLRP3 inflammasome activation is a two-step process. The first step involves a priming signal provided by microbial molecules or endogenous cytokines, which upregulates the transcription of inactive NLRP3, pro-IL-1β and pro-IL-18. The second step is characterized by the oligomerization of NLRP3 and subsequent assembly of NLRP3, ASC and pro-caspase-1 into a complex [5]. This signal is provided by numerous stimuli such as ATP, pore-forming toxins, viral RNA, etc. Most of them induce potassium efflux, calcium signaling, reactive oxygen species generation, mitochondrial dysfunction and lysosomal rupture [6].

Our study clearly shows the role of the inflammasome and in particular IL-1β in the pathogenesis of HMPV using a pharmacological approach, BMDM NLRP3 KO cells and IL-1β-/- mice. As a crucial component of the innate immune system, NLRP3 inflammasome serves an important role in host defense by recognizing RNA viral pathogens and triggering immune responses [36]. Although NLRP3 inflammasome has been reported to be implicated in many RNA viral diseases with distinct functions [7, 8], little is known about the involvement of this protein complex in the pathogenesis of HMPV. In such a context, this present study shows for the first time that NLRP3 inflammasome plays a detrimental role during HMPV infection and that such effect is mediated by the viral SH protein.

 

Source:

http://doi.org/10.1371/journal.ppat.1007689

 

0 0 vote
Article Rating
Subscribe
Notify of
guest
0 Comments
Inline Feedbacks
View all comments