Specific pathways mediating inflammasome activation by Candida parapsilosis

Adél Tóth,Erik Zajta,Katalin Csonka,Mihai G Netea,Attila Gácser,Csaba Vágvölgyi

doi:10.1038/srep43129

Abstract

Candida albicans and C. parapsilosis are human pathogens causing severe infections. The NLRP3 inflammasome plays a crucial role in host defence against C. albicans, but it has been previously unknown whether C. parapsilosis activates this complex. Here we show that C. parapsilosis induces caspase-1 activation and interleukin-1β (IL-1β) secretion in THP-1, as well as primary, human macrophages. IL-1β secretion was dependent on NLRP3, K+-efflux, TLR4, IRAK, Syk, caspase-1, caspase-8 and NADPH-oxidase. Importantly, while C. albicans induced robust IL-1β release after 4 h, C. parapsilosis was not able to stimulate the production of IL-1β after this short incubation period. We also found that C. parapsilosis was phagocytosed to a lesser extent, and induced significantly lower ROS production and lysosomal cathepsin B release compared to C. albicans, suggesting that the low extent of inflammasome activation by C. parapsilosis may result from a delay in the so-called “signal 2”. In conclusion, this is the first study to examine the molecular pathways responsible for the IL-1β production in response to a non-albicans Candida species, and these results enhance our understanding about the immune response against C. parapsilosis.

Highlights

Invasive fungal infections pose a serious health problem worldwide, amongst immunocompromised patients[1]
Since C. albicans is a potent inducer of IL-1βin THP-1 cells[25], we stimulated THP-1 macrophages with C. albicans and found that this species induced a robust IL-1βproduction by 4 h incubation at an MOI of 5 (Fig. 1d)
We investigated the molecular mechanisms of inflammasome activation in human macrophages in response to C. parapsilosis

Summary

Introduction

Invasive fungal infections pose a serious health problem worldwide, amongst immunocompromised patients[1]. The activation of the NLRP3 inflammasome is a two-step process: firstly, “signal 1” – that is typically delivered by pattern recognition receptors – initiates both IL1B gene transcription as well as the priming of the inflammasome by up-regulating NLRP3 mRNA and triggering post-translational changes in the NLRP3 protein, and secondly, “signal 2” induces the activation of the complex[17]. Inflammasome activation triggered by C. albicans infection can lead to pyroptosis in macrophages It is a proinflammatory form of programmed cell death mediated by caspase-1 activation and characterized by the loss of cell integrity[19,20]. Inflammasome activation is necessary for the processing of IL-18, another pro-inflammatory cytokine that plays an important role in the activation of Th1 lymphocytes[23]

Methods

Results

Conclusion