Turning Up the Heat: Inflammasome Activation by Fungal Pathogens

Tavares, Aldo Henrique; Bürgel, Pedro Henrique; Bocca, Anamélia Lorenzetti

doi:10.1371/journal.ppat.1004948

Cited by 44 publications

(57 citation statements)

References 38 publications

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“…Inflammasome is reported to be associated with and acts as a defense mechanism against fungal infections [28]. Here, we sought to investigate whether H .…”

Section: Resultsmentioning

confidence: 99%

Dectin-2 is a primary receptor for NLRP3 inflammasome activation in dendritic cell response to Histoplasma capsulatum

et al. 2017

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Inflammasome is an intracellular protein complex that serves as cytosolic pattern recognition receptor (PRR) to engage with pathogens and to process cytokines of the interleukin-1 (IL-1) family into bioactive molecules. It has been established that interleukin-1β (IL-1β) is important to host defense against Histoplasma capsulatum infection. However, the detailed mechanism of how H. capsulatum induces inflammasome activation leading to IL-1β production has not been studied. Here, we showed in dendritic cells (DCs) that H. capsulatum triggers caspase-1 activation and IL-1β production through NLRP3 inflammasome. By reciprocal blocking of Dectin-1 or Dectin-2 in single receptor-deficient DCs and cells from Clec4n-/-, Clec7a-/-, and Clec7a-/-Clec4n-/- mice, we discovered that while Dectin-2 operates as a primary receptor, Dectin-1 serves as a secondary one for NLRP3 inflammasome. In addition, both receptors trigger Syk-JNK signal pathway to activate signal 1 (pro-IL-1β synthesis) and signal 2 (activation of caspase-1). Results of pulmonary infection with H. capsulatum showed that CD103+ DCs are one of the major producers of IL-1β and Dectin-2 and Dectin-1 double deficiency abolishes their IL-1β response to the fungus. While K+ efflux and cathepsin B (but not ROS) function as signal 2, viable but not heat-killed H. capsulatum triggers profound lysosomal rupture leading to cathepsin B release. Interestingly, cathepsin B release is regulated by ERK/JNK downstream of Dectin-2 and Dectin-1. Our study demonstrates for the first time the unique roles of Dectin-2 and Dectin-1 in triggering Syk-JNK to activate signal 1 and 2 for H. capsulatum-induced NLRP3 inflammasome activation.

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“…Inflammasome is reported to be associated with and acts as a defense mechanism against fungal infections [28]. Here, we sought to investigate whether H .…”

Section: Resultsmentioning

confidence: 99%

Dectin-2 is a primary receptor for NLRP3 inflammasome activation in dendritic cell response to Histoplasma capsulatum

et al. 2017

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“…It has been demonstrated that some Saps are pro-inflammatory proteins capable of inducing a potent damage response through endocellular inflammasome receptors, particularly the NLRP3 inflammasome, in both hemopoietic and epithelial tissues [37–39]. While adding to the list of other identified or supposed fungal inflammasome activators [40], Saps are the first identified fungal inducers of inflammasome activation of a pure protein nature. Importantly, Sap-induced pro-inflammatory activity, unlike all other Sap functions, does not rely on enzymatic activity [37].…”

Section: A Blend Of Immunoevasion and Immunoactivationmentioning

confidence: 99%

Aspartyl Proteinases of Eukaryotic Microbial Pathogens: From Eating to Heating

2016

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“…Unless otherwise indicated (Table 1, Notes column), all KO mice in Table 1 are Casp1 −/− Casp11 −/− mice. It should be noted that while many survival studies have been performed with bacteria, fewer have been published with viral, fungal, and parasitic infection (further discussed below) (15–18). After collation of published survival studies (Table 1), it was striking that most changes in lethal dose were estimated to be in the 1–5 fold range.…”

Section: Introductionmentioning

confidence: 99%

Reassessing the Evolutionary Importance of Inflammasomes

Maltez

Miao

2016

The Journal of Immunology

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Inflammasomes monitor the cytosol for microbial contamination or perturbation, and are thus predicted to provide potent defense against infection. However, the compendium of data from murine infection models suggests that inflammasomes merely delay the course of disease, allowing the host time to mount an adaptive response. Interpretations of such results are confounded by inflammasome evasion strategies of vertebrate-adapted pathogens. Conversely, environmental opportunistic pathogens have not evolved in the context of inflammasomes, and are therefore less likely to evade them. Indeed, opportunistic pathogens do not normally cause disease in wild type animals. Accordantly, the extreme virulence of two opportunistic bacterial pathogens, Burkholderia thailandensis and Chromobacterium violaceum, is fully counteracted by inflammasomes in murine models. This leads us to propose a new hypothesis: perhaps animals maintain inflammasomes over evolutionary time not to defend against vertebrate-adapted pathogens, but instead to counteract infection by a plethora of undiscovered opportunistic pathogens residing in the environment.

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Turning Up the Heat: Inflammasome Activation by Fungal Pathogens

Cited by 44 publications

References 38 publications

Dectin-2 is a primary receptor for NLRP3 inflammasome activation in dendritic cell response to Histoplasma capsulatum

Dectin-2 is a primary receptor for NLRP3 inflammasome activation in dendritic cell response to Histoplasma capsulatum

Aspartyl Proteinases of Eukaryotic Microbial Pathogens: From Eating to Heating

Reassessing the Evolutionary Importance of Inflammasomes

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