Abstract
Talaromyce marneffei is an important thermally dimorphic pathogen causing disseminated mycoses in immunocompromised individuals in southeast Asia. Previous studies have suggested that NLRP3 inflammasome plays a critical role in antifungal immunity. However, the mechanism underlying the role of NLRP3 inflammasome activation in host defense against T. marneffei remains unclear. We show that T. marneffei yeasts but not conidia induce potent IL-1β production. The IL-1β response to T. marneffei yeasts is differently regulated in different cell types; T. marneffei yeasts alone are able to induce IL-1β production in human PBMCs and monocytes, whereas LPS priming is essential for IL-1β response to yeasts. We also find that Dectin-1/Syk signaling pathway mediates pro-IL-1β production, and NLRP3-ASC-caspase-1 inflammasome is assembled to trigger the processing of pro-IL-1β into IL-1β. In vivo, mice deficient in NLRP3 or caspase-1 exhibit higher mortality rate and fungal load compared to wild-type mice after systemic T. marneffei infection, which correlates with the diminished recruitment of CD4 T cells into granulomas in knockout mice. Thus, our study first demonstrates that NLRP3 inflammasome contributes to host defense against T. marneffei infection.
Highlights
Talaromyce marneffei is an opportunistic dimorphic pathogenic fungus that causes fatal systemic mycosis in immunocompromised hosts in southeast Asia [1]
To dissect the production of cytokines elicited by T. marneffei, freshly isolated human peripheral blood mononuclear cells (PBMCs) were co-cultured with T. marneffei yeasts or conidia at 0.5 multiplicity of infection (MOI) for indicated incubation time points
In contrast to T. marneffei yeasts, only minimal levels of IL-1b was detected in Peripheral blood mononuclear cells (PBMCs) co-cultured with conidia at 5 days post infection (Figure 1C), whereas TNF-a production began to increase steadily after 2 days of incubation (Figure 1D)
Summary
Talaromyce marneffei is an opportunistic dimorphic pathogenic fungus that causes fatal systemic mycosis in immunocompromised hosts in southeast Asia [1]. It is considered as an AIDS-defining disease ranking the third most common opportunistic infection in HIV-positive patients following tuberculosis and cryptococcosis in endemic areas [1,2,3]. T. marneffei is thermally dimorphic; it grows as a mold bearing conidia when cultured at 25°C, whereas it converts into yeast cells at 37°C [3]. It is believed that airborne T. marneffei conidia are inhaled by patients from the surrounding environment. Yeast cells are phagocytosed by Talaromyces marneffei Activates NLRP3 Inflammasome pulmonary macrophages. The proliferating yeast cells within macrophages trigger granuloma formation, followed by the dissemination of yeast cells into other organs, such as the liver, spleen, skin, via bloodstream [3, 12]
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