Abstract
Cryptococcus neoformans and Cryptococcus gattii cause life-threatening meningoencephalitis or lung diseases in immunocompetent individuals or immunocompromised ones. C. neoformans and C. gattii are subdivided into five serotypes based on their capsular glucuronoxylomannan (GXM). C. neoformans consists of serotypes A, D, and AD hybrid, and C. gattii consists of serotypes B and C. Given structural differences of GXM between C. neoformans and C. gattii, it remains unclear that how innate immune system recognizes GXM. Here, we report that C-type lectin receptor Dectin-3 (MCL encoded by Clec4d) is a direct receptor for GXMs from C. neoformans serotype AD (C.n-AD) and C. gattii serotype B (C.g-B). GXMs from C.n-AD and C.g-B activated NF-κB and ERK pathways to induce pro-inflammatory cytokine production, whereas it was completely abolished due to deficiency of Dectin-3 or caspase recruitment domain family member 9 (CARD9). Upon pulmonary C.n-AD and C.g-B infection, Dectin-3- and CARD9-deficient mice were highly susceptible and showed augmented lung injury due to impairment of alveolar macrophage accumulation and killing activities. Our study provides the first biological and genetic evidence demonstrating that Dectin-3 recognizes GXM of C.n-AD and C.g-B to initiate host defense against cryptococcosis.
Highlights
The saprophytic, encapsulated fungal pathogens Cryptococcus neoformans and Cryptococcus gattii can cause life-threatening meningoencephalitis and pneumonia in both immunocompromised and immunocompetent individuals, which is called cryptococcosis [1]
To explore whether Dectin-3 is required for C.g-B induced pro-inflammation responses, we stimulated bone marrow-derived macrophages (BMDMs) from wild-type (WT, Clec4d+/+) and Dectin-3-deficient (Clec−/−) mice with thin- and thick-capsulated C.g-B, and found that both thin- and thick-capsulated C.g-B strongly induced nuclear translocation of NF-κB (p65 subunit) (Figure 1B), together with IκBα phosphorylation and degradation (Figure 1C)
We found that secretion of pro-inflammation cytokines including TNF-α and IL-6 were increased in WT BMDMs when stimulated with thin- and thick-capsulated C.g-B, whereas Dectin-3 deficiency significantly impaired these responses (Figure 1D)
Summary
The saprophytic, encapsulated fungal pathogens Cryptococcus neoformans and Cryptococcus gattii can cause life-threatening meningoencephalitis and pneumonia in both immunocompromised and immunocompetent individuals, which is called cryptococcosis [1]. C. neoformans has been classified into three serotypes including A, D, and AD hybrid whereas serotypes B and C have been recognized as a separate species called C. gattii based on antigenic differences in the polysaccharide capsules of the fungus [2,3,4]. Infection by C. gattii including serotype B and C (C.g-B and C.g-C) is much less common in immunocompromised patients but is thought to be more virulent than C. neoformans and causes disseminated infections even in healthy hosts [8]. It was thought that C. gattii infections were restricted to tropical and subtropical regions [9], but the emergence of the outbreak events due to C. gattii infections in temperate areas of North America suggest a more global distribution of this yeast [10, 11]
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