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Secreted fungal effector triggers allergic inflammation via Toll-like receptor 4 to enable lethal infection

ABSTRACT: Invasive fungal pathogens are major causes of human mortality and morbidity1,2. While numerous secreted effector proteins that reprogram innate immunity to promote virulence have been identified in pathogenic bacteria, there are no examples of analogous secreted effector proteins produced by human fungal pathogens. Cryptococcus neoformans, the most common cause of fungal meningitis and a major AIDS pathogen, induces a pathogenic type 2 response characterized by pulmonary eosinophilia and alternatively activated macrophages3-8. Here, we identify Cpl1 as an effector protein secreted by C. neoformans that drives alternative activation (also known as M2 polarization) of macrophages to enable pulmonary infection. We observed that Cpl1-enhanced macrophage polarization requires Toll-like receptor 4, best known as a receptor for bacterial endotoxin, but is also a poorly understood mediator of allergen-induced type 2 responses9-12. We show that this effect is due to Cpl1 itself and not contamination by lipopolysaccharide. Cpl1 is essential for virulence, drives polarization of interstitial macrophages in vivo, and requires type 2 cytokine signaling for its impact on infectivity. Strikingly, C. neoformans selectively associates with polarized interstitial macrophages during infection, suggesting a mechanism by which C. neoformans generates its own intracellular replication niche within the host. This work identifies a novel circuit whereby a secreted effector protein produced by a human fungal pathogen reprograms innate immunity, revealing an unexpected role for Toll-like receptor 4 in pathogenesis of infectious disease.

ORGANISM(S): Mus musculus

PROVIDER: GSE203483 | GEO | 2022/08/12

REPOSITORIES: GEO

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Secreted fungal effector triggers allergic inflammation via Toll-like receptor 4 to enable lethal infection

Project description:Secreted fungal effector triggers allergic inflammation via Toll-like receptor 4 to enable lethal infection

| PRJNA840930 | ENA

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