Biology subjects

Dang, E. V.

Publications and source records attributed to Dang, E. V..

4 recordsLinked to original sources

bioRxiv2025

Spatial organization of pulmonary type 2 inflammation by a macrophage-derived cholesterol metabolite

Effective pulmonary immunity requires the precise spatial organization of immune cells, yet the mechanisms guiding their intratissue positioning during inflammation remain unclear. Here, we identify a cholesterol-derived chemotactic axis that spatially organizes T helper 2 (TH2) cells during fungal-induced pulmonary type 2 inflammation. Inflammation-expanded macrophages expressing cholesterol-25-hydroxylase (CH25H) produce 25-hydroxycholesterol, which is converted into the oxysterol 7,25-dihydroxycholesterol to attract GPR183-expressing TH2 cells into infectious lesions. This TH2 positioning suppresses interferon-{gamma} responsiveness in inflammatory Ly6C macrophages, promoting fungal persistence. Disruption of this axis via TH2-specific GPR183 deletion restores type 1 macrophage activation and enhances fungal clearance. Our findings reveal a macrophage-driven, metabolite-based mechanism of immunosuppressive cell positioning in inflamed lung tissue.

immunology↗

bioRxiv2025

Alternatively activated monocyte-derived myeloid cells promote extracellular pathogen persistence within pulmonary fungal granulomas.

Inhaled fungal pathogens often generate granuloma-contained latent infections that can reactivate to cause invasive disease. However, the mechanisms underlying the inability to generate sterilizing immunity against latent infection remains poorly understood. Here, we leveraged spatial transcriptomics and flow cytometry to characterize the immune dynamics and cellular architecture of cryptococcal granulomas. Using fate mapping and murine genetic tools, we demonstrate that alternative activation of monocyte-derived myeloid cells by CD4+ T helper 2 cells antagonizes pulmonary fungal clearance during latent infection. In contrast to the prevailing view in the field, we find that alternatively activated myeloid cells are not an intrinsic replication niche for the fungus and more broadly, Cryptococcus predominantly resides in the extracellular environment. We propose a T helper 2 cell-myeloid circuit establishes a local immunosuppressive environment to drive extracellular fungal persistence, which could be leveraged as a new target for host-directed therapy to treat latent fungal infections.

immunology↗

bioRxiv2022

Deep tissue infection by an invasive human fungal pathogen requires novel lipid-based suppression of the IL-17 response

Candida albicans is the most common cause of human fungal infection, but the mechanisms of invasive pathogenesis remain poorly defined. Here we identify an unexpected mechanism: lipid-mediated immunosuppression. Through forward genetics, we found that C. albicans secretes a lipase, Lip2, that is critical for invasive disease. Murine infection with C. albicans strains that lack Lip2 display an exaggerated host IL-17 response that leads to fungal clearance from solid organs and host survival. IL-17 signaling is required for Lip2 action. The lipase activity of Lip2 inhibits IL-17 production indirectly through suppression of IL-23 production by tissue resident dendritic cells. We conclude that C. albicans suppresses antifungal IL-17 defense in solid organs by altering the tissue lipid milieu.

microbiology↗

bioRxiv2021

Mechanism of innate immune reprogramming by a fungal meningitis pathogen

How deadly fungal pathogens overcome mammalian innate immunity is largely unknown. Cryptococcus neoformans, the most common cause of fungal meningitis, induces a pathogenic type 2 response characterized by pulmonary eosinophilia and alternatively activated macrophages. Using forward genetics, we identified a fungal secreted protein, Cpl1, necessary and sufficient to enhance alternative activation of primary macrophages in vitro. Cpl1-enhanced polarization requires Toll-like receptor 4, a known mediator of allergen-induced type 2 responses. Cpl1 is essential for virulence, drives polarization of interstitial macrophages in vivo, and requires type 2 cytokine signaling for its impact on infectivity. C. neoformans selectively associates with polarized interstitial macrophages during infection, supporting a direct hostpathogen interaction. This work identifies a secreted effector produced by a human fungal pathogen that reprograms innate immunity to enable tissue infection. One sentence summaryIdentification of a secreted fungal effector that promotes virulence by enhancing type 2 inflammation

immunology↗