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bioRxiv · 10.1101/2021.09.02.458767

Mechanism of innate immune reprogramming by a fungal meningitis pathogen

Dang, E. V.·Lei, S.·Radkov, A.·Madhani, H.
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Abstract

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

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Dang, E. V., Lei, S., Radkov, A., Madhani, H.. 2021-09-02. Mechanism of innate immune reprogramming by a fungal meningitis pathogen. https://doi.org/10.1101/2021.09.02.458767

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