Secreted fungal virulence effector triggers allergic inflammation via TLR4 - Nature.com
Abstract
Invasive fungal pathogens are major causes of human mortality and morbidity1,2. Although numerous secreted effector proteins that reprogram innate immunity to promote virulence have been identified in pathogenic bacteria, so far, 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 pathogen in AIDS, induces a pathogenic type 2 response characterized by pulmonary eosinophilia and alternatively activated macrophages3,4,5,6,7,8. 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 in mice. We observed that CPL1-enhanced macrophage polarization requires Toll-like receptor 4, which is best known as a receptor for bacterial endotoxin but is also a poorly understood mediator of allergen-induced type 2 responses9,10,11,12. We show that this effect is caused by CPL1 itself and not by contaminating lipopolysaccharide. CPL1 is essential for virulence, drives polarization of interstitial macrophages in vivo, and requires type 2 cytokine signalling for its effect on infectivity. Notably, C. neoformans associates selectively 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 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 promoting the pathogenesis of infectious disease.
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Data availability
The primary read files as well as expression count files for RNA-seq data in this paper are available to download from the Gene Expression Omnibus under accession number GSE203483. Source data are provided with this paper.
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Acknowledgements
We thank G. Barton for provision of Tlr2−/−, Tlr4−/− and Tlr2−/−Tlr4−/− mice, and R. Ricardo-Gonzalez for provision of Il4ra−/− and Stat6−/− mice; S. Chou for advice on protein purification; J. Cyster and E. Goldberg for critically reading the manuscript, discussions and advice; and S. Catania and M. Boucher for discussions and advice. Support was provided by the Chan–Zuckerberg Biohub, US National Institutes of Health, Jane Coffin Childs Memorial Fund for Medical Research Fellowship and Beckman Foundation.
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