Secreted fungal virulence effector triggers allergic inflammation via TLR4

• Published in: Nature (London) 2022-08, Vol.608 (7921), p.161-167
• Main Authors: Dang, Eric V., Lei, Susan, Radkov, Atanas, Volk, Regan F., Zaro, Balyn W., Madhani, Hiten D.
• Format: Article
• Language: English
• Subjects: 13/106; 13/21; 13/31; 631/250/255/1672; 631/326/193/2542; 64/60; 82/83; Allergens; Animals; Circuits; Cryptococcosis - immunology; Cryptococcosis - microbiology; Cryptococcosis - pathology; Cryptococcus neoformans; Cryptococcus neoformans - immunology; Cryptococcus neoformans - pathogenicity; Cytokines; Cytokines - immunology; Drug resistance; Endotoxins; Eosinophilia; Fatalities; Flow cytometry; Fungal infections; Fungal Proteins - immunology; Fungal Proteins - metabolism; Fungi; Genes; Genotype & phenotype; Humanities and Social Sciences; Hypersensitivity; Hypersensitivity - immunology; Hypersensitivity - microbiology; Immune system; Immunity; Immunity, Innate; Infections; Infectious diseases; Infectivity; Inflammation; Inflammation - immunology; Inflammation - microbiology; Innate immunity; Lipopolysaccharides; Lipopolysaccharides - immunology; Lung - immunology; Lung - microbiology; Lung diseases; Macrophages; Macrophages - cytology; Macrophages - immunology; Macrophages - microbiology; Mammals; Meningitis; Mice; multidisciplinary; Nitric oxide; Pathogenesis; Pathogens; Polarization; Proteins; Science; Science (multidisciplinary); TLR4 protein; Toll-Like Receptor 4 - immunology; Toll-Like Receptor 4 - metabolism; Toll-like receptors; Tumor necrosis factor-TNF; Virulence; Virulence Factors - immunology; Yeast
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/s41586-022-05005-4

Invasive fungal pathogens are major causes of human mortality and morbidity 1 , 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 macrophages 3 – 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 responses 9 – 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. Cryptococcus neoformans secretes CPL1 protein, which induces alternative activation of macrophages via Toll-like receptor 4 in mice and is essential for fungal virulence.