Secreted fungal virulence effector triggers allergic inflammation via TLR4

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 receptor4, 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 receptor4 in promoting the pathogenesis of infectious disease.

Automated summary

This study identifies an effector protein secreted by Cryptococcus neoformans that drives alternative activation of macrophages, enabling pulmonary infection in mice. The effect is mediated by Toll-like receptor 4 and requires type 2 cytokine signaling. CPL1 is essential for virulence and selectively associates with polarized interstitial macrophages during infection, revealing a mechanism by which the fungus generates its own replication niche within the host.