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

Area of Science:

• Mycology
• Immunology
• Infectious Diseases

Background:

• Candida albicans is a common human fungal pathogen.
• Interleukin-17 (IL-17) is vital for antifungal immunity, particularly against superficial infections.
• The role of IL-17 in invasive candidiasis remains less understood.

Purpose of the Study:

• To investigate the mechanism by which Candida albicans evades the host immune response during invasive infection.
• To identify virulence factors involved in suppressing antifungal immunity.

Main Methods:

• Forward genetic screen in a mouse model of bloodstream infection.
• Analysis of IL-17 and IL-23 production in wild-type and mutant C. albicans infected mice.
• In vitro assays to assess dendritic cell activation and the effect of lipase hydrolysis products.

Main Results:

• Lip2, a C. albicans secreted lipase, was identified as an essential virulence factor.
• Mice infected with C. albicans lacking Lip2 showed enhanced IL-17 responses, leading to fungal clearance and improved survival.
• Lip2-mediated suppression of IL-17 requires both lipase activity and IL-17 signaling, acting indirectly by inhibiting IL-23 production from dendritic cells.
• Palmitic acid, a Lip2 hydrolysis product, suppressed dendritic cell activation in vitro.

Conclusions:

• Candida albicans employs the lipase Lip2 to suppress the antifungal IL-17 immune defense in solid organs.
• This suppression is achieved by altering the tissue lipid milieu, specifically inhibiting IL-23 production via palmitic acid.
• Targeting Lip2 or its products could be a strategy to enhance antifungal immunity against invasive candidiasis.