Aspergillus Cell Wall Melanin Blocks LC3-Associated Phagocytosis to Promote Pathogenicity

Concealing pathogen-associated molecular patterns (PAMPs) is a principal strategy used by fungi to avoid immune recognition. Surface exposure of PAMPs during germination can leave the pathogen vulnerable. Accordingly, β-glucan surface exposure during Aspergillus fumigatus germination activates an Atg5-dependent autophagy pathway termed LC3-associated phagocytosis (LAP), which promotes fungal killing. We found that LAP activation also requires the genetic, biochemical or biological (germination) removal of A. fumigatus cell wall melanin. The attenuated virulence of melanin-deficient A. fumigatus is restored in Atg5-deficient macrophages and in mice upon conditional inactivation of Atg5 in hematopoietic cells. Mechanistically, Aspergillus melanin inhibits NADPH oxidase-dependent activation of LAP by excluding the p22phox subunit from the phagosome. Thus, two events that occur concomitantly during germination of airborne fungi, surface exposure of PAMPs and melanin removal, are necessary for LAP activation and fungal killing. LAP blockade is a general property of melanin pigments, a finding with broad physiological implications. [Display omitted] •Activation of LC3-associated phagocytosis (LAP) requires removal of Aspergillus melanin•Melanin inhibition of LAP promotes Aspergillus virulence in vivo•Melanin inhibits LAP by excluding p22phox NADPH oxidase subunit from the phagosome•LAP blockade is a general property of melanin pigments PAMP exposure during Aspergillus germination activates LC3-associated phagocytosis (LAP), which promotes fungal killing. Akoumianaki et al. report that LAP activation also requires the removal of fungal cell wall melanin. Melanin functions via excluding the p22phox NADPH oxidase subunit from the phagosome. LAP blockade is a general property of melanin pigments.