Phagolysosomal proteomics identifies DHN-melanin-regulated processes in activated macrophage in response to Aspergillus fumigatus conidia

Infection by the human pathogenic fungus Aspergillus fumigatus is initialized by the outgrowth of asexual spores (conidia) into the lung tissue of the immunocompromised host following an inhalation of the airborne conidia. The resident phagocytes, the alveolar macrophages are the first immune cells to encounter invading conidia. However, A. fumigatus conidia employ versatile mechanisms to evade the host immune defense and establish a severe invasive infection. Previously, we showed that depending on the presence of conidial 1,8-dihydroxynaphthalene (DHN) melanin, A. fumigatus circumvents intracellular killing by manipulating the phagolysosomal maturation process. Here, by comparative dual proteomics we analyzed proteins of phagolysosomes containing melanized wild-type or non-melanized pksP mutant conidia. Bioinformatics compiled a regulatory module of differentially abundant proteins that mirrors processes targeted by the fungus for immune evasion. Those are i.e. vATPAse-driven phagolysosomal acidification, endocytic trafficking, signal transduction, energy metabolism and immune response. In detail, we found alterations of vATPase complex assembly and impaired abundances of mTOR and MAPK signaling molecules, Rab5 and Vamp8 mediators of endosomal trafficking as well as Lamp1 and cathepsin Z lysosomal markers.