Aspergillus post-phagocytic clearance failure of macrophage in COVID-19-associated pulmonary aspergillosis: role of autophagy-lysosome axis dysregulation

Abstract The core issue of COVID-19-associated pulmonary aspergillosis (CAPA) may not be simply increased fungal exposure or widespread immune suppression, but rather the failure of intracellular clearance programs after macrophage phagocytosis in the context of severe viral lung injury. Although alveolar macrophages (AMs) can recognize and engulf inhaled Aspergillus spores, the true determinant of antifungal outcomes is their ability to continuously advance the fungal containing compartment into a mature, acidified, and hydrolytically degradable terminal lysosomal environment. This article proposes that the dysfunction of macrophages in CAPA can be understood as an imbalance in the autophagy lysosome clearance axis: Aspergillus fumigatus ( A. fumigatus ) may actively disrupt phagocytic functionalization and lysosome delivery, while SARS-CoV-2-related lung injury may further weaken autophagy support, organelle quality control, and lysosome terminal execution ability. This framework is intended to integrate available CAPA observations with mechanistic evidence from fungal and viral models, helps to explain the contradictory phenotype of persistent inflammation but inefficient fungal clearance in CAPA, and shifts the research focus from a single autophagy marker or inflammatory indicator to the overall functional integrity of the intracellular clearance program after phagocytosis. Restoring the antifungal clearance ability of macrophages around this axis may provide new mechanistic ideas for host directed interventions of CAPA.