Phagosomal LC3's Alternative Role

Descripción del proyecto

Disección de la interacción hospedador-hongo

El «Aspergillus fumigatus» es un patógeno oportunista y puede causar infecciones respiratorias graves en individuos con sistemas inmunitarios comprometidos. Comprender la interacción entre el «A. fumigatus» y las células inmunitarias del hospedador es fundamental para combatir este tipo de infecciones. El «A. fumigatus» suele ser eliminado por los macrófagos alveolares mediante fagocitosis, pero el hongo ha desarrollado estrategias para eludir este proceso. El equipo del proyecto POLAR, financiado con fondos europeos, pretende investigar el mecanismo molecular de la formación de fagosomas y la reparación de membranas durante la infección por «A. fumigatus». Los hallazgos del proyecto guiarán el diseño de estrategias inmunomoduladoras nuevas contra los patógenos fúngicos y profundizarán nuestra comprensión de la biología de los macrófagos.

Objetivo

The opportunistic fungus Aspergillus fumigatus is an emerging cause of life-threatening respiratory infections in an expanding group of patients with acquired innate immune defects. Dissecting the molecular dynamics of fungal-host interplay mediating sterilizing immunity against A. fumigatus is crucial to gain insight in disease pathogenesis and develop novel immunomodulatory therapies. Physiologically, Aspergillus fumigatus conidia are eliminated inside Alveolar Macrophages (AMs) via activation of the LC3 associated phagocytosis (LAP) pathway. A. fumigatus cell wall melanin blocks LAP to promote pathogenicity. Intracellular germination of A. fumigatus conidia results in exposure of immunostimulatory fungal molecules concomitantly with melanin removal and triggers NADPH oxidase-dependent activation of LAP. The molecular mechanism of LC3 conjugation on A. fumigatus phagosome membrane and the physiological function of LAP on AM biology and antifungal host defense remain elusive. Of interest, pilot studies in the host lab demonstrate that infection of AMs and other types of macrophages with live conidia of A. fumigatus results in a unique pattern of pulsatile LC3 recruitment on the phagosome membrane, which is accompanied by waves of increased phagosome permeability. These findings imply for a novel mechanism of LC3+ phagosome (LAPosome) formation via cytosolic sensing of fungal vita-PAMPs and suggests for an unconventional function of LAPosomes in regulation of membrane repair mechanisms in response to damage induced by Aspergillus infection. This research project aims to understand the precise host and pathogen molecular determinants of LAPosome formation and exploit the intriguing role of LC3 on regulation of phagosomal membrane repair during A. fumigatus infection. Using A. fumigatus as a model pathogen, this project with provide fundamental insights on the role of LAP in macrophage biology paving the way for new host-directed strategies.