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Identifier

000444117

Title

Exploring the mechanisms of LAP pathway activation by Aspergillus fumigatus

Alternative Title

Μελέτη των μηχανισμών ενεργοποίησης του LAP μονοπατιού από τον μύκητα Aspergillus fumigatus

Author

Γκουντζινοπούλου, Μαρίνα-Ελλάδα

Thesis advisor

Χαμηλός, Γεώργιος

Reviewer

Βεργίνης, Π.
Μπερτσιάς, Γεώργιος

Abstract

Aspergillus fumigatus is a saprophytic organism that belongs to the Ascomycetes family of filamentous fungi (molds) and contributes to the decomposition of dead organic matter for the proper recycling of carbon and nitrogen in nature. This ubiquitous filamentous fungus produces thousands of conidia (spores), which spread through the air in long distances due to their small size (2-3 um diameter) and participate in the degradation of organic material. All humans inhale hundreds of A. fumigatus conidia on a daily basis, which, are successfully eliminated by lung tissue resident macrophages. However, in severely immunocompromised patients with qualitative or quantitative disorders in phagocytes, A. fumigatus has the ability to escape killing by phagocytes (macrophages and neutrophils), germinate into long filamentous forms (hyphae), which invade lung tissue and cause life threatening disease. Invasive fungal diseases caused by Aspergillus is associated with significant mortality of 40-50% despite the appropriate antifungal treatment. For this reason, understanding immunopathogenesis of fungal diseases is an unmet need for development of new therapeutic strategies aiming to restore the underlying host immune defects. Herein, we focus on a major antifungal immune pathway termed LC3-associated phagocytosis (LAP), which is activated during phagocytosis of Aspergillus conidia and promotes fungal killing. More specifically, we highlight important differences in activation of LAP by live Aspergillus conidia as compared to different cell wall components of the fungus focusing on the role of melanin degradation and removal from the fungal cell wall during phagocytosis. In particular, previous work with melanin deficient Aspergillus mutants demonstrated that this molecule specifically inhibits LAP to promote virulence. In contrast to these previous findings, our preliminary work suggest an activity of melanin degradation product(s) as vita-PAMP(s) during live infection of macrophages. In addition, in order to study this phenotype in primary monocytes/macrophages of healthy individuals and patients with invasive aspergillosis, we developed and tested a cryopreservation assay in healthy human peripheral blood mononuclear cells (PBMCs), which allows evaluation of phagosome biogenesis and LAP.

Language

English

Subject

DHN -μελανίνη

Phagocytosis

Vita-PAMPs

φαγοκυττάρωση

Issue date

2021-12-01

Collection

School/Department--School of Medicine--Department of Medicine--Post-graduate theses

Type of Work--Post-graduate theses