| 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.
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Exploring the mechanisms of LAP pathway activation by Aspergillus fumigatus
