Biology subjects

Chamilos, G.

Publications and source records attributed to Chamilos, G..

4 recordsLinked to original sources

bioRxiv2025

Mucoricin binding to β-glucan sites on germinating Mucorales spores disrupts neutrophil swarming to promote pathogenicity

Mucormycosis is an emerging, life-threatening infection caused by Mucorales fungi with incompletely understood immunopathogenesis. We found that unlike other fungal pathogens, Mucorales trigger coordinated neutrophil clustering (swarming) upon swelling of fungal spores. Neutrophil swarms efficiently eliminate germinating Mucorales via ROS production, upon sensing of {beta}-glucan by complement receptor 3 (CR3). Impaired neutrophil clustering in mucormycosis-predisposing conditions, allows for mucoricin toxin production by germinating Mucorales. Released mucoricin selectively binds to {beta}-glucan on the surface of Mucorales, creating a molecular trap that induces neutrophil apoptosis and swarming disruption, leading to invasive fungal disease. Suppression of mucoricin, either genetically or physiologically by albumin-bound free fatty acids, stabilizes neutrophil clusters leading to abrogation of fungal pathogenicity. Additionally, prophylactic GM-CSF administration prevents mucoricin-induced neutrophil death, and protects mice from mucormycosis. Our work identifies neutrophil swarming as the primary target of mucoricin and provides compelling evidence for therapeutic harnessing of this pathway to improve mucormycosis outcome.

immunology↗

bioRxiv2024

Neosynthesized polar and non-polar plasma membrane cargoes follow distinct trafficking routes in Aspergillus nidulans

Membrane proteins are sorted to the plasma membrane (PM) via Golgi-dependent trafficking. However, our recent studies challenged the essentiality of Golgi in the biogenesis of specific transporters. Here, we investigate the trafficking mechanisms of membrane proteins by following the localization of the polarized R-SNARE SynA versus the non-polarized transporter UapA, synchronously co-expressed in wild-type or isogenic genetic backgrounds repressible for conventional cargo secretion. In wild-type, the two cargoes dynamically label distinct secretory compartments, highlighted by the finding that, unlike SynA, UapA does not colocalize with the late-Golgi. In line with early partitioning into distinct secretory carriers, the two cargoes collapse in distinct ERES in a sec31ts background. Trafficking via distinct cargo-specific carriers is further supported by showing that repression of proteins essential for conventional cargo secretion does not affect UapA trafficking, while blocking SynA secretion. Overall, this work establishes the existence of distinct, cargo-dependent, trafficking mechanisms, initiating at ERES and being differently dependent on Golgi and SNARE interactions.

cell biology↗

bioRxiv2021

Mucoricin is a Ricin-Like Toxin that is Critical for the Pathogenesis of Mucormycosis

Fungi of the order Mucorales cause mucormycosis, a lethal infection with an incompletely understood pathogenesis. We now demonstrate that Mucorales fungi produce a toxin that plays a central role in virulence. Polyclonal antibodies against this toxin inhibit its ability to damage human cells in vitro, and prevent hypovolemic shock, organ necrosis, and death in mice with mucormycosis. RNAi inhibition of the toxin in Rhizopus delemar, compromises the ability of the fungus to damage host cells and attenuates virulence in mice. This 17 kDa toxin has structural and functional features of the plant toxin, ricin, including the ability to inhibit protein synthesis by its N-glycosylase activity, the existence of a motif that mediates vascular leak, and a lectin sequence. Antibodies against the toxin inhibit R. delemar- or toxin-mediated vascular permeability in vitro and cross-react with ricin. A monoclonal anti-ricin B chain antibody binds to the toxin and also inhibits its ability to cause vascular permeability. Therefore, we propose the name "mucoricin" for this toxin. Not only is mucoricin important in the pathogenesis of mucormycosis but our data suggest that a ricin- like toxin is produced by organisms beyond the plant and bacterial kingdoms. Importantly, mucoricin should be a promising therapeutic target.

microbiology↗

bioRxiv2019

Flotillin-dependent lipid-raft microdomains are required for functional phagolysosomes against fungal infections

Lipid rafts form signaling platforms on biological membranes with incompletely characterized role in immune response to infection. Here we report that lipid raft microdomains are essential components of the phagolysosomal membrane of macrophages. Genetic deletion of the lipidraft chaperons flotillin-1 and flotillin-2 demonstrate that the assembly of both major defense complexes vATPase and NADPH oxidase on the phagolysosomal membrane requires lipid rafts. Furthermore, we discovered a new virulence mechanism leading to the dysregulation of lipid-raft formation by melanized wild-type conidia of the important human-pathogenic fungus Aspergillus fumigatus. This results in reduced phagolysosomal acidification. Phagolysosomes with ingested melanized conidia contain a reduced amount of free Ca2+ ions as compared to phagolysosomes with melanin-free conidia. In agreement with a role of Ca2+ for generation of functional lipid rafts, we show that Ca2+-dependent calmodulin activity is required for lipid-raft formation on the phagolysosome. We identified a single nucleotide polymorphism in the human FLOT1 gene that results in heightened susceptibility for invasive aspergillosis in hematopoietic stem-cell transplant recipients. Collectively, flotillin-dependent lipid rafts on the phagolysosomal membrane play an essential role in protective antifungal immunity in humans.

microbiology↗