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Identifier 000460111
Title Exploring molecular mechanisms of neutrophil interaction with the fungal cell wall
Alternative Title Διερεύνηση των μοριακών μηχανισμών λήψης αποφάσεων των ουδετερόφιλων κατά την δυναμική αλληλεπίδρασή τους με το κυτταρικό τοίχωμα των μυκητών
Author Σερτεδάκης, Ματθαίος Ν.
Thesis advisor Χαμηλός, Γεώργιος
Reviewer Μητρούλης, Ιωάννης
Latge, Jean-Paul
Abstract Neutrophils serve as the first line of defense in our immune system against microbial pathogens, especially fungi. When compared to other phagocytes, neutrophils employ an impressive array of specialized effector mechanisms, including phagocytosis, degranulation and extracellular vehicle release, neutrophil extracellular trap (NET) formation, and coordinated clustering towards a target (swarming), to combat invading pathogens. The dynamic changes in size, shape, and surface composition of cell wall of airborne filamentous fungi (molds) during physiological interaction with phagocytes triggers unique immune responses, making them model pathogens to understand neutrophil biology. Accordingly, molds such as Aspergillus spp. and the Mucorales are emerging causes of life-threatening respiratory infections in an expanding population of immunocompromised patients with incompletely understood defects in neutrophil function. In this study, we aimed to gain molecular insights on the physiological mechanisms of neutrophil decision-making during interaction with Mucorales conidia. Of interest, Mucorales, in stark contrast to other fungal pathogens, are inhibited via neutrophil swarming. We found that neutrophils form specifically clusters (swarm) around the head of germinating conidia of Mucorales, a response that is mediated by β-glucan exposure on this region of the fungal cell wall. Recognition of this immunostimulatory polysaccharide occurs via activation of Complement Receptor 3 (CR3), rather than Dectin-1, the specialized receptor for β-glucan in macrophages. This recognition induces a robust and prolonged Ca2+ influx. Neutrophil activation during swarming is characterized by excessive expansion of the plasma membrane associated with profound changes in actin cytoskeleton organization. Enzymatic degradation of βglucan abolishes the swarming phenotype, rendering the fungus immunologically inert. Importantly, we additionally found that the mechanosensitive enzyme cPLA2, which is physiologically regulated by cytosolic Ca2+ and changes in membrane tension, orchestrated initiation of neutrophil swarming towards Mucorales through its translocation to the nuclear membrane for subsequent LTB4 release. Collectively, our findings set the stage for a new understanding of cell-cell interactions using the fungal cell wall as a model.
Language English
Subject Rhizopus delemar
Swarming
Λήψη αποφάσεων
Ουδετερόφιλα
Φαινόμενο σμήνους
Issue date 2023-11-24
Collection   School/Department--School of Sciences and Engineering--Department of Biology--Post-graduate theses
  Type of Work--Post-graduate theses
Permanent Link https://elocus.lib.uoc.gr//dlib/f/e/8/metadata-dlib-1698995663-369932-761.tkl Bookmark and Share
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