LUCA CAVINATO

Dottore di ricerca

ciclo: XXXIII



Titolo della tesi: Microbicidal activity of human monocytes and macrophages against Pseudomonas aeruginosa

Professional phagocytes, such as monocytes and macrophages, are cells specialized in the engulfment of particles and microbes, which contribute to eliminate invading microorganisms from tissues and organs. After the engulfment, intracellular microorganisms are killed through an arsenal of microbicidal mechanisms which act in a time-dependent manner. First, the interaction between phagocytes and pathogens, mediated by specific interactions between pathogen associated molecules (surface carbohydrates, peptidoglycans and lipoproteins) and pattern recognition receptors) or indirectly by opsonins, promotes engulfment and subsequent entrapment of microorganisms in ex novo and immature vacuole, defined phagosome. Subsequently phagosomes maturation, which lead to formation of the mature phagolysosome, allows the acquirement of unique features including the activation of the of V-ATPase and the NOX2 NADPH oxidase. While the V-ATPase by pumping H⁺ into the phagosome lumen induces acidification and activation of acidic hydrolases, the NOX2 NADPH oxidase induces the oxidative burst, a rapid increase of reactive oxygen species (ROS) production. These non-oxidative and oxidative mechanisms both contribute to destroy the engulfed microorganisms. Indeed, phagosome acidification by V-ATPase while directly inhibiting the survival of low-pH sensitive bacteria, activates lysosome lytic enzymes such as lipases and proteases. On the other hand, NOX2 activation releases superoxide anion (O2⁻) within the phagosome where it can dismutate, spontaneously or enzymatically, into hydrogen peroxide (H2O2), a potent microbicidal effector. Alternatively, the low pH of the phagosome may promote O2⁻ protonation to HO2 allowing its efflux from the phagosome, favored by its neutral charge, and triggering other microbicidal mechanisms, such as autophagy. Importantly, these early microbicidal pathways (phagosome acidification and oxidative burst) represent an important host defense and many bacteria have evolved evasion strategies to counteract their activity. A very recent publication addressed the role of the non-oxidative and oxidative pathways in macrophage-mediated microorganisms killing. Interestingly, it has been proposed that these two pathways cooperate to guarantee their maximal efficacy as evidenced by the inhibition of phago-lysosomal fusion by excessive O2⁻ production suggesting that V-ATPase- and NOX2- dependent bacterial killing is the result of an equilibrium of the activity of these two processes. Cystic Fibrosis (CF) is a genetic disease caused by multiple mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which encodes a chloride channel localized in the epithelial membranes. Although CF affects the functionality of multiple organs, pulmonary disease is the main cause of morbidity and mortality of CF patients. Dysfunctional CFTR determines ions imbalance in the airways, as well as in other epithelia, leading to fluid depletion, sticky mucus formation and acidic airway surface liquid (ASL) which alter the pulmonary environment, favouring recurrent bacterial infection and exuberant inflammatory response. Collectively, these dysfunctions lead to a rapid decline of lung functionality. Pseudomonas aeruginosa, a Gram-negative bacterium, is the most predominant pathogens that colonizes CF lung. The reason of P. aeruginosa predominance has been ascribed to its genome and metabolic plasticity that make this pathogen to easily adapt to the CF lung environment. This in addition to the well-known microbicidal defects of CF phagocytes, may explain the chronic colonization of CF airways by P. aeruginosa. Indeed, multiple mechanisms have been proposed to contribute to the defective killing activity of CF phagocytes, such as phagosome acidification, autophagy and ROS production. The latter has been shown to be defective in murine CF macrophages albeit no dysfunction was observed in the human counterpart as assessed by ROS measurements and, more importantly, by the preservation of the oxidative P. aeruginosa killing in human CF macrophages and autophagy. Collectively, these studies suggest that CFTR plays an essential role in the physiological activity of innate immune cells, and that dysfunctional CFTR contributes to the defective phagocytosis and killing of CF macrophages. Further investigations aimed to elucidate the interactions between phagocytes and pathogens such as P. aeruginosa, are required to better understand the complex and continuously evolving dynamics that occur during the host-pathogen interface. Therefore, a deeper and more global comprehension of the host-pathogen interaction might contribute to elucidate the not understood defects in the elimination of pathogens by CF phagocytes.

Produzione scientifica

11573/1670853 - 2022 - Elexacaftor-Tezacaftor-Ivacaftor corrects monocyte microbicidal deficiency in cystic fibrosis
Cavinato, Luca; Luly, Francesco R.; Pastore, Valentina; Chiappetta, Daniele; Sangiorgi, Gloria; Ferrara, Eva; Baiocchi, Pia; Mandarello, Giuseppe; Cimino, Giuseppe; Del Porto, Paola; Ascenzioni, Fiorentina - 01a Articolo in rivista
rivista: EUROPEAN RESPIRATORY JOURNAL (Blackwell Munksgaard:PO Box 2148, Periodicals Department, DK-1016 Copenhagen K Denmark:011 45 33 755913, EMAIL: agentservices@oxon.blackwellpublishing.com, INTERNET: http://www.blackwellmunksgaard.com, Fax: 011 45 77 333377) pp. - - issn: 0903-1936 - wos: WOS:001003280600007 (15) - scopus: 2-s2.0-85149874072 (15)

11573/1386014 - 2020 - Escaping the Phagocytic Oxidative Burst: The Role of SODB in the Survival of Pseudomonas aeruginosa Within Macrophages
Cavinato, L.; Genise, E.; Luly, F. R.; Domenico, E. G. D.; Del Porto, P.; Ascenzioni, F. - 01a Articolo in rivista
rivista: FRONTIERS IN MICROBIOLOGY (Lausanne : Frontiers Research Foundation, 2010-) pp. - - issn: 1664-302X - wos: WOS:000526968200001 (26) - scopus: 2-s2.0-85082713264 (26)

11573/1433609 - 2020 - A novel colistin adjuvant identified by virtual screening for ArnT inhibitors
Ghirga, Francesca; Stefanelli, Roberta; Cavinato, Luca; Lo Sciuto, Alessandra; Corradi, Silvia; Quaglio, Deborah; Calcaterra, Andrea; Casciaro, Bruno; Loffredo, Maria Rosa; Cappiello, Floriana; Morelli, Patrizia; Antonelli, Alberto; Rossolini, Gian Maria; Mangoni, Marialuisa; Mancone, Carmine; Botta, Bruno; Mori, Mattia; Ascenzioni, Fiorentina; Imperi, Francesco - 01a Articolo in rivista
rivista: JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY (Oxford University Press:Journals Department, Great Clarendon Street, Oxford OX2 6DP United Kingdom:011 44 1865 556767, EMAIL: jnlorders@oup.co.uk, INTERNET: http://www.oup.co.uk, Fax: 011 44 1865 267485) pp. 2564-2572 - issn: 0305-7453 - wos: WOS:000574367100026 (14) - scopus: 2-s2.0-85089713563 (16)

11573/1473577 - 2020 - Anti-inflammatory potential of cow, donkey and goat milk extracellular vesicles as revealed by metabolomic profile
Mecocci, S.; Gevi, F.; Pietrucci, D.; Cavinato, L.; Luly, F. R.; Pascucci, L.; Petrini, S.; Ascenzioni, F.; Zolla, L.; Chillemi, G.; Cappelli, K. - 01a Articolo in rivista
rivista: NUTRIENTS (Basel, Switzerland: Molecular Diversity Preservation International (MDPI)) pp. 1-26 - issn: 2072-6643 - wos: WOS:000586998200001 (21) - scopus: 2-s2.0-85091446608 (21)

11573/1444335 - 2020 - Ent-beyerane diterpenes as a key platform for the development of arnt-mediated colistin resistance inhibitors
Quaglio, D.; Mangoni, M. L.; Stefanelli, R.; Corradi, S.; Casciaro, B.; Vergine, V.; Lucantoni, F.; Cavinato, L.; Cammarone, S.; Loffredo, M. R.; Cappiello, F.; Calcaterra, A.; Erazo, S.; Ghirga, F.; Mori, M.; Imperi, F.; Ascenzioni, F.; Botta, B. - 01a Articolo in rivista
rivista: JOURNAL OF ORGANIC CHEMISTRY ([Washington, D.C: American Chemical Society) pp. 10891-10901 - issn: 0022-3263 - wos: WOS:000563754800052 (14) - scopus: 2-s2.0-85091138745 (16)

11573/1329470 - 2019 - MiR-146a is over-expressed and controls IL-6 production in cystic fibrosis macrophages
Luly, Francesco Renato; Leveque, M.; Licursi, V.; Cimino, G.; Martin-Chouly, C.; Theret, N.; Negri, R.; Cavinato, L.; Ascenzioni, F.; Del Porto, P. - 01a Articolo in rivista
rivista: SCIENTIFIC REPORTS (London: Springer Nature London: Nature Publishing Group) pp. - - issn: 2045-2322 - wos: WOS:000494945700026 (33) - scopus: 2-s2.0-85074711373 (32)

11573/1114548 - 2018 - Assembly and functional analysis of an S/MAR based episome with the cystic fibrosis transmembrane conductance regulator gene
De Rocco, Davide; Pompili, Barbara; Castellani, Stefano; Morini, Elena; Cavinato, Luca; Cimino, Giuseppe; Mariggiò, Maria A.; Guarnieri, Simone; Conese, Massimo; Porto, Paola Del; Ascenzioni, Fiorentina - 01a Articolo in rivista
rivista: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES (Basel (Matthaeustrasse 11) : Molecular Diversity Preservation International MDPI) pp. 1-15 - issn: 1661-6596 - wos: WOS:000434978700299 (8) - scopus: 2-s2.0-85045949464 (8)

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