Abstract
Phagocytosis is a key mechanism of innate immunity, and promotion of phagosome maturation may represent a therapeutic target to enhance antibacterial host response. Phagosome maturation is favored by the timely and coordinated intervention of lipids and may be altered in infections. Here we used apoptotic body-like liposomes (ABL) to selectively deliver bioactive lipids to innate cells, and then tested their function in models of pathogen-inhibited and host-impaired phagosome maturation. Stimulation of macrophages with ABLs carrying phosphatidic acid (PA), phosphatidylinositol 3-phosphate (PI3P) or PI5P increased intracellular killing of BCG, by inducing phagosome acidification and ROS generation. Moreover, ABLs carrying PA or PI5P enhanced ROS-mediated intracellular killing of Pseudomonas aeruginosa, in macrophages expressing a pharmacologically-inhibited or a naturally-mutated cystic fibrosis transmembrane conductance regulator. Finally, we show that bronchoalveolar lavage cells from patients with drug-resistant pulmonary infections increased significantly their capacity to kill in vivo acquired bacterial pathogens when ex vivo stimulated with PA- or PI5P-loaded ABLs. Altogether, these results provide the proof of concept of the efficacy of bioactive lipids delivered by ABL to enhance phagosome maturation dependent antimicrobial response, as an additional host-directed strategy aimed at the control of chronic, recurrent or drug-resistant infections.
Highlights
Among the effector phases of innate immune response, phagocytosis represents the most important effector mechanism deputed to elimination of invading bacterial pathogens
We show that ABLs can be exploited to deliver selected second lipid messengers (i.e. PA, PI3P, PI5P, Arachidonic acid, sphingosine 1-phosphate, lysobisphosphatidic acid) known to positively regulate phagosome maturation[5]; their efficacy, as novel host-directed therapeutic approach, has been evaluated in models of i) bacterial interference of phagolysosome biogenesis, ii) genetically impaired phagolysosome-dependent antimicrobial response, and iii) drug-resistant pulmonary infections
The ABL preparations containing the selected lipids were preliminarily tested in flow cytometry for size distribution by comparing their forward scatter parameters (FS) with the FS of commercially available beads of known diameter
Summary
Among the effector phases of innate immune response, phagocytosis represents the most important effector mechanism deputed to elimination of invading bacterial pathogens. These liposomes were prepared in order to contain i) phosphatidylserine (PS) at the outer surface of the liposome membrane, to make them resembling apoptotic bodies, and ii) a bioactive lipid, such as PA, at the inner surface By this strategy, it has been possible to rescue PA-dependent phagolysosome maturation and antimicrobial response to MTB, both in vitro and in a mouse model of TB in vivo[20]. We show that ABLs can be exploited to deliver selected second lipid messengers (i.e. PA, PI3P, PI5P, Arachidonic acid, sphingosine 1-phosphate, lysobisphosphatidic acid) known to positively regulate phagosome maturation[5]; their efficacy, as novel host-directed therapeutic approach, has been evaluated in models of i) bacterial interference of phagolysosome biogenesis, ii) genetically impaired phagolysosome-dependent antimicrobial response, and iii) drug-resistant pulmonary infections
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