title: Chloroquine modulates the fungal immune response in phagocytic cells from patients with chronic granulomatous disease.
abstract: Invasive aspergillosis is a major threat to patients with chronic granulomatous disease (CGD). Fungal pathogenesis is the result of a diminished antifungal capacity and dysregulated inflammation. A deficient NADPH-oxidase complex results in defective phagolysosomal alkalization. To investigate the contribution of defective pH regulation in phagocytes among patients with CGD during fungal pathogenesis, we evaluated the effect of the acidotropic, antimalarial drug chloroquine (CQ) on the antifungal capacity of polymorphonuclear cells (PMNs) and on the inflammatory response of peripheral blood mononuclear cells (PBMCs). Chloroquine exerted a direct pH-dependent antifungal effect on Aspergillus fumigatus and Aspergillus nidulans; it increased the antifungal activity of PMNs from patients with CGD at a significantly lower concentration, compared with the concentration for PMNs from healthy individuals; and decreased the hyperinflammatory state of PBMCs from patients with CGD, as observed by decreased tumor necrosis factor α and interleukin 1β release. Chloroquine targets both limbs of fungal pathogenesis and might be of great value in the clearance of invasive aspergillosis in patients with CGD.
authors.affiliation: Department of Pediatrics, Radboud University Nijmegen Medical Centre, The Netherlands. s.henriet@cukz.umcn.nl
authors.forename: Stefanie S V
authors.initials: SS
authors.lastname: Henriet
authors.forename: Jop
authors.initials: J
authors.lastname: Jans
authors.forename: Elles
authors.initials: E
authors.lastname: Simonetti
authors.forename: Kyung J
authors.initials: KJ
authors.lastname: Kwon-Chung
authors.forename: Antonius J M M
authors.initials: AJ
authors.lastname: Rijs
authors.forename: Peter W M
authors.initials: PW
authors.lastname: Hermans
authors.forename: Steve M
authors.initials: SM
authors.lastname: Holland
authors.forename: Marien I
authors.initials: MI
authors.lastname: de Jonge
authors.forename: Adilia
authors.initials: A
authors.lastname: Warris
mesh_terms: D000935:Antifungal Agents / Q000494:pharmacology; D000962:Antimalarials / Q000494:pharmacology; D001228:Aspergillosis / Q000150:complications / Q000276:immunology* / Q000382:microbiology; D001232:Aspergillus fumigatus / Q000187:drug effects / Q000276:immunology*; D001233:Aspergillus nidulans / Q000187:drug effects / Q000276:immunology*; D002738:Chloroquine / Q000494:pharmacology*; D016207:Cytokines / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006105:Granulomatous Disease, Chronic / Q000150:complications / Q000276:immunology / Q000382:microbiology*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000235:genetics; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000172:deficiency / Q000235:genetics; D010586:Phagocytes / Q000187:drug effects / Q000276:immunology* / Q000382:microbiology; D010588:Phagosomes / Q000187:drug effects / Q000276:immunology / Q000382:microbiology
chemical_list: D000935:Antifungal Agents; D000962:Antimalarials; D016207:Cytokines; D008562:Membrane Glycoproteins; D002738:Chloroquine; C056558:CYBB protein, human; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; C060505:neutrophil cytosolic factor 1
keywords: Aspergillus spp.; antifungal activity; chloroquine; chronic granulomatous disease; cytokines; inflammation; mononuclear cells; pathogenesis; polymorphonuclear cells