title: Hypoxia in Leishmania major skin lesions impairs the NO-dependent leishmanicidal activity of macrophages.
abstract: Cure of infections with Leishmania major is critically dependent on the ability of macrophages to induce the type 2 nitic oxide (NO) synthase (NOS2) that produces high levels of NO in the presence of ample oxygen. Therefore, we analyzed the oxygen levels found in leishmanial skin lesions and their effect on the NOS2-dependent leishmanicidal activity of macrophages (MΦ). When L. major skin lesions of self-healing C57BL/6 mice reached their maximum size, the infected tissue displayed low oxygen levels (pO2∼21 Torr). MΦ activated under these oxygen tensions failed to produce sufficient amounts of NO to clear L. major. Nos2-deficient and hypoxic wild-type macrophages displayed a similar phenotype. Killing was restored when MΦ were reoxygenated or exposed to a NO donor. The resolution of the lesion in C57BL/6 mice was paralleled by an increase of lesional pO2. When mice were kept under normobaric hypoxia, this caused a persistent suppression of the lesional pO2 and a concurrent increase of the parasite load. In Nos2-deficient mice, there was no effect of atmospheric hypoxia. Low oxygen levels found at leishmanial skin lesions impaired the NOS2-dependent leishmanicidal activity of MΦ. Hence, tissue oxygenation represents an underestimated local milieu factor that participates in the persistence of Leishmania.
authors.affiliation: Mikrobiologisches Institut-Klinische Mikrobiologie, Immunologie und Hygiene, Universitätsklinikum Erlangen und Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Mahnke
authors.affiliation: Institut für Analytische Chemie, Chemo- und Biosensorik, Universität Regensburg, Regensburg, Germany.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Meier
authors.affiliation: Mikrobiologisches Institut-Klinische Mikrobiologie, Immunologie und Hygiene, Universitätsklinikum Erlangen und Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Valentin
authors.initials: V
authors.lastname: Schatz
authors.affiliation: Mikrobiologisches Institut-Klinische Mikrobiologie, Immunologie und Hygiene, Universitätsklinikum Erlangen und Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Julian
authors.initials: J
authors.lastname: Hofmann
authors.affiliation: Mikrobiologisches Institut-Klinische Mikrobiologie, Immunologie und Hygiene, Universitätsklinikum Erlangen und Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Kirstin
authors.initials: K
authors.lastname: Castiglione
authors.affiliation: Mikrobiologisches Institut-Klinische Mikrobiologie, Immunologie und Hygiene, Universitätsklinikum Erlangen und Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Schleicher
authors.affiliation: Institut für Analytische Chemie, Chemo- und Biosensorik, Universität Regensburg, Regensburg, Germany.
authors.forename: Otto S
authors.initials: OS
authors.lastname: Wolfbeis
authors.affiliation: Mikrobiologisches Institut-Klinische Mikrobiologie, Immunologie und Hygiene, Universitätsklinikum Erlangen und Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Bogdan
authors.affiliation: Mikrobiologisches Institut-Klinische Mikrobiologie, Immunologie und Hygiene, Universitätsklinikum Erlangen und Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany. Electronic address: Jonathan.Jantsch@uk-erlangen.de.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Jantsch
mesh_terms: D000818:Animals; D001119:Arginase / Q000235:genetics / Q000378:metabolism; D001273:Atmosphere Exposure Chambers; D000860:Hypoxia / Q000378:metabolism* / Q000469:parasitology / Q000473:pathology; D018320:Leishmania major / Q000378:metabolism*; D016773:Leishmaniasis, Cutaneous / Q000378:metabolism* / Q000473:pathology; D008264:Macrophages / Q000378:metabolism / Q000469:parasitology*; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism*; D010100:Oxygen / Q000378:metabolism; D010641:Phenotype; D012867:Skin / Q000378:metabolism / Q000469:parasitology / Q000473:pathology
chemical_list: D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; C544448:Arg1 protein, mouse; D001119:Arginase; D010100:Oxygen