title: Low-oxygen tensions found in Salmonella-infected gut tissue boost Salmonella replication in macrophages by impairing antimicrobial activity and augmenting Salmonella virulence.
abstract: In Salmonella infection, the Salmonella pathogenicity island-2 (SPI-2)-encoded type three secretion system (T3SS2) is of key importance for systemic disease and survival in host cells. For instance, in the streptomycin-pretreated mouse model SPI-2-dependent Salmonella replication in lamina propria CD11c(-)CXCR1(-) monocytic phagocytes/macrophages (MΦ) is required for the development of colitis. In addition, containment of intracellular Salmonella in the gut critically depends on the antimicrobial effects of the phagocyte NADPH oxidase (PHOX), and possibly type 2 nitric oxide synthase (NOS2). For both antimicrobial enzyme complexes, oxygen is an essential substrate. However, the amount of available oxygen upon enteroinvasive Salmonella infection in the gut tissue and its impact on Salmonella-MΦ interactions was unknown. Therefore, we measured the gut tissue oxygen levels in a model of Salmonella enterocolitis using luminescence two-dimensional in vivo oxygen imaging. We found that gut tissue oxygen levels dropped from ∼78 Torr (∼11% O2) to values of ∼16 Torr (∼2% O2) during infection. Because in vivo virulence of Salmonella depends on the Salmonella survival in MΦ, Salmonella-MΦ interaction was analysed under such low oxygen values. These experiments revealed an increased intracellular replication and survival of wild-type and t3ss2 non-expressing Salmonella. These findings were paralleled by blunted nitric oxide and reactive oxygen species (ROS) production and reduced Salmonella ROS perception. In addition, hypoxia enhanced SPI-2 transcription and translocation of SPI-2-encoded virulence protein. Neither pharmacological blockade of PHOX and NOS2 nor impairment of T3SS2 virulence function alone mimicked the effect of hypoxia on Salmonella replication under normoxic conditions. However, if t3ss2 non-expressing Salmonella were used, hypoxia did not further enhance Salmonella recovery in a PHOX and NOS2-deficient situation. Hence, these data suggest that hypoxia-induced impairment of antimicrobial activity and Salmonella virulence cooperate to allow for enhanced Salmonella replication in MΦ.
authors.affiliation: Mikrobiologisches Institut - Klinische Mikrobiologie, Immunologie und Hygiene, Institut für Klinische Mikrobiologie und Hygiene, Universitätsklinikum Erlangen und Friedrich-Alexander Universität (FAU) Erlangen-Nürnberg, Erlangen, Germany.|Institut für Klinische Mikrobiologie und Hygiene, Universitätsklinikum Regensburg und Universität Regensburg, Regensburg, Germany.
authors.forename: Jonas
authors.initials: J
authors.lastname: Jennewein
authors.affiliation: Mikrobiologisches Institut - Klinische Mikrobiologie, Immunologie und Hygiene, Institut für Klinische Mikrobiologie und Hygiene, Universitätsklinikum Erlangen und Friedrich-Alexander Universität (FAU) Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Jasmin
authors.initials: J
authors.lastname: Matuszak
authors.affiliation: Robert Koch-Institut, Bereich Wernigerode, Wernigerode, Germany.
authors.forename: Steffi
authors.initials: S
authors.lastname: Walter
authors.affiliation: Institut für Mikrobiologie, ETH Zürich, Zürich, Switzerland.
authors.forename: Boas
authors.initials: B
authors.lastname: Felmy
authors.affiliation: Robert Koch-Institut, Bereich Wernigerode, Wernigerode, Germany.
authors.forename: Kathrin
authors.initials: K
authors.lastname: Gendera
authors.affiliation: Institut für Klinische Mikrobiologie und Hygiene, Universitätsklinikum Regensburg und Universität Regensburg, Regensburg, Germany.
authors.forename: Valentin
authors.initials: V
authors.lastname: Schatz
authors.affiliation: Institut für Klinische Mikrobiologie und Hygiene, Universitätsklinikum Regensburg und Universität Regensburg, Regensburg, Germany.
authors.forename: Monika
authors.initials: M
authors.lastname: Nowottny
authors.affiliation: Presens GmbH, Regensburg, Germany.
authors.forename: Gregor
authors.initials: G
authors.lastname: Liebsch
authors.affiliation: Abteilung Mikrobiologie, Fachbereich Biologie / Chemie, Universität Osnabrück, Osnabrück, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Hensel
authors.affiliation: Institut für Mikrobiologie, ETH Zürich, Zürich, Switzerland.
authors.forename: Wolf-Dietrich
authors.initials: WD
authors.lastname: Hardt
authors.affiliation: Robert Koch-Institut, Bereich Wernigerode, Wernigerode, Germany.
authors.forename: Roman G
authors.identifier: http://orcid.org/0000-0002-5718-4758
authors.initials: RG
authors.lastname: Gerlach
authors.affiliation: Mikrobiologisches Institut - Klinische Mikrobiologie, Immunologie und Hygiene, Institut für Klinische Mikrobiologie und Hygiene, Universitätsklinikum Erlangen und Friedrich-Alexander Universität (FAU) Erlangen-Nürnberg, Erlangen, Germany.|Institut für Klinische Mikrobiologie und Hygiene, Universitätsklinikum Regensburg und Universität Regensburg, Regensburg, Germany.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Jantsch
mesh_terms: D000693:Anaerobiosis; D000818:Animals; D004195:Disease Models, Animal; D054884:Host-Pathogen Interactions; D007413:Intestinal Mucosa / Q000737:chemistry* / Q000276:immunology / Q000382:microbiology; D008264:Macrophages / Q000276:immunology* / Q000382:microbiology*; D008810:Mice, Inbred C57BL; D010100:Oxygen / Q000032:analysis*; D012475:Salmonella / Q000254:growth & development / Q000276:immunology* / Q000378:metabolism / Q000502:physiology*; D012480:Salmonella Infections / Q000382:microbiology / Q000473:pathology; D014774:Virulence
chemical_list: D010100:Oxygen