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Cu,Zn-superoxide dismutase of Francisella tularensis LVS is a virulence factor
Umeå universitet, Medicinsk fakultet, Klinisk mikrobiologi. Umeå universitet, Medicinsk fakultet, Klinisk mikrobiologi, Klinisk bakteriologi.
Umeå universitet, Medicinsk fakultet, Klinisk mikrobiologi, Klinisk bakteriologi.
Umeå universitet, Medicinsk fakultet, Klinisk mikrobiologi. Umeå universitet, Medicinsk fakultet, Klinisk mikrobiologi, Klinisk bakteriologi.
(Engelska)Manuskript (Övrig (populärvetenskap, debatt, mm))
Identifikatorer
URN: urn:nbn:se:umu:diva-4427OAI: oai:DiVA.org:umu-4427DiVA, id: diva2:143531
Tillgänglig från: 2005-03-15 Skapad: 2005-03-15 Senast uppdaterad: 2010-01-14Bibliografiskt granskad
Ingår i avhandling
1. Reactive oxygen and nitrogen in host defence against Francisella tularensis
Öppna denna publikation i ny flik eller fönster >>Reactive oxygen and nitrogen in host defence against Francisella tularensis
2005 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

Francisella tularensis, the causative agent of tularemia, is a potent human and animal pathogen. Initially upon infection of the host, intramacrophage proliferation of F. tularensis occurs but after activation of the acquired host immunity, the phagocytes become activated to kill the bacterium. In my thesis, I focused on mechanisms utilized by F. tularensis to survive intracellularly and on host mechanisms responsible for macrophage-mediated killing and control of infection.

The F. tularensis-specific protein IglC has been previously shown to be essential to the intramacrophage proliferation and virulence of the bacterium in mice. By electron microscopy of macrophages infected with either the live vaccine strain of F. tularensis or an isogenic mutant, denoted ∆iglC, expression of IglC was found to be necessary for the bacterium to escape from the phagosome. IFN-g-activated macrophages significantly inhibited the escape of the live vaccine strain of F. tularensis from the phagosome.

iNOS and phox generate NO and O2-, respectively. These molecules and their reaction products possess both bactericidal and immunoregulatory properties. We investigated the capability of IFN-g-activated peritoneal exudate cells from gene deficient iNOS-/- or p47phox-/- mice to control an intracellular F. tularensis LVS infection. iNOS was found to contribute significantly to the IFN-g induced killing, while phox contributed only to a minor extent. Unexpectedly, bacteria were eradicated even in the absence of both a functional phox and an active iNOS. The eradication was found to depend on ONOO-, the reaction product of NO and O2-, because addition of a decomposition catalyst of ONOO- completely inhibited the killing.

Studies on iNOS-/- or p47phox-/- mice infected with F. tularensis LVS showed phox to be important during the first days of infection, a stage when iNOS seemed dispensable. Eventually, iNOS-/- mice died of the infection, suggesting a role of iNOS later in the course of infection. iNOS-/- mice exhibited elevated IFN-g serum levels and severe liver damage suggesting that the outcome of infection was at least in part related to an uncontrolled immune response.

Several pathogenic bacteria express Cu,Zn-SOD, which in combination with other enzymes detoxifies reactive oxygen species produced by the host. A deletion mutant of F. tularensis LVS lacking the gene encoding Cu,Zn-SOD was attenuated at least 100-fold compared to LVS in mice. In peritoneal exudate cells from mice, Cu,Zn-SOD was found to be required for effective intramacrophage proliferation and, in mice, important for bacterial replication at the very early phase of infection.

In summary, the most conspicuous findings were a capability of IFN-g activated macrophages to retain F. tularensis LVS in the phagosome, an essential role of ONOO- in intracellular killing of F. tularensis, and an importance of Cu,Zn-SOD to the virulence of F. tularensis LVS.

Ort, förlag, år, upplaga, sidor
Umeå: Klinisk mikrobiologi, 2005. s. 55
Serie
Umeå University medical dissertations, ISSN 0346-6612 ; 954
Nyckelord
Cell and molecular biology, Francisella tularensis, inducible nitric oxide synthase, phagocyte oxidase, macrophages, Cell- och molekylärbiologi
Nationell ämneskategori
Biokemi och molekylärbiologi
Forskningsämne
klinisk bakteriologi
Identifikatorer
urn:nbn:se:umu:diva-474 (URN)91-7305-851-3 (ISBN)
Disputation
2005-04-15, E04, 6E, Norrlands Universitetssjukhus i Umeå, Umeå, 09:00 (Engelska)
Opponent
Handledare
Tillgänglig från: 2005-03-15 Skapad: 2005-03-15 Senast uppdaterad: 2009-11-19Bibliografiskt granskad

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