Lack of OxyR and KatG Results in Extreme Susceptibility ofFrancisella tularensisLVS to Oxidative Stress and Marked AttenuationIn vivo.
Francisella tularensisis an intracellular bacterium and as such is expected to encounter a continuous attack by reactive oxygen species (ROS) in its intracellular habitat and efficiently coping with oxidative stress is therefore essential for its survival. The oxidative stress response system ofF. tularensisis complex and includes multiple antioxidant enzymes and pathways, including the transcriptional regulator OxyR and the H2O2-decomposing enzyme catalase, encoded bykatG. The latter is regulated by OxyR. A deletion of either of these genes, however, does not severely compromise the virulence ofF. tularensisand we hypothesized that if the bacterium would be deficient of both catalase and OxyR, then the oxidative defense and virulence ofF. tularensiswould become severely hampered. To test this hypothesis, we generated a double deletion mutant, ΔoxyR/ΔkatG, ofF. tularensisLVS and compared its phenotype to the parental LVS strain and the corresponding single deletion mutants. In accordance with the hypothesis, ΔoxyR/ΔkatGwas distinctly more susceptible than ΔoxyRand ΔkatGto H2O2, ONOO-, and [Formula: see text], moreover, it hardly grew in mouse-derived BMDM or in mice, whereas ΔkatGand ΔoxyRgrew as well asF. tularensisLVS in BMDM and exhibited only slight attenuation in mice. Altogether, the results demonstrate the importance of catalase and OxyR for a robust oxidative stress defense system and that they act cooperatively. The lack of both functions renderF. tularensisseverely crippled to handle oxidative stress and also much attenuated for intracellular growth and virulence.
Clinical Bacteriology, and Laboratory for Molecular Infection Medicine Sweden, Department of Clinical Microbiology, Umeå University Umeå, Sweden.
Marie
M
Honn
Clinical Bacteriology, and Laboratory for Molecular Infection Medicine Sweden, Department of Clinical Microbiology, Umeå University Umeå, Sweden.
Helena
H
Lindgren
Clinical Bacteriology, and Laboratory for Molecular Infection Medicine Sweden, Department of Clinical Microbiology, Umeå University Umeå, Sweden.
Gurram K
GK
Bharath
Clinical Bacteriology, and Laboratory for Molecular Infection Medicine Sweden, Department of Clinical Microbiology, Umeå University Umeå, Sweden.
Anders
A
Sjöstedt
D000818:Animals; D002374:Catalase / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005604:Francisella tularensis / Q000187:drug effects* / Q000235:genetics / Q000472:pathogenicity*; D017353:Gene Deletion; D008088:Listeriosis / Q000382:microbiology; D008264:Macrophages / Q000382:microbiology; D051379:Mice; D016877:Oxidants / Q000633:toxicity*; D018384:Oxidative Stress; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D014774:Virulence
D016877:Oxidants; D012097:Repressor Proteins; D002374:Catalase
Francisella tularensis; KatG; OxyR; oxidative stress; virulence