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Infection and Immunity, March 2007, p. 1303-1309, Vol. 75, No. 3
0019-9567/07/$08.00+0     doi:10.1128/IAI.01717-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Resistance of Francisella tularensis Strains against Reactive Nitrogen and Oxygen Species with Special Reference to the Role of KatG{triangledown}

Helena Lindgren,1* Hua Shen,2 Carl Zingmark,1 Igor Golovliov,1 Wayne Conlan,2 and Anders Sjöstedt1

Department of Clinical Microbiology, Clinical Bacteriology, Umeå University, SE-90185 Umeå, Sweden,1 National Research Council Canada, Institute for Biological Sciences, Ottawa, Ontario, Canada2

Received 26 October 2006/ Returned for modification 15 November 2006/ Accepted 22 December 2006

Francisella tularensis is a facultative intracellular bacterial pathogen capable of proliferating within host macrophages. The mechanisms that explain the differences in virulence between various strains of the species are not well characterized. In the present study, we show that both attenuated (strain LVS) and virulent (strains FSC200 and SCHU S4) strains of the pathogen replicate at similar rates in resting murine peritoneal exudate cells (PEC). However, when PEC were activated by exposure to gamma interferon (IFN-{gamma}), they killed LVS more rapidly than virulent strains of the pathogen. Addition of NG-monomethyl-L-arginine, an inhibitor of inducible nitric oxide synthase, to IFN-{gamma}-treated PEC, completely inhibited killing of the virulent strains, whereas it only partially blocked the killing of LVS. Similarly, in a cell-free system, SCHU S4 and FSC200 were more resistant to killing by H2O2 and ONOO– than F. tularensis LVS. Catalase encoded by katG is a bacterial factor that can detoxify bactericidal compounds such as H2O2 and ONOO–. To investigate its contribution to the virulence of F. tularensis, katG deletion-containing mutants of SCHU S4 and LVS were generated. Both mutants demonstrated enhanced susceptibility to H2O2 in vitro but replicated as effectively as the parental strains in unstimulated PEC. In mice, LVS-{Delta}katG was significantly attenuated compared to LVS whereas SCHU S4-{Delta}katG, despite slower replication, killed mice as quickly as SCHU S4. This implies that clinical strains of the pathogen have katG-independent mechanisms to combat the antimicrobial effects exerted by H2O2 and ONOO–, the loss of which could have contributed to the attenuation of LVS.

* Corresponding author. Mailing address: Department of Clinical Microbiology, Clinical Bacteriology, Umeå University, SE-901 85 Umeå, Sweden. Phone: 46 90 785 8787. Fax: 46 90 785 2225. E-mail: Helena.Lindgren{at}climi.umu.se.

{triangledown} Published ahead of print on 8 January 2007.

Editor: D. L. Burns

Infection and Immunity, March 2007, p. 1303-1309, Vol. 75, No. 3
0019-9567/07/$08.00+0     doi:10.1128/IAI.01717-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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