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Infection and Immunity, May 2001, p. 3164-3174, Vol. 69, No. 5
0019-9567/01/$04.00+0   DOI: 10.1128/IAI.69.5.3164-3174.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Disruption of the Genes for ClpXP Protease in Salmonella enterica Serovar Typhimurium Results in Persistent Infection in Mice, and Development of Persistence Requires Endogenous Gamma Interferon and Tumor Necrosis Factor Alpha

Tomoko Yamamoto,1,* Hiroshi Sashinami,2 Akiko Takaya,1 Toshifumi Tomoyasu,1 Hidenori Matsui,3 Yuji Kikuchi,3 Tomoko Hanawa,4 Shigeru Kamiya,4 and Akio Nakane2

Division of Microbiology, Faculty of Pharmaceutical Sciences, Chiba University, Chiba 263-8522,1 Department of Bacteriology, Hirosaki University School of Medicine, Hirosaki 036-8562,2 Center for Basic Research, The Kitasato Institute, Tokyo 108-8642,3 and Department of Infectious Diseases, Kyorin University School of Medicine, Mitaka 181-8611,4 Japan

Received 4 December 2000/Returned for modification 8 January 2001/Accepted 9 February 2001

The enteric pathogen Salmonella enterica serovar Typhimurium, similar to other facultative intracellular pathogens, has been shown to respond to the hostile conditions inside macrophages of the host organism by producing a set of stress proteins that are also induced by various environmental stresses. The stress-induced ClpXP protease is a member of the ATP-dependent proteases, which are known to be responsible for more than 90% of all proteolysis in Escherichia coli. To investigate the contribution of the ClpXP protease to the virulence of serovar Typhimurium we initially cloned the clpP and clpX operon from the pathogenic strain serovar Typhimurium chi 3306 and then created insertional mutations in the clpP and/or clpX gene. The Delta clpP and Delta clpX mutants were used to inoculate BALB/c mice by either the intraperitoneal or the oral route and found to be limited in their ability to colonize organs of the lymphatic system and to cause systemic disease in the host. A variety of experiments were performed to determine the possible reasons for the loss of virulence. An oxygen-dependent killing assay using hydrogen peroxide and paraquat (a superoxide anion generator) and a serum killing assay using murine serum demonstrated that all of the serovar Typhimurium Delta clpP and Delta clpX mutants were as resistant to these killing mechanisms as the wild-type strain. On the other hand, the macrophage survival assay revealed that all these mutants were more sensitive to the intracellular environment than the wild-type strain and were unable to grow or survive within peritoneal macrophages of BALB/c mice. In addition, it was revealed that the serovar Typhimurium ClpXP-depleted mutant was not completely cleared but found to persist at low levels within spleens and livers of mice. Interferon gamma-deficient mice and tumor necrosis factor alpha-deficient mice failed to survive the attenuated serovar Typhimurium infections, suggesting that both endogenous cytokines are essential for regulation of persistent infection with serovar Typhimurium.

* Corresponding author. Mailing address: Division of Microbiology, Faculty of Pharmaceutical Sciences, Chiba University, 1-33 Yayoi-cho, Inage-ku, Chiba 263-8522, Japan. Phone: 81-43-290-2928. Fax: 81-43-290-2929. E-mail: tomoko-y{at}p.chiba-u.ac.jp.

Infection and Immunity, May 2001, p. 3164-3174, Vol. 69, No. 5
0019-9567/01/$04.00+0   DOI: 10.1128/IAI.69.5.3164-3174.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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