The role of DNA base excision repair in the pathogenesis of Salmonella enterica serovar Typhimurium

Akamol E. Suvarnapunya, H. A.Daniel Lagasse, Murry A. Stein

Research output: Contribution to journalArticlepeer-review

49 Scopus citations

Abstract

The intracellular pathogen, Salmonella enterica serovar Typhimurium, is able to proliferate in phagocytes, although reactive oxygen and nitrogen intermediates are lethal to most phagocytosed bacteria. To determine whether repair of oxidatively damaged DNA is involved in S. typhimurium intramacrophage proliferation, null mutants of the DNA base excision repair (BER) system were generated. These mutants were deficient in discrete enzymes (Δnth, Δnei, Δxth, Δnfo) or in the defined glycosylase (Δnth/nei) and endonuclease (Δtxth/nfo) steps. In this study, S. typhimurium BER mutants are characterized for the first time. In vitro characterization of the Salmonella BER mutants revealed phenotypes that are mostly consistent with characterized Escherichia coli BER mutants. These strains were used to evaluate the role of BER in the context of Salmonella virulence. S. typhimurium Δxth and Δxth/nfo were significantly impaired for survival in both cultured and primary macrophages activated with interferon (IFN)-γ. Survival of Δxth and Δxth/nfo was improved nearly to wild-type levels in activated primary macrophages lacking both phagocyte oxidase and inducible nitric oxide synthase. In the murine typhoid fever model, Δnth/nei was fivefold attenuated and Δxth/nfo was 12-fold attenuated compared with wild type. These data indicate that DNA oxidation is a mechanism that macrophages use to damage intracellular Salmonella, and suggest that BER-mediated repair of this damage may be important in the establishment of Salmonella infection. We speculate that adaptation to a pathogenic lifestyle may influence the acquisition and retention of redundant BER enzymes.

Original languageEnglish (US)
Pages (from-to)549-559
Number of pages11
JournalMolecular Microbiology
Volume48
Issue number2
DOIs
StatePublished - Apr 2003
Externally publishedYes

ASJC Scopus subject areas

  • Microbiology
  • Molecular Biology

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