An Essential Role for DNA Adenine Methylation in Bacterial Virulence

Author:

Heithoff Douglas M.1,Sinsheimer Robert L.1,Low David A.1,Mahan Michael J.1

Affiliation:

1. Department of Molecular, Cellular, and Developmental Biology, University of California, Santa Barbara, CA 93106, USA.

Abstract

Salmonella typhimurium lacking DNA adenine methylase (Dam) were fully proficient in colonization of mucosal sites but showed severe defects in colonization of deeper tissue sites. These Dam mutants were totally avirulent and were effective as live vaccines against murine typhoid fever. Dam regulated the expression of at least 20 genes known to be induced during infection; a subset of these genes are among those activated by the PhoP global virulence regulator. PhoP, in turn, affected Dam methylation at specific genomic sites, as evidenced by alterations in DNA methylation patterns. Dam inhibitors are likely to have broad antimicrobial action, and Dam derivatives of these pathogens may serve as live attenuated vaccines.

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Multidisciplinary

Reference31 articles.

1. M. G. Marinus in Escherichia coli and Salmonella : Cellular and Molecular Biology F. Neidhardt Ed. (American Society for Microbiology Washington DC ed. 2 1996) pp. 782–791.

2. J. A. Roberts et al. J. Urol. 133 1068 (1985).

3. van der Woude M., Braaten B., Low D., Trends Microbiol. 4, 5 (1996).

4. The dam102 ::Mu d -Cm and mutS121 ::Tn 10 alleles (and additional alleles below) were transduced into virulent S. typhimurium strain 14028 resulting in strains MT2116 and MT2127 respectively. dam Δ 232 (MT2188) was constructed using internal oligonucleotides that serve as polymerase chain reaction primers designed to construct an in-frame 300-bp deletion of defined dam sequence. dcm1 ::Km (MT2198) was constructed according to (26); the Km resistance determinant is associated with an internal deletion of >600 bp of dcm sequence. lrp31 ::Km is a null insertion in the lrp gene (MT2126).

5. High Mutation Frequencies Among Escherichia coli and Salmonella Pathogens

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