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.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adenine / metabolism
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Animals
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Bacterial Proteins / metabolism
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Bacterial Vaccines*
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DNA Methylation*
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DNA, Bacterial / metabolism
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Gene Expression Regulation, Bacterial
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Genes, Bacterial
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Lethal Dose 50
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Methylation
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Mice
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Mice, Inbred BALB C
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Mutation
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Peyer's Patches / microbiology
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Salmonella Infections, Animal / immunology
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Salmonella Infections, Animal / microbiology*
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Salmonella Infections, Animal / prevention & control
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Salmonella typhimurium / enzymology*
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Salmonella typhimurium / genetics
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Salmonella typhimurium / immunology
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Salmonella typhimurium / pathogenicity*
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Site-Specific DNA-Methyltransferase (Adenine-Specific) / antagonists & inhibitors
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Site-Specific DNA-Methyltransferase (Adenine-Specific) / genetics
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Site-Specific DNA-Methyltransferase (Adenine-Specific) / metabolism*
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Vaccines, Attenuated
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Virulence / genetics
Substances
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Bacterial Proteins
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Bacterial Vaccines
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DNA, Bacterial
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Vaccines, Attenuated
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PhoP protein, Bacteria
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Dam methyltransferase
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Site-Specific DNA-Methyltransferase (Adenine-Specific)
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Adenine