Negative regulation of Salmonella pathogenicity island 2 is required for contextual control of virulence during typhoid.
Salmonella enterica relies on a type III secretion system encoded in Salmonella pathogenicity island-2 (SPI-2) to survive and replicate within macrophages at systemic sites during typhoid. SPI-2 virulence is induced upon entry into macrophages, but the mechanisms of SPI-2 gene control in vivo remain unclear, particularly with regard to negative regulators that control the contextual activation of SPI-2. Here, we identified and characterized YdgT as a negative modulator of the SPI-2 pathogenicity island and established that this negative regulation is central to systemic pathogenesis because ydgT mutants overexpressing typhoid virulence genes were ultimately attenuated during infection. ydgT mutants displayed a biphasic virulence phenotype during in vivo competitive infections that consisted of an early "gain-of-virulence" dependent on SPI-2 activation, followed by attenuation later in infection indicating that proper contextual regulation of SPI-2 by YdgT is necessary for full virulence during systemic colonization. These data suggest that overexpression of virulence-associated type III secretion genes can have an adverse effect on bacterial pathogenesis in vivo.
Coombes
Brian K
BK
Michael Smith Laboratories, Department of Microbiology and Immunology, University of British Columbia, Vancouver, BC, Canada V6T 1Z4.
Wickham
Mark E
ME
Lowden
Michael J
MJ
Brown
Nat F
NF
Finlay
B Brett
BB
D000818:Animals; D001426:Bacterial Proteins / Q000378:metabolism*; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D020869:Gene Expression Profiling; D015964:Gene Expression Regulation, Bacterial / Q000235:genetics*; D006367:HeLa Cells; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012485:Salmonella typhi / Q000378:metabolism / Q000472:pathogenicity*; D014435:Typhoid Fever / Q000378:metabolism*; D014774:Virulence
D001426:Bacterial Proteins; D004268:DNA-Binding Proteins; D008565:Membrane Proteins; C440638:SPI-2 protein, Salmonella