A pH-sensitive switch activates virulence in Salmonella

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Abstract

The transcriptional regulator SsrB acts as a switch between virulent and biofilm lifestyles of non-typhoidal Salmonella enterica serovar Typhimurium. During infection, phosphorylated SsrB activates genes on Salmonella Pathogenicity Island-2 (SPI-2) essential for survival and replication within the macrophage. Low pH inside the vacuole is a key inducer of expression and SsrB activation. Previous studies demonstrated an increase in SsrB protein levels and DNA-binding affinity at low pH; the molecular basis was unknown (Liew et al., 2019). This study elucidates its underlying mechanism and in vivo significance. Employing single-molecule and transcriptional assays, we report that the SsrB DNA binding domain alone (SsrBc) is insufficient to induce acid pH-sensitivity. Instead, His12, a conserved residue in the receiver domain, confers pH sensitivity to SsrB allosterically. Acid-dependent DNA binding was highly cooperative, suggesting a new configuration of SsrB oligomers at SPI-2-dependent promoters. His12 also plays a role in SsrB phosphorylation; substituting His12 reduced phosphorylation at neutral pH and abolished pH-dependent differences. Failure to flip the switch in SsrB renders Salmonella avirulent and represents a potential means of controlling virulence.

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All data generated or analysed during this study are included in the manuscript and supporting file; Source Data files have been provided for Figures 1-4, and figure supplements for Figures 2 and 3.

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Dasvit Shetty

Mechanobiology Institute, National University of Singapore, Singapore, Singapore

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0001-8778-3615
Linda J Kenney

2Department of Biochemistry and Molecular Biology, The University of Texas Medical Branch at Galveston, Galveston, United States

For correspondence
likenney@utmb.edu

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-8658-0717

Funding

Mechanobiology Institute, Singapore (Regional centre of excellence)

Dasvit Shetty
Linda J Kenney

University of Texas Medical Branch

Linda J Kenney

Cancer Prevention and Research Institute of Texas (RP200650)

Linda J Kenney

Texas STAR

Linda J Kenney

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

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This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.