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Active downregulation of the type III secretion system at higher local cell densities promotes Yersinia replication and dissemination

ABSTRACT: The T3SS injectisome is used by Gram-negative bacteria, including important pathogens, to manipulate eukaryotic target cells by injecting effector proteins. Some bacterial species display bimodal expression of the T3SS, allowing the T3SS-negative population to benefit from the activity of their T3SS-positive siblings without investing into assembly and production of the injectisome. In contrast, Yersinia enterocolitica, a main T3SS model organism that uses the system to evade the host immune response, was thought to uniformly express and assemble injectisomes, which are then activated by target cell contact. In this study, we found that at higher local bacterial concentrations, Yersinia actively downregulates T3SS expression, assembly and activity. This effect is reversible, highly specific, and distinct from stationary phase adaptation. A key player is the main T3SS transcription factor VirF, which is downregulated at the higher cell densities suppressing T3SS activity and whose in trans expression restores T3SS expression and assembly. Transcript analysis showed this effect is conferred by increased levels of the regulatory RNAs csrBC, which sequester the regulatory protein CsrA and destabilize the virF mRNA. Downregulation of the VirF-dependent adhesin YadA led to a drastic reduction of bacterial cell adhesion. We propose that the phenotype described in this study, active downregulation of cell attachment and T3SS secretion at higher local bacterial densities, is a strategy implemented to favor bacterial replication and dissemination during infection.

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ORGANISM(S): Yersinia Enterocolitica Lc20

SUBMITTER: Timo Glatter

LAB HEAD: Timo Glatter

PROVIDER: PXD052013 | Pride | 2025-08-05

REPOSITORIES: Pride

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Project description:Many species of pathogenic bacteria harbor critical plasmid-encoded virulence factors, and yet the regulation of plasmid replication is often poorly understood despite playing key role in plasmid-encoded gene expression. Human pathogenic Yersinia, including the plague agent Yersinia. pestis and its close relative Y. pseudotuberculosis, require the type III secretion system (T3SS) virulence factor to subvert host defense mechanisms and colonize host tissues. The Yersinia T3SS is encoded on the IncFII plasmid for Yersinia virulence (pYV). Several layers of gene regulation enables a large increase in expression of Yersinia T3SS genes at mammalian body temperature. Surprisingly, T3SS expression is also controlled at the level of gene dosage. The number of pYV molecules relative to the number of chromosomes per cell, referred to as plasmid copy number, increases with temperature. The ability to increase and maintain elevated pYV plasmid copy number, and therefore T3SS gene dosage, at 37˚C is important for Yersinia virulence. In addition, pYV is highly stable in Yersinia at all temperatures, despite being dispensable for growth outside the host. Yet how Yersinia reinforces elevated plasmid replication and plasmid stability remains unclear. In this study, we show that the chromosomal gene pcnB encoding the polyadenylase PAP I is required for regulation of pYV plasmid copy number (PCN), maintenance of pYV in the bacterial population outside the host, robust T3SS activity, and Yersinia virulence in a mouse infection model. Likewise, pcnB/PAP I is also required for robust expression of the Shigella flexneri virulence plasmid-encoded T3SS that, similar to Yersinia, is encoded on a virulence plasmid whose replication is regulated by sRNA. Furthermore, Yersinia and Shigella pcnB/PAP I is required for maintaining normal PCN of model antimicrobial resistance (AMR) plasmids whose replication is regulated by sRNA, thereby increasing antibiotic resistance by ten-fold. These data suggest that pcnB/PAP I contributes to the spread and stabilization of sRNA-regulated virulence and AMR plasmids in bacterial pathogens, and is essential in maintaining the gene dosage required to mediate plasmid-encoded traits. Importantly pcnB/PAP I has been bioinformatically identified in many species of bacteria despite being studied in only a few species to date. Our work highlights the potential importance of pcnB/PAP I in antibiotic resistance, and shows for the first time that pcnB/PAP I reinforces PCN andpromotes virulence plasmid stability in natural pathogenic hosts with a direct impact on bacterial virulence.

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Active downregulation of the type III secretion system at higher local cell densities promotes Yersinia replication and dissemination

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