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Horizontally acquired regulatory gene activates ancestral regulatory system to promote Salmonella virulence.

ABSTRACT: Horizontally acquired genes are typically regulated by ancestral regulators. This regulation enables expression of horizontally acquired genes to be coordinated with that of preexisting genes. Here, we report a singular example of the opposite regulation: a horizontally acquired gene that controls an ancestral regulator, thereby promoting bacterial virulence. We establish that the horizontally acquired regulatory gene ssrB is necessary to activate the ancestral regulatory system PhoP/PhoQ of Salmonella enterica serovar Typhimurium (S. Typhimurium) in mildly acidic pH, which S. Typhimurium experiences inside macrophages. SsrB promotes phoP transcription by binding upstream of the phoP promoter. SsrB also increases ugtL transcription by binding to the ugtL promoter region, where it overcomes gene silencing by the heat-stable nucleoid structuring protein H-NS, enhancing virulence. The largely non-pathogenic species S. bongori failed to activate PhoP/PhoQ in mildly acidic pH because it lacks both the ssrB gene and the SsrB binding site in the target promoter. Low Mg2+ activated PhoP/PhoQ in both S. bongori and ssrB-lacking S. Typhimurium, indicating that the SsrB requirement for PhoP/PhoQ activation is signal-dependent. By controlling the ancestral genome, horizontally acquired genes are responsible for more crucial abilities, including virulence, than currently thought.

SUBMITTER: Choi J

PROVIDER: S-EPMC7641745 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Horizontally acquired regulatory gene activates ancestral regulatory system to promote Salmonella virulence.

Choi Jeongjoon J Groisman Eduardo A EA

Nucleic acids research 20201101 19

Horizontally acquired genes are typically regulated by ancestral regulators. This regulation enables expression of horizontally acquired genes to be coordinated with that of preexisting genes. Here, we report a singular example of the opposite regulation: a horizontally acquired gene that controls an ancestral regulator, thereby promoting bacterial virulence. We establish that the horizontally acquired regulatory gene ssrB is necessary to activate the ancestral regulatory system PhoP/PhoQ of Sal ...[more]

PMID: 33045730

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Project description:SgrS RNA is a model for the large class of Hfq-associated small RNAs that act to post-transcriptionally regulate bacterial mRNAs. The function of SgrS is well-characterized in non-pathogenic Escherichia coli where it was originally shown to counteract glucose-phosphate stress by acting as a repressor of ptsG mRNA which encodes the major glucose transporter. We have discovered new SgrS targets in Salmonella Typhimurium, a pathogen related to E. coli, which recently acquired a quarter of all genes by horizontal gene transfer. We demonstrate that the conserved short seed region of SgrS that recognizes ptsG was recruited to target the Salmonella-specific sopD mRNA of a secreted virulence protein. The SgrS-sopD interaction is exceptionally selective; we find that sopD2 mRNA whose gene arose from sopD duplication during Salmonella evolution, is deaf to SgrS owing to a non-productive G:U pair in the potential SgrS-sopD2 RNA duplex versus G:C in SgrS-sopD. In other words, SgrS discriminates the two virulence factor mRNAs at the level of a single hydrogen bond. Our study suggests that bacterial pathogens employ their large suites of conserved Hfq-associated regulators to integrate horizontally acquired genes into existing post-transcriptional networks, just as conserved transcription factors are recruited to tame foreign genes at the DNA level. The results graphically illustrate the importance of the seed regions of bacterial small RNAs to select new targets with high fidelity, and argue that target predictions must consider all-or-none decisions by individual seed nucleotides. To determine the targets of the small regulatory RNA SgrS in S. Typhimurium, we looked at the effect of a short pulse of SgrS over-expression on the Salmonella transcriptome. To achieve over-expression, the sgrS gene was cloned in the pBAD plasmid and induced with 0.2% L-arabinose for 10 min. We then extracted the total RNA for transcriptional profiling. A strain carrying the pBAD plasmid w/o insert was used as negative control. 3 biological replicates were performed. This sRNA target identification strategy has been described in Papenfort et al; Molecular Microbiology (2006) 62(6), 1674–1688.

Project description:The transcription factors HilA and SsrB activate expression of two type III secretion systems (T3SSs) and cognate effectors that reprogram host cell functions to benefit infecting Salmonella in the host. These transcription factors, the secretion systems, and the effectors are all encoded by horizontally acquired genes. Using quantitative proteomics, we quantified the abundance of 2,149 proteins from hilA or ssrB Salmonella in vitro. Our results suggest that the HilA regulon does not extend significantly beyond proteins known to be involved in direct interactions with intestinal epithelium. On the other hand, SsrB influences the expression of a diverse range of proteins, many of which are ancestral to the acquisition of ssrB. In addition to the known regulon of T3SS-related proteins, we show that, through SodCI and bacterioferritin, SsrB controls resistance to reactive oxygen species and that SsrB down-regulates flagella and motility. This indicates that SsrB-controlled proteins not only redirect host cell membrane traffic to establish a supportive niche within host cells but also have adapted to the chemistry and physical constraints of that niche.Expression of T3SSs typically requires a transcription factor that is linked in a genomic island. Studies of the targets of HilA and SsrB have focused on almost exclusively on T3SS substrates that are either linked or encoded in distinct genomic islands. By broadening our focus, we found that the regulon of SsrB extended considerably beyond T3SS-2 and its substrates, while that of HilA did not. That at least two SsrB-regulated processes streamline existence in the intracellular niche afforded by T3SS-2 seems to be a predictable outcome of evolution and natural selection. However, and importantly, these are the ?rst such functions to be implicated as being SsrB dependent. The concept of T3SS-associated transcription factors coordinating manipulations of host cells together with distinct bacterial processes for increased efficiency has unrealized implications for numerous host-pathogen systems.

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Horizontally acquired regulatory gene activates ancestral regulatory system to promote Salmonella virulence.

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Horizontally acquired regulatory gene activates ancestral regulatory system to promote Salmonella virulence.

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