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  • Review Article
  • Published:

Pushing the envelope: extracytoplasmic stress responses in bacterial pathogens

Key Points

  • Pathogenic bacteria must be able to sense when they are within the host, and respond to the assault of the host defences. One way of sensing this change of environment is through the extracytoplasmic (envelope) stress responses (ESRs). The ESRs respond to damage or changes in the cell envelope, such as accumulation of outer-membrane proteins in the periplasm.

  • The ESR of Gram-negative bacteria consists of at least four separate pathways, regulated by σE (RpoE), CpxAR, BaeSR and phage shock proteins (PSP). The importance of ESR pathways has been most intensively studied for the former two regulons.

  • σE is an alternative sigma factor encoded by rpoE. A clear role for σE in the pathogenesis of pathogens with diverse lifestyles has been demonstrated. Genes controlled by σE are important in bacterial defence against different antimicrobial defences encountered in vivo, such as antimicrobial peptides and reactive oxygen species. Many genes are now known to be regulated by σE in Escherichia coli and Salmonella spp. In the case of Salmonella spp., several of these are important for virulence.

  • CpxAR (Cpx) is a typical two-component regulator. A major role for the Cpx system is regulating and monitoring the biogenesis of complex surface virulence factors such as pili/fimbiae and type III and type IV secretion systems. However, a role for Cpx during infection has been shown for only one organism, Salmonella enterica serovar Typhimurium.

  • Regulation of these responses is crucial to ensure that they are switched on only at the appropriate moment. The complexity of this regulation for all prongs of the ESR is becoming more apparent, and there seems to be a degree of overlap at both the functional and regulatory levels across the pathways.

  • This review describes the regulation of each pathway of the ESR and discusses the importance of the ESRs in various pathogenic Gram-negative bacteria.

Abstract

Despite being nutrient rich, the tissues and fluids of vertebrates are hostile to microorganisms, and most bacteria that attempt to take advantage of this environment are rapidly eliminated by host defences. Pathogens have evolved various means to promote their survival in host tissues, including stress responses that enable bacteria to sense and adapt to adverse conditions. Many different stress responses have been described, some of which are responsive to one or a small number of cues, whereas others are activated by a broad range of insults. The surface layers of pathogenic bacteria directly interface with the host and can bear the brunt of the attack by the host armoury. Several stress systems that respond to perturbations in the microbial cell outside of the cytoplasm have been described and are known collectively as extracytoplasmic or envelope stress responses (ESRs). Here, we review the role of the ESRs in the pathogenesis of Gram-negative bacterial pathogens.

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Figure 1: Model for regulation of σE activity by regulated intramembrane proteolysis (RIP) in Escherichia coli.
Figure 2: Model for regulation of the CpxRA pathway.
Figure 3: Model for phage shock protein (PSP) response regulation.

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DATABASES

Entrez Genome Project

Actinobacillus pleuropneumoniae

Caenorhabditis elegans

Chlamydia trachomatis

Escherichia coli

Haemophilus influenzae

Legionella pneumophila

Pseudomonas aeruginosa

Salmonella enterica serovar Typhimurium

Vibrio cholerae

Yersinia enterocolitica

FURTHER INFORMATION

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Glossary

Outer-membrane proteins

Polypeptides in Gram-negative bacteria that are located in the outer membrane.

Sigma factor

A subunit of RNA polymerase that determines the DNA-binding specificity depending on the sigma factor bound.

Two-component regulator

Consists of a histidine kinase (HK) and a response regulator (RR). The HK senses the change in environment and relays the message to the RR through a phosphorylation event. The phosphorylated RR binds to specific DNA-binding sites that regulate transcription of a subset of genes.

Chaperones

Molecules that participate in the folding/assembly of other proteins but do not form part of the final structure themselves.

PDZ domain

Protein domain found in signalling proteins of bacteria and eukaryotes. The PDZ domain consists of 80?90 amino acids typically arranged as 6 β-strands and 2 α-helices. The PDZ domain recognizes peptide sequences typically in the C terminus of the target protein. Most proteins with PDZ domains are located in the plasma membrane.

Regulated intra-membrane proteolysis

(RIP). A conserved mechanism for controlling several important signalling pathways in both prokaryotes and eukaryotes. It normally involves the release of a cytoplasmic membrane-bound transcription factor, which in this context is a sigma factor.

Type III secretion system

(TTSS). Used by many pathogenic bacteria to inject virulence proteins directly into host cells through needle-like structures. Also used by the bacteria to export flagellum-protein subunits.

Pili/fimbriae

Filamentous surface structures that are more rigid, but thinner and shorter, than flagella. They mediate adhesion to both biotic and abiotic surfaces.

Curli

A type of fimbriae that mediate binding to components of the extracellular matrix, often implicated in biofilm formation.

Type IV secretion system

(TFSS). Used to deliver proteins or DNA across the bacterial cell envelope.

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Rowley, G., Spector, M., Kormanec, J. et al. Pushing the envelope: extracytoplasmic stress responses in bacterial pathogens. Nat Rev Microbiol 4, 383–394 (2006). https://doi.org/10.1038/nrmicro1394

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