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Regulation of Virulence

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  • Authors: Christian Jenul1, Alexander R. Horswill2
  • Editors: Vincent A. Fischetti4, Richard P. Novick5, Joseph J. Ferretti6, Daniel A. Portnoy7, Miriam Braunstein8, Julian I. Rood9
  • VIEW AFFILIATIONS HIDE AFFILIATIONS
    Affiliations: 1: Department of Immunology and Microbiology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045; 2: Department of Immunology and Microbiology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045; 3: Department of Veterans Affairs Eastern Colorado Healthcare System, Aurora, CO 80012; 4: The Rockefeller University, New York, NY; 5: Skirball Institute for Molecular Medicine, NYU Medical Center, New York, NY; 6: Department of Microbiology & Immunology, University of Oklahoma Health Science Center, Oklahoma City, OK; 7: Department of Molecular and Cellular Microbiology, University of California, Berkeley, Berkeley, CA; 8: Department of Microbiology and Immunology, University of North Carolina-Chapel Hill, Chapel Hill, NC; 9: Infection and Immunity Program, Monash Biomedicine Discovery Institute, Monash University, Melbourne, Australia
  • Source: microbiolspec April 2019 vol. 6 no. 1 doi:10.1128/microbiolspec.GPP3-0031-2018
  • Received 04 May 2018 Accepted 16 August 2018 Published 05 April 2019
  • Alexander R. Horswill, [email protected]
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  • Abstract:

    is a Gram-positive opportunistic pathogen that has evolved a complex regulatory network to control virulence. One of the main functions of this interconnected network is to sense various environmental cues and respond by altering the production of virulence factors necessary for survival in the host, including cell surface adhesins and extracellular enzymes and toxins. Of these regulatory systems, one of the best studied is the accessory gene regulator (), which is a quorum-sensing system that senses the local concentration of a cyclic peptide signaling molecule. This system allows to sense its own population density and translate this information into a specific gene expression pattern. Besides , this pathogen uses other two-component systems to sense specific cues and coordinates responses with cytoplasmic regulators of the SarA protein family and alternative sigma factors. These divergent regulatory systems integrate the various environmental and host-derived signals into a network that ensures optimal pathogen response to the changing conditions. This article gives an overview of the most important and best-studied regulatory systems and summarizes the functions of these regulators during host interactions. The regulatory systems discussed include the quorum-sensing system; the SaeRS, SrrAB, and ArlRS two-component systems, the cytoplasmic SarA-family regulators (SarA, Rot, and MgrA); and the alternative sigma factors (SigB and SigH).

  • Citation: Jenul C, Horswill A. 2019. Regulation of Virulence. Microbiol Spectrum 6(1):GPP3-0031-2018. doi:10.1128/microbiolspec.GPP3-0031-2018.

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/content/journal/microbiolspec/10.1128/microbiolspec.GPP3-0031-2018
2019-04-05
2019-10-16

Abstract:

is a Gram-positive opportunistic pathogen that has evolved a complex regulatory network to control virulence. One of the main functions of this interconnected network is to sense various environmental cues and respond by altering the production of virulence factors necessary for survival in the host, including cell surface adhesins and extracellular enzymes and toxins. Of these regulatory systems, one of the best studied is the accessory gene regulator (), which is a quorum-sensing system that senses the local concentration of a cyclic peptide signaling molecule. This system allows to sense its own population density and translate this information into a specific gene expression pattern. Besides , this pathogen uses other two-component systems to sense specific cues and coordinates responses with cytoplasmic regulators of the SarA protein family and alternative sigma factors. These divergent regulatory systems integrate the various environmental and host-derived signals into a network that ensures optimal pathogen response to the changing conditions. This article gives an overview of the most important and best-studied regulatory systems and summarizes the functions of these regulators during host interactions. The regulatory systems discussed include the quorum-sensing system; the SaeRS, SrrAB, and ArlRS two-component systems, the cytoplasmic SarA-family regulators (SarA, Rot, and MgrA); and the alternative sigma factors (SigB and SigH).

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Figures

Image of FIGURE 1
FIGURE 1

Schematic of the molecular organization, signal biosynthesis, and transduction cascade of the quorum-sensing system. The autoinducing peptide (AIP) signal is encoded within the AgrD peptide. AgrD is processed and transported into the environment by AgrB with the aid of signal peptidase SpsB. When the extracellular AIP concentration reaches a critical level, the signal is sensed by the histidine kinase AgrC, which undergoes autophosphorylation. Then the phosphate is relayed to AgrA, which in turn can bind the P2 and P3 promoters, driving expression of the RNAII and RNAIII transcripts, respectively. The RNAII transcript harbors the operon, encoding the primary machinery for AIP biosynthesis and detection. RNAIII is the main effector molecule of the system and drives expression of downstream target genes. Phosphorylated AgrA also binds the promoters for the phenol-soluble modulin (PSM) genes, leading to their expression.

Source: microbiolspec April 2019 vol. 6 no. 1 doi:10.1128/microbiolspec.GPP3-0031-2018
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Image of FIGURE 2
FIGURE 2

The autoinducing peptides (AIPs) and interference within strains. Every strain has a single system that can produce one of four different AIP signal structures. Each of the AIPs has a five-residue cyclic thiolactone ring, but the amino acids within the ring and the N-terminal extension are variable. The type I and IV AIPs differ by only one amino acid and can function interchangeably, while the type II and III AIPs are more divergent. Interference is observed between the three groups of AIPs as shown. In each case, the cognate AIP signal from a producing strain cross-inhibits the AgrC receptor, and in turn inhibits function, on an strain representing a different group.

Source: microbiolspec April 2019 vol. 6 no. 1 doi:10.1128/microbiolspec.GPP3-0031-2018
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Image of FIGURE 3
FIGURE 3

Schematic of the molecular organization and signal transduction of the SaeRS TCS. (Top) The histidine-kinase SaeS phosphorylates its cognate response regulator SaeR. Phosphorylated SaeR can then bind to the promoter region of target genes and induce expression of numerous virulence factors (listed). The phosphorelay from SaeS to SaeR is inhibited by the combined action of SaeP and SaeQ. (Bottom) The gene cluster consists of four genes: , , , and . All four genes are transcribed from the P1 promoter. In addition, transcription of and is enhanced via the P3 promoter, which is located within the coding region of .

Source: microbiolspec April 2019 vol. 6 no. 1 doi:10.1128/microbiolspec.GPP3-0031-2018
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Image of FIGURE 4
FIGURE 4

The promoter region and SarA regulatory network. gene expression is driven by three promoters (P1, P2, and P3) as shown. The alternative sigma factor σ (SigB) drives expression of by binding to the P3 promoter. The binding of SarR to all three promoters inhibits expression and impedes autoregulation by SarA. Finally, SarA is an activator of the system, and it can also function as a negative regulator of the three SarA-like proteins SarH1, SarT, and Rot.

Source: microbiolspec April 2019 vol. 6 no. 1 doi:10.1128/microbiolspec.GPP3-0031-2018
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Image of FIGURE 5
FIGURE 5

Regulatory pathway of ArlRS TCS and MgrA in biofilm formation and clumping. The ArlRS TCS is activated by an unknown signal and subsequently activates MgrA, which in turn represses the production of large surface proteins (Ebh, SraP, and SasG), allowing ClfA/ClfB to interact with fibrinogen (Fg). Neighboring cells binding to the dimeric Fg molecule leads to clumping. When ArlRS is inhibited, MgrA is not expressed and the repression of the large surface proteins (Ebh, SraP, and SasG) is relieved, preventing proper interactions of ClfA/ClfB with Fg. At the same time, SasG overproduction leads to homodimeric interactions with other cells expressing SasG, resulting in enhanced biofilm formation. This figure is a reproduction from one published in reference 84 .

Source: microbiolspec April 2019 vol. 6 no. 1 doi:10.1128/microbiolspec.GPP3-0031-2018
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Image of FIGURE 6
FIGURE 6

Interaction network of the major global regulators. The schematic depicts a comprehensive overview of five regulatory systems, including the quorum-sensing system, the ArlRS and SaeRS TCS, and three members of the SarA-protein family (SarA, Rot, and MgrA). The virulence-associated traits controlled by each regulator are also shown.

Source: microbiolspec April 2019 vol. 6 no. 1 doi:10.1128/microbiolspec.GPP3-0031-2018
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Tables

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TABLE 1

Major virulence regulatory systems of

Source: microbiolspec April 2019 vol. 6 no. 1 doi:10.1128/microbiolspec.GPP3-0031-2018
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TABLE 2

Regulators impacting system function

Source: microbiolspec April 2019 vol. 6 no. 1 doi:10.1128/microbiolspec.GPP3-0031-2018

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