Discrimination and Integration of Stress Signals by Pathogenic Bacteria

Fang, Ferric C.; Frawley, Elaine R.; Tapscott, Timothy; Vázquez‐Torres, Andrés

doi:10.1016/j.chom.2016.07.010

Cited by 25 publications

(18 citation statements)

References 111 publications

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“…The ability of bacteria to modify gene expression levels in adaptation to external influences is key to many aspects of bacterial pathogenesis [ 1 ]. Two-component regulatory systems (TCS) are a major mechanism by which bacteria detect and respond to diverse environmental factors [ 2 , 3 ].…”

Section: Introductionmentioning

confidence: 99%

Phosphatase activity of the control of virulence sensor kinase CovS is critical for the pathogenesis of group A streptococcus

et al. 2018

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The control of virulence regulator/sensor kinase (CovRS) two-component system is critical to the infectivity of group A streptococcus (GAS), and CovRS inactivating mutations are frequently observed in GAS strains causing severe human infections. CovS modulates the phosphorylation status and with it the regulatory effect of its cognate regulator CovR via its kinase and phosphatase activity. However, the contribution of each aspect of CovS function to GAS pathogenesis is unknown. We created isoallelic GAS strains that differ only by defined mutations which either abrogate CovR phosphorylation, CovS kinase or CovS phosphatase activity in order to test the contribution of CovR phosphorylation levels to GAS virulence, emergence of hypervirulent CovS-inactivated strains during infection, and GAS global gene expression. These sets of strains were created in both serotype M1 and M3 backgrounds, two prevalent GAS disease-causing serotypes, to ascertain whether our observations were serotype-specific. In both serotypes, GAS strains lacking CovS phosphatase activity (CovS-T284A) were profoundly impaired in their ability to cause skin infection or colonize the oropharynx in mice and to survive neutrophil killing in human blood. Further, response to the human cathelicidin LL-37 was abrogated. Hypervirulent GAS isolates harboring inactivating CovRS mutations were not recovered from mice infected with M1 strain M1-CovS-T284A and only sparsely recovered from mice infected with M3 strain M3-CovS-T284A late in the infection course. Consistent with our virulence data, transcriptome analyses revealed increased repression of a broad array of virulence genes in the CovS phosphatase deficient strains, including the genes encoding the key anti-phagocytic M protein and its positive regulator Mga, which are not typically part of the CovRS transcriptome. Taken together, these data establish a key role for CovS phosphatase activity in GAS pathogenesis and suggest that CovS phosphatase activity could be a promising therapeutic target in GAS without promoting emergence of hypervirulent CovS-inactivated strains.

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Section: Introductionmentioning

confidence: 99%

Phosphatase activity of the control of virulence sensor kinase CovS is critical for the pathogenesis of group A streptococcus

et al. 2018

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“…A defining feature of bacterial pathogens is the ability to sense host metabolites and precisely coordinate the expression of multiple virulence factors (Fang, Frawley, Tapscott, & Vazquez‐Torres, ; Fang, Frawley, Tapscott, & Vazquez‐Torres, ; Finlay & Cossart, ; Olive & Sassetti, ). Bile is a well‐characterised host metabolite, biosynthesised from cholesterol by hepatocytes in the liver (Joyce & Gahan, ; Vitek & Haluzik, ).…”

Section: Introductionmentioning

confidence: 99%

The bile salt sodium taurocholate inducesCampylobacter jejuniouter membrane vesicle production and increases OMV-associated proteolytic activity

Elmi

Dorey

Watson

et al. 2017

Cellular Microbiology

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Campylobacter jejuni, the leading cause of bacterial acute gastroenteritis worldwide, secretes an arsenal of virulence-associated proteins within outer membrane vesicles (OMVs). C. jejuni OMVs contain three serine proteases (HtrA, Cj0511, and Cj1365c) that cleave the intestinal epithelial cell (IEC) tight and adherens junction proteins occludin and E-cadherin, promoting enhanced C. jejuni adhesion to and invasion of IECs. C. jejuni OMVs also induce IECs innate immune responses. The bile salt sodium taurocholate (ST) is sensed as a host signal to coordinate the activation of virulence-associated genes in the enteric pathogen Vibrio cholerae. In this study, the effect of ST on C. jejuni OMVs was investigated. Physiological concentrations of ST do not have an inhibitory effect on C. jejuni growth until the early stationary phase. Coculture of C. jejuni with 0.1% or 0.2% (w/v) ST stimulates OMV production, increasing both lipid and protein concentrations. C. jejuni ST-OMVs possess increased proteolytic activity and exhibit a different protein profile compared to OMVs isolated in the absence of ST. ST-OMVs exhibit enhanced cytotoxicity and immunogenicity to T84 IECs and enhanced killing of Galleria mellonella larvae. ST increases the level of mRNA transcripts of the OMVs-associated serine protease genes and the cdtABC operon that encodes the cytolethal distending toxin. Coculture with ST significantly enhances the OMVs-induced cleavage of E-cadherin and occludin. C. jejuni OMVs also cleave the major endoplasmic reticulum chaperone protein BiP/GRP78 and this activity is associated with the Cj1365c protease. These data suggest that C. jejuni responds to the presence of physiological concentrations of the bile salt ST that increases OMV production and the synthesis of virulence-associated factors that are secreted within the OMVs. We propose that these events contribute to pathogenesis.

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“…The apo-SlyA spectrum is well dispersed (Figure 2), with ∼85% of the expected resonances observed. However, wide variation among individual resonances with respect to peak width and intensity may signify [1] weak non-specific interactions between SlyA dimers, [2] varying rates of exchange of amide protons with solvent, or [3] conformational exchange. Previous studies of MarR found that apo-MarR is also highly disordered (8), suggesting that the observed spectral characteristics of apo-SlyA can be ascribed to the presence of multiple conformational states in solution.…”

Section: Resultsmentioning

confidence: 99%

The Evolution of SlyA/RovA Transcription Factors From Repressors to Counter-Silencers inEnterobacteriaceae

Will

Brzović

Trong

et al. 2018

Preprint

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31Gene duplication and subsequent evolutionary divergence have allowed conserved proteins 32 to develop unique roles. The MarR family of transcription factors (TFs) has undergone extensive 33 duplication and diversification in bacteria, where they act as environmentally-responsive 34 repressors of genes encoding efflux pumps that confer resistance to xenobiotics, including many 35 antimicrobial agents. We have performed structural, functional, and genetic analyses of 36 representative members of the SlyA/RovA lineage of MarR TFs, which retain some ancestral 37 functions, including repression of their own expression and that of divergently-transcribed multi-38 drug efflux pumps, as well as allosteric inhibition by aromatic carboxylate compounds. However, 39 SlyA and RovA have acquired the ability to counter-silence horizontally-acquired genes, which 40 has greatly facilitated the evolution of Enterobacteriaceae by horizontal gene transfer. 41 SlyA/RovA TFs in different species have independently evolved novel regulatory circuits to 42 provide the enhanced levels of expression required for their new role. Moreover, in contrast to 43 MarR, SlyA is not responsive to copper. These observations demonstrate the ability of TFs to 44 acquire new functions as a result of evolutionary divergence of both cis-regulatory sequences and 45 in trans interactions with modulatory ligands.46 Evolution of SlyA Transcription Factors Will, et al. 109been conserved not due to their primordial role in regulating antimicrobial resistance but rather as 110 a consequence of their counter-silencing function, which is essential to maintain the regulated 111 expression of horizontally-acquired genes in Enterobacteriaceae. 112 113 Results 114 Evolution of SlyA Transcription Factors Will, et al. 6 Salicylate-mediated inhibition of SlyA activity. As environmentally-responsive repressors 115 whose conformation and regulatory actions are modulated by small aromatic carboxylates (12, 116 14), MarR family TFs are inhibited by salicylate in vitro (12). In their structural analyses of SlyA-117 DNA interactions, Dolan et al, (33) inferred from our structural data (see below) that salicylate 118 might regulate SlyA. Using electrophoretic mobility shift assays, they demonstrated that salicylate 119 inhibits DNA-binding by SlyA. To confirm that this influences the function of SlyA as a 120 transcriptional regulator, we performed in vitro transcription assays (IVTs) of slyA and the 121 divergently transcribed ydhIJK efflux pump operon. Supercoiled plasmid DNA containing the 122 slyA-ydhIJK region was incubated with RNA polymerase (RNAP) and increasing SlyA 123 concentrations in the presence or absence of salicylate. SlyA repressed slyA transcription 124 approximately 5.3-fold, while ydhI transcription was inhibited ~19-fold (Figure 1A, B). The 125 addition of 2mM sodium salicylate reduced SlyA-mediated repression to 2.8-fold and 3.2-fold, 126 respectively, indicating that the sensitivity to aromatic carboxylates observed in classical MarR 127TFs...

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Discrimination and Integration of Stress Signals by Pathogenic Bacteria

Cited by 25 publications

References 111 publications

Phosphatase activity of the control of virulence sensor kinase CovS is critical for the pathogenesis of group A streptococcus

Phosphatase activity of the control of virulence sensor kinase CovS is critical for the pathogenesis of group A streptococcus

The bile salt sodium taurocholate inducesCampylobacter jejuniouter membrane vesicle production and increases OMV-associated proteolytic activity

The Evolution of SlyA/RovA Transcription Factors From Repressors to Counter-Silencers inEnterobacteriaceae

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