Global transcriptional profiling reveals Streptococcus agalactiae genes controlled by the MtaR transcription factor

Bryan, Joshua; Liles, Roxanne; Cvek, Urška; Trutschl, Marjan; Shelver, Daniel

doi:10.1186/1471-2164-9-607

Cited by 24 publications

(36 citation statements)

References 41 publications

(64 reference statements)

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“…CpsY shares homology (83% identity) with a LysR family transcriptional regulator of S. mutans (MetR), as well as to proteins in S. iniae (CpsY) and S. agalactiae (MtaR) that regulate methionine transport (25), amino acid metabolism (26), and resistance to neutrophilmediated killing and survival in vivo (27)(28)(29). This led us to hypothesize that CpsY functions as a transcriptional regulator of GAS metabolism required for survival in human host blood.…”

Section: Discussionmentioning

confidence: 99%

“…This analysis confirmed that CpsY activity is associated with low-level repression of mntE and Spy0500, as well as induction of emm1 and mur1.2. Further examination of the Spy0500 sequence found 79% identity to the N-acetylmuramoyl-L-alanine amidase encoded by the murA gene characterized as regulated by CpsY in S. iniae (29) and MtaR in S. agalactiae (26). Thus, it appears that the sequence annotated in the MGAS5005 genome as murA (M5005_Spy0548) does not correspond to the homolog of the CpsY-regulated murA characterized in other streptococci.…”

Section: Spy0500])mentioning

confidence: 99%

“…GAS CpsY displays 83% identity with MetR, a LysR family transcriptional regulator of Streptococcus mutans shown to activate transcription of genes involved in methionine biosynthesis (metE) and uptake (atmB) in a homocysteine-dependent manner (24). Homologs of CpsY found in Streptococcus iniae and Streptococcus agalactiae (MtaR) have been characterized as virulence determinants that regulate methionine transport (25), amino acid metabolism (26), and cell wall modifications necessary for resistance to neutrophilmediated killing and survival in vivo (27)(28)(29). Thus, CpsY appears to play a crucial role as a transcriptional regulator in the development of streptococcal invasive disease through the promotion of immune cell resistance and host niche adaptation.…”

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The Transcriptional Regulator CpsY Is Important for Innate Immune Evasion in Streptococcus pyogenes

et al. 2017

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As an exclusively human pathogen, Streptococcus pyogenes (the group A streptococcus [GAS]) has specifically adapted to evade host innate immunity and survive in multiple tissue niches, including blood. GAS can overcome the metabolic constraints of the blood environment and expresses various immunomodulatory factors necessary for survival and immune cell resistance. Here we present our investigation of one such factor, the predicted LysR family transcriptional regulator CpsY. The encoding gene, cpsY, was initially identified as being required for GAS survival in a transposon-site hybridization (TraSH) screen in whole human blood. CpsY is homologous with transcriptional regulators of Streptococcus mutans (MetR), Streptococcus iniae (CpsY), and Streptococcus agalactiae (MtaR) that regulate methionine transport, amino acid metabolism, resistance to neutrophil-mediated killing, and survival in vivo. Our investigation indicated that CpsY is involved in GAS resistance to innate immune cells of its human host. However, GAS CpsY does not manifest the in vitro phenotypes of its homologs in other streptococcal species. GAS CpsY appears to regulate a small set of genes that is markedly different from the regulons of its homologs. The differential expression of these genes depends on the growth medium, and CpsY modestly influences their expression. The GAS CpsY regulon includes known virulence factors (mntE, speB, spd, nga [spn], prtS [SpyCEP], and sse) and cell surface-associated factors of GAS (emm1, mur1.2, sibA [cdhA], and M5005_Spy0500). Intriguingly, the loss of CpsY in GAS does not result in virulence defects in murine models of infection, suggesting that CpsY function in immune evasion is specific to the human host.

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Section: Discussionmentioning

confidence: 99%

Section: Spy0500])mentioning

confidence: 99%

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The Transcriptional Regulator CpsY Is Important for Innate Immune Evasion in Streptococcus pyogenes

et al. 2017

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“…In previous studies, CmbR (FhuR) and MetR were shown to control sulfur amino acid metabolism genes in L. lactis and methionine genes in S. mutans and Streptococcus agalactiae, respectively (12,19,(56)(57)(58). A phylogenic analysis of these proteins and their homologues from 14 Streptococcus genomes, presented in Fig.…”

Section: Identification Of Two Ltrrs Involved In Sulfur Amino Acid Sumentioning

confidence: 99%

Three Paralogous LysR-Type Transcriptional Regulators Control Sulfur Amino Acid Supply in Streptococcus mutans

et al. 2010

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The genome of Streptococcus mutans encodes 4 LysR-type transcriptional regulators (LTTRs), three of which, MetR, CysR (cysteine synthesis regulator), and HomR (homocysteine synthesis regulator), are phylogenetically related. MetR was previously shown to control methionine metabolic gene expression. Functional analysis of CysR and HomR was carried out by phenotypical studies and transcriptional analysis. CysR is required to activate the transcription of cysK encoding the cysteine biosynthesis enzyme, tcyABC and gshT genes encoding cysteine and glutathione transporter systems, and homR. HomR activates the transcription of metBC encoding methionine biosynthesis enzymes, tcyDEFGH involved in cysteine transport, and still uncharacterized thiosulfate assimilation genes. Control of HomR by CysR provides evidence of a cascade regulation for sulfur amino acid metabolism in S. mutans. Two conserved motifs were found in the promoter regions of CysR and HomR target genes, suggesting their role in the regulator binding recognition site. Both CysR and HomR require O-acetylserine to activate transcription. A global sulfur amino acid supply gene regulatory pathway is proposed for S. mutans, including the cascade regulation consequent to transcriptional activation of HomR by CysR. Phylogenetic study of MetR, CysR, and HomR homologues and comparison of their potential regulatory patterns among the Streptococcaceae suggest their rapid evolution.

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“…Rather, CpsY was renamed MtaR in S. agalactiae (48) and MetR in Streptococcus mutans (50) because of its influence on methionine biosynthesis and uptake. However, the regulatory function of MtaR in S. agalactiae appears to extend beyond methionine metabolism (6).…”

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confidence: 99%

The Streptococcus iniae Transcriptional Regulator CpsY Is Required for Protection from Neutrophil-Mediated Killing and Proper Growth In Vitro

Allen

Neely

2011

Infect Immun

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The ability of a pathogen to metabolically adapt to the local environment for optimal expression of virulence determinants is a continued area of research. Orthologs of the Streptococcus iniae LysR family regulator CpsY have been shown to regulate methionine biosynthesis and uptake pathways but appear to influence expression of several virulence genes as well. An S. iniae mutant with an in-frame deletion of cpsY (⌬cpsY mutant) is highly attenuated in a zebrafish infection model. The ⌬cpsY mutant displays a methionine-independent growth defect in serum, which differs from the methionine-dependent defect observed for orthologous mutants of Streptococcus mutans and Streptococcus agalactiae. On the contrary, the ⌬cpsY mutant can grow in excess of the wild type (WT) when supplemented with proteose peptone, suggesting an inability to properly regulate growth. CpsY is critical for protection of S. iniae from clearance by neutrophils in whole blood but is dispensable for intracellular survival in macrophages. Susceptibility of the ⌬cpsY mutant to killing in whole blood is not due to a growth defect, because inhibition of neutrophil phagocytosis rescues the mutant to WT levels. Thus, CpsY appears to have a pleiotropic regulatory role for S. iniae, integrating metabolism and virulence. Furthermore, S. iniae provides a unique model to investigate the paradigm of CpsY-dependent regulation during systemic streptococcal infection.Our understanding of the diverse repertoire of transcriptional signaling networks that orchestrate optimal expression of virulence genes dependent upon the metabolic status of the cell is quickly expanding (49,60). Metabolic adaptations to the various environments encountered by a pathogen within a host prove to be tremendously complex (14). Recent work on streptococcal pathogens has revealed components of these regulatory pathways that relate the nutritional status of the cell to the control of growth phase and expression of virulence genes (1,21,23,24,36,40,51).Streptococcus iniae is a major aquatic pathogen (15, 16) that causes an invasive systemic infection with severe bacteremia culminating in meningoencephalitis (2). Many instances of zoonoses have been reported as a result of handling infected fish, which typically results in a bacteremic cellulitis (17,28,56). The severity of an S. iniae infection is due in part to the ability to rapidly disseminate from the site of infection through the bloodstream and invade systemic tissues (34).The complex pathogenicity of S. iniae, and other systemic streptococcal pathogens, is reflected in the diversity of genes that are critical to a successful infection (3,22,55). Several classical streptococcal virulence factors have been shown to be important for the virulence of S. iniae, including the SivS/Rregulated streptolysin S (sagA) and CAMP factor (cfi) (4, 31), as well as the major surface M protein (siM) (30). S. iniae also contains a polysaccharide capsule that functions for protection from phagocytic clearance in whole blood (32,34,39). Furthermore, sev...

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Global transcriptional profiling reveals Streptococcus agalactiae genes controlled by the MtaR transcription factor

Cited by 24 publications

References 41 publications

The Transcriptional Regulator CpsY Is Important for Innate Immune Evasion in Streptococcus pyogenes

The Transcriptional Regulator CpsY Is Important for Innate Immune Evasion in Streptococcus pyogenes

Three Paralogous LysR-Type Transcriptional Regulators Control Sulfur Amino Acid Supply in Streptococcus mutans

The Streptococcus iniae Transcriptional Regulator CpsY Is Required for Protection from Neutrophil-Mediated Killing and Proper Growth In Vitro

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