Mg<sup>2+</sup> signalling defines the group A streptococcal CsrRS (CovRS) regulon

Gryllos, Ioannis; Grifantini, Renata; Colaprico, Annalisa; Jiang, Sheng-Mei; DeForce, Emelia; Håkansson, Anders P.; Telford, John L.; Grandi, Guido; Wessels, Michael R.

doi:10.1111/j.1365-2958.2007.05818.x

Cited by 73 publications

(116 citation statements)

References 51 publications

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“…The expression of various virulence factors produced by S. pyogenes is enhanced by the CovRS two-component system signal transduction pathway under various stress conditions, including the low level of pH, the host antimicrobial peptide LL-37, and a low concentration of extracellular Mg 2ϩ (45)(46)(47)(48)(49). In addition, pepO gene expression has been demonstrated to be negatively regulated by CovRS (17).…”

Section: Discussionmentioning

confidence: 99%

Streptococcus pyogenes Endopeptidase O Contributes to Evasion from Complement-mediated Bacteriolysis via Binding to Human Complement Factor C1q

Honda-Ogawa

Sumitomo

Mori

et al. 2017

Journal of Biological Chemistry

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Edited by Luke O'NeillStreptococcus pyogenes secretes various virulence factors for evasion from complement-mediated bacteriolysis. However, full understanding of the molecules possessed by this organism that interact with complement C1q, an initiator of the classical complement pathway, remains elusive. In this study, we identified an endopeptidase of S. pyogenes, PepO, as an interacting molecule, and investigated its effects on complement immunity and pathogenesis. Enzyme-linked immunosorbent assay and surface plasmon resonance analysis findings revealed that S. pyogenes recombinant PepO bound to human C1q in a concentration-dependent manner under physiological conditions. Sites of inflammation are known to have decreased pH levels, thus the effects of PepO on bacterial evasion from complement immunity was analyzed in a low pH condition. Notably, under low pH conditions, PepO exhibited a higher affinity for C1q as compared with IgG, and PepO inhibited the binding of IgG to C1q. In addition, pepO deletion rendered S. pyogenes more susceptible to the bacteriocidal activity of human serum. Also, observations of the morphological features of the pepO mutant strain (⌬pepO) showed damaged irregular surfaces as compared with the wild-type strain (WT). WT-infected tissues exhibited greater severity and lower complement activity as compared with those infected by ⌬pepO in a mouse skin infection model. Furthermore, WT infection resulted in a larger accumulation of C1q than that with ⌬pepO. Our results suggest that interaction of S. pyogenes PepO with C1q interferes with the complement pathway, which enables S. pyogenes to evade complement-mediated bacteriolysis under acidic conditions, such as seen in inflammatory sites.The human pathogen Streptococcus pyogenes is a ␤-hemolytic Gram-positive bacterium that causes a wide variety of diseases in various anatomical sites. Superficial infection of S. pyogenes generally leads to local suppurative lesions, such as seen in pharyngitis and impetigo cases. Such mucosal and skin infections are occasionally followed by onset of immune sequelae, including acute rheumatic fever and acute glomerulonephritis. Furthermore, S. pyogenes infection can also cause invasive diseases, such as necrotizing fasciitis, cellulitis, bacteremia, and streptococcal toxic shock syndrome (STSS), 2 with a high mortality rate, which has been a serious problem throughout the world (1-3).Host possesses various immune systems such as the complement system, one of the most important components of innate immunity, that contributes to host defense against pathogens, especially in the early stage of infection (4). Recognition of an invading pathogen is the trigger for complement pathway activation, and then each complement factor is activated in a sequential manner with precise control (5). Together with opsonization, complement-mediated direct killing of pathogens is attributable to formation of the membrane attack complex (MAC), which consists of late complement factors and induces bacteriolysis by pore formati...

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Section: Discussionmentioning

confidence: 99%

Streptococcus pyogenes Endopeptidase O Contributes to Evasion from Complement-mediated Bacteriolysis via Binding to Human Complement Factor C1q

Honda-Ogawa

Sumitomo

Mori

et al. 2017

Journal of Biological Chemistry

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“…Regulation of MgtE in response to Mg 2ϩ via a riboswitch has been demonstrated in Bacillus subtilis (8); however, there is no homologue present in S. pneumoniae. Furthermore, in Streptococcus pyogenes, a two-component system, CsrRS (CovRS), has been reported to respond to external Mg 2ϩ concentrations (19,20). However, so far no transporters in this organism have been characterized.…”

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Deletion of a Cation Transporter Promotes Lysis in Streptococcus pneumoniae

et al. 2011

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Streptococcus pneumoniae is a significant human pathogen which causes respiratory and serious invasive diseases. Mg 2؉ is essential for life, and its concentration varies throughout the human body. Magnesium uptake plays an important role in the virulence of many bacterial pathogens. To study the Mg 2؉ uptake of S. pneumoniae strain D39, a mutant was generated in SPD1383, a P-type ATPase with homology to the Salmonella Mg 2؉ transporter MgtA, which has also been shown to be a Ca 2؉ exporter in strain TIGR4. Under low-Ca 2؉ conditions, mutation led to a growth defect in complex medium and the gene was nearly essential for growth under low-Mg 2؉ conditions. Addition of Mg 2؉ restored the normal growth of the mutant in all cases, but the addition of other divalent cations had no effect. Addition of Ca 2؉ , Mn 2؉ , and Zn 2؉ in the presence of high Mg 2؉ concentrations inhibited restoration of growth. The mutant was unable to proliferate in blood, which was also alleviated by the addition of Mg 2؉ . The protein was located in the membrane and produced in various S. pneumoniae strains and pathogenic streptococcal species. Surprisingly, mutation of the gene led to an elevated toxicity for endothelial cells. This was caused by an increased amount of pneumolysin in the medium, mediated by elevated lysis of the mutant. Thus, in this study, we uncovered a role for SPD1383 in Mg 2؉ uptake and hypothesize that the protein is a Mg 2؉/ Ca 2؉ antiporter. Furthermore, a disturbance in Mg 2؉ homeostasis seems to promote lysis of S. pneumoniae.

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“…In group A Streptococcus (Streptococcus pyogenes, or GAS), CsrRS is a major global regulatory system that can repress as many as 15% of chromosomal genes, including a number of surface-associated and secreted proteins that mediate virulence and host-pathogen interactions (3,16,18,33,39). Mg 2ϩ and the human cathelicidin antimicrobial peptide LL-37 have been identified as opposing signals that act through CsrS to regulate an extensive repertoire of GAS genes (17,(20)(21)(22). An orthologue of the CsrRS system has been identified in GBS (27,31).…”

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confidence: 99%

CsrRS Regulates Group BStreptococcusVirulence Gene Expression in Response to Environmental pH: a New Perspective on Vaccine Development

et al. 2009

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To identify factors involved in the response of group B streptococci (GBS) to environmental pH, we performed a comparative global gene expression analysis of GBS at acidic and neutral pHs. We found that the transcription of 317 genes was increased at pH 5.5 relative to that at pH 7.0, while 61 genes were downregulated. The global response to acid stress included the differential expression of genes involved in transport, metabolism, stress response, and virulence. Known vaccine candidates, such as BibA and pilus components, were also regulated by pH. We observed that many of the genes involved in the GBS response to pH are known to be controlled by the CsrRS two-component system. Comparison of the regulon of wild-type strain 2603 V/R with that of a csrRS deletion mutant strain revealed that the pH-dependent regulation of 90% of the downregulated genes and 59.3% of the up-regulated genes in strain 2603 V/R was CsrRS dependent and that many virulence factors were overexpressed at high pH. Beta-hemolysin regulation was abrogated by selective inactivation of csrS, suggesting the implication of the CsrS protein in pH sensing. These results imply that the translocation of GBS from the acidic milieu of the vagina to the neutral pH of the neonatal lung signals the up-regulation of GBS virulence factors and conversion from a colonizing to an invasive phenotype. In addition, the fact that increased exposure of BibA on the bacterial surface at pH 7.0 induced opsonophagocytic killing of GBS in immune serum highlights the importance of pH regulation in the protective efficacy of specific antibodies to surface-exposed GBS proteins.

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Mg²⁺ signalling defines the group A streptococcal CsrRS (CovRS) regulon

Cited by 73 publications

References 51 publications

Streptococcus pyogenes Endopeptidase O Contributes to Evasion from Complement-mediated Bacteriolysis via Binding to Human Complement Factor C1q

Streptococcus pyogenes Endopeptidase O Contributes to Evasion from Complement-mediated Bacteriolysis via Binding to Human Complement Factor C1q

Deletion of a Cation Transporter Promotes Lysis in Streptococcus pneumoniae

CsrRS Regulates Group BStreptococcusVirulence Gene Expression in Response to Environmental pH: a New Perspective on Vaccine Development

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Mg2+ signalling defines the group A streptococcal CsrRS (CovRS) regulon

Cited by 73 publications

References 51 publications

Streptococcus pyogenes Endopeptidase O Contributes to Evasion from Complement-mediated Bacteriolysis via Binding to Human Complement Factor C1q

Streptococcus pyogenes Endopeptidase O Contributes to Evasion from Complement-mediated Bacteriolysis via Binding to Human Complement Factor C1q

Deletion of a Cation Transporter Promotes Lysis in Streptococcus pneumoniae

CsrRS Regulates Group BStreptococcusVirulence Gene Expression in Response to Environmental pH: a New Perspective on Vaccine Development

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Mg²⁺ signalling defines the group A streptococcal CsrRS (CovRS) regulon