Streptococcus pyogenes in Human Plasma

Malmström, Johan; Karlsson, Christofer; Nordenfelt, Pontus; Ossola, Reto; Weisser, Hendrik; Quandt, Andreas; Hansson, Karin; Aebersold, Ruedi; Malmström, Lars; Björck, Lars

doi:10.1074/jbc.m111.267674

Cited by 39 publications

(39 citation statements)

References 51 publications

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“…Subsequent in silico analyses of protein DG12 (or the S. canis ' protein G homolog, respectively) revealed the presence of the GA modules facilitating albumin-binding in protein G, but also a complete lack of the C-terminal C repeats which mediate IgG-Fc binding. Maintaining albumin-binding activity might be advantageous for S. canis , since it promotes acquisition and uptake of nutrients, such as fatty acids (Malmström et al, 2012), but also facilitates antibacterial activity by interacting with the chemokine MIG/CXCL9 (Egesten et al, 2011). However, the question as to why S. canis has lost one of its Fc receptors crucial for colonization of mucosal surfaces, is beyond the scope of this study.…”

Section: Discussionmentioning

confidence: 99%

SCM, the M Protein of Streptococcus canis Binds Immunoglobulin G

Bergmann

Eichhorn

Kohler

et al. 2017

Front. Cell. Infect. Microbiol.

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The M protein of Streptococcus canis (SCM) is a virulence factor and serves as a surface-associated receptor with a particular affinity for mini-plasminogen, a cleavage product of the broad-spectrum serine protease plasmin. Here, we report that SCM has an additional high-affinity immunoglobulin G (IgG) binding activity. The ability of a particular S. canis isolate to bind to IgG significantly correlates with a scm-positive phenotype, suggesting a dominant role of SCM as an IgG receptor. Subsequent heterologous expression of SCM in non-IgG binding S. gordonii and Western Blot analysis with purified recombinant SCM proteins confirmed its IgG receptor function. As expected for a zoonotic agent, the SCM-IgG interaction is species-unspecific, with a particular affinity of SCM for IgGs derived from human, cats, dogs, horses, mice, and rabbits, but not from cows and goats. Similar to other streptococcal IgG-binding proteins, the interaction between SCM and IgG occurs via the conserved Fc domain and is, therefore, non-opsonic. Interestingly, the interaction between SCM and IgG-Fc on the bacterial surface specifically prevents opsonization by C1q, which might constitute another anti-phagocytic mechanism of SCM. Extensive binding analyses with a variety of different truncated SCM fragments defined a region of 52 amino acids located in the central part of the mature SCM protein which is important for IgG binding. This binding region is highly conserved among SCM proteins derived from different S. canis isolates but differs significantly from IgG-Fc receptors of S. pyogenes and S. dysgalactiae sub. equisimilis, respectively. In summary, we present an additional role of SCM in the pathogen-host interaction of S. canis. The detailed analysis of the SCM-IgG interaction should contribute to a better understanding of the complex roles of M proteins in streptococcal pathogenesis.

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Section: Discussionmentioning

confidence: 99%

SCM, the M Protein of Streptococcus canis Binds Immunoglobulin G

Bergmann

Eichhorn

Kohler

et al. 2017

Front. Cell. Infect. Microbiol.

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“…Protein digestion was carried out as previously described [37]. The resulting peptide mixtures were concentrated using spin-columns from Harvard Apparatus using the manufactures' instructions.…”

Section: Methodsmentioning

confidence: 99%

A Novel Role for Pro-Coagulant Microvesicles in the Early Host Defense against Streptococcus pyogenes

et al. 2013

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Previous studies have shown that stimulation of whole blood or peripheral blood mononuclear cells with bacterial virulence factors results in the sequestration of pro-coagulant microvesicles (MVs). These particles explore their clotting activity via the extrinsic and intrinsic pathway of coagulation; however, their pathophysiological role in infectious diseases remains enigmatic. Here we describe that the interaction of pro-coagulant MVs with bacteria of the species Streptococcus pyogenes is part of the early immune response to the invading pathogen. As shown by negative staining electron microscopy and clotting assays, pro-coagulant MVs bind in the presence of plasma to the bacterial surface. Fibrinogen was identified as a linker that, through binding to the M1 protein of S. pyogenes, allows the opsonization of the bacteria by MVs. Surface plasmon resonance analysis revealed a strong interaction between pro-coagulant MVs and fibrinogen with a KD value in the nanomolar range. When performing a mass-spectrometry-based strategy to determine the protein quantity, a significant up-regulation of the fibrinogen-binding integrins CD18 and CD11b on pro-coagulant MVs was recorded. Finally we show that plasma clots induced by pro-coagulant MVs are able to prevent bacterial dissemination and possess antimicrobial activity. These findings were confirmed by in vivo experiments, as local treatment with pro-coagulant MVs dampens bacterial spreading to other organs and improved survival in an invasive streptococcal mouse model of infection. Taken together, our data implicate that pro-coagulant MVs play an important role in the early response of the innate immune system in infectious diseases.

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“…S5 in the supplemental material). Pyrimidine and purine bases and nucleosides are either unavailable or at very low concentrations as exogenous nutrients (40,41), especially in human plasma, where S. pyogenes increases the de novo synthesis of both pyrimidines and purines (42). Spy_0687 (mvaS1) and Spy_0686 (mvaA), which encode HMG-coenzyme A (CoA) synthase and HMG-CoA reductase, two enzymes that control entry points to the mevalonate pathway, were upregulated in the fabT deletion mutant by Ͼ1.7-fold during the stationary phase.…”

Section: Identification Of Acquired Polymorphisms In Serotype M1 Stramentioning

confidence: 99%

Genomic Landscape of Intrahost Variation in Group A Streptococcus: Repeated and Abundant Mutational Inactivation of the fabT Gene Encoding a Regulator of Fatty Acid Synthesis

et al. 2016

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dTo obtain new information about Streptococcus pyogenes intrahost genetic variation during invasive infection, we sequenced the genomes of 2,954 serotype M1 strains recovered from a nonhuman primate experimental model of necrotizing fasciitis. A total of 644 strains (21.8%) acquired polymorphisms relative to the input parental strain. The fabT gene, encoding a transcriptional regulator of fatty acid biosynthesis genes, contained 54.5% of these changes. The great majority of polymorphisms were predicted to deleteriously alter FabT function. Transcriptome-sequencing (RNA-seq) analysis of a wild-type strain and an isogenic fabT deletion mutant strain found that between 3.7 and 28.5% of the S. pyogenes transcripts were differentially expressed, depending on the growth temperature (35°C or 40°C) and growth phase (mid-exponential or stationary phase). Genes implicated in fatty acid synthesis and lipid metabolism were significantly upregulated in the fabT deletion mutant strain. FabT also directly or indirectly regulated central carbon metabolism genes, including pyruvate hub enzymes and fermentation pathways and virulence genes. Deletion of fabT decreased virulence in a nonhuman primate model of necrotizing fasciitis. In addition, the fabT deletion strain had significantly decreased survival in human whole blood and during phagocytic interaction with polymorphonuclear leukocytes ex vivo. We conclude that FabT mutant progeny arise during infection, constitute a metabolically distinct subpopulation, and are less virulent in the experimental models used here. Streptococcus pyogenes is a Gram-positive bacterium that causes a range of diseases in humans, including pharyngitis, superficial and deep skin infections, acute rheumatic fever, poststreptococcal glomerulonephritis, bacteremia, and necrotizing fasciitis ("flesh-eating disease") (1, 2). Globally, there are over 700 million group A streptococcus (GAS) infections annually (3). It has been estimated that 9,000 to 11,500 cases of invasive GAS disease occur each year in the United States, resulting in 1,000 to 1,800 deaths annually (4; http://www.cdc.gov). Rheumatic fever, necrotizing fasciitis, and toxic shock syndrome are responsible for the high morbidity and mortality rates due to GAS infections (5).Advances in DNA sequencing and related technologies have facilitated genome-wide dissection of genetic events involved in colonization (6), immune evasion (7), virulence (8-10), and the evolution and spread of highly virulent S. pyogenes clones (11-13). To advance our understanding of S. pyogenes molecular-pathogenesis events occurring during invasive infection, we performed whole-genome sequencing of 2,954 isolates recovered from a nonhuman primate model of necrotizing fasciitis. The resulting genome sequence data stimulated us to construct an isogenic fabT deletion mutant strain and to compare its global transcriptome and virulence attributes with those of the wild-type parental strain. MATERIALS AND METHODSBacterial strains and growth conditions. Escherichia coli strai...

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Streptococcus pyogenes in Human Plasma

Cited by 39 publications

References 51 publications

SCM, the M Protein of Streptococcus canis Binds Immunoglobulin G

SCM, the M Protein of Streptococcus canis Binds Immunoglobulin G

A Novel Role for Pro-Coagulant Microvesicles in the Early Host Defense against Streptococcus pyogenes

Genomic Landscape of Intrahost Variation in Group A Streptococcus: Repeated and Abundant Mutational Inactivation of the fabT Gene Encoding a Regulator of Fatty Acid Synthesis

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