Dataset Information

Immunoglobulin Attenuates Streptokinase-Mediated Virulence in Streptococcus dysgalactiae Subspecies equisimilis Necrotizing Fasciitis.

ABSTRACT: Background:Necrotizing fasciitis (NF) retains a very high mortality rate despite prompt and adequate antibiotic treatment and surgical debridement. Necrotizing fasciitis has recently been associated with Streptococcus dysgalactiae subspecies equisimilis (SDSE). Methods:We investigated the causes of a very severe clinical manifestation of SDSE-NF by assessing both host and pathogen factors. Results:We found a lack of streptokinase-function blocking antibodies in the patient resulting in increased streptokinase-mediated fibrinolysis and bacterial spread. At the same time, the clinical SDSE isolate produced very high levels of streptokinase. Exogenous immunoglobulin Gs (ex-IgGs) efficiently blocked streptokinase-mediated fibrinolysis in vitro, indicating a protective role against the action of streptokinase. In vivo, SDSE infection severity was also attenuated by ex-IgGs in a NF mouse model. Conclusions:These findings illustrate for the first time that the lack of specific antibodies against streptococcal virulence factors, such as streptokinase, may contribute to NF disease severity. This can be counteracted by ex-IgGs.

SUBMITTER: Andreoni F

PROVIDER: S-EPMC7263839 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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Immunoglobulin Attenuates Streptokinase-Mediated Virulence in Streptococcus dysgalactiae Subspecies equisimilis Necrotizing Fasciitis.

Andreoni Federica F Ugolini Fabio F Keller Nadia N Neff Andrina A Nizet Victor V Hollands Andrew A Marques Maggio Ewerton E Zinkernagel Annelies S AS Schuepbach Reto A RA

The Journal of infectious diseases 20180101 2

<h4>Background</h4>Necrotizing fasciitis (NF) retains a very high mortality rate despite prompt and adequate antibiotic treatment and surgical debridement. Necrotizing fasciitis has recently been associated with Streptococcus dysgalactiae subspecies equisimilis (SDSE).<h4>Methods</h4>We investigated the causes of a very severe clinical manifestation of SDSE-NF by assessing both host and pathogen factors.<h4>Results</h4>We found a lack of streptokinase-function blocking antibodies in the patient ...[more]

PMID: 29099935

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Project description:BACKGROUND:During the past decades, Streptococcus dysgalactiae subspecies equisimilis (SDSE) has been increasingly recognized as an important human pathogen. Osteoarticular infections is one of the predominant disease manifestations of SDSE, but the pathogenetic rationale for its arthritogenicity has yet to be unravelled. We aimed to explore if the rising incidence of osteoarticular infections caused by this pathogen in our region emanated from clonal expansion of strains with enhanced tropism for bone and joint tissue components or orthopaedic implants. RESULTS:Twenty-nine SDSE-isolates associated with osteoarticular infections were retrospectively identified. Their genomic content and affinity for fibronectin, collagen and stainless steel were compared to 24 temporally and geographically matched SDSE blood culture isolates obtained from patients without bone or joint infections. Despite a thorough genetic and phenotypic dissection, neither the presence or absence of any single gene, nor the binding abilities of the SDSE isolates, were predictive of clinical entity. SNP analysis revealed a heterogenous population, and a correlation between phylogenetic relationships and disease manifestation was not evident. However, we identified a strong concordance between phenotypic binding abilities and genetic variations in the pilus-region, also denoted as the FCT-region (Fibronectin binding, Collagen binding and T-antigen). This observation could be related to the ample and varied repertoire of putative adhesins residing within this region, including proteins predicted to adhere to fibronectin and collagen, as well as fibrinogen. CONCLUSIONS:SDSE strains associated with osteoarticular infections do not emanate from subpopulation characterized by distinct genetic or phenotypic traits. The genetic architecture of the pilus region was predictive of the adhesive properties of the SDSE-isolates, but its role in tissue tropism needs further investigation. To the best of our knowledge, this is the first comprehensive characterization of the genetic landscape of the SDSE pilus region.

Project description:Streptococcus dysgalactiae subsp. equisimilis is a bacterial pathogen that is increasingly recognized as a cause of severe human infections. Much less is known about the genomics and infection pathogenesis of S. dysgalactiae subsp. equisimilis strains compared to the closely related bacterium Streptococcus pyogenes. To address these knowledge deficits, we sequenced to closure the genomes of seven S. dysgalactiae subsp. equisimilis human isolates, including six that were emm type stG62647. Recently, for unknown reasons, strains of this emm type have emerged and caused an increasing number of severe human infections in several countries. The genomes of these seven strains vary between 2.15 and 2.21 Mbp. The core chromosomes of these six S. dysgalactiae subsp. equisimilis stG62647 strains are closely related, differing on average by only 495 single-nucleotide polymorphisms, consistent with a recent descent from a common progenitor. The largest source of genetic diversity among these seven isolates is differences in putative mobile genetic elements, both chromosomal and extrachromosomal. Consistent with the epidemiological observations of increased frequency and severity of infections, both stG62647 strains studied were significantly more virulent than a strain of emm type stC74a in a mouse model of necrotizing myositis, as assessed by bacterial CFU burden, lesion size, and survival curves. Taken together, our genomic and pathogenesis data show the strains of emm type stG62647 we studied are closely genetically related and have enhanced virulence in a mouse model of severe invasive disease. Our findings underscore the need for expanded study of the genomics and molecular pathogenesis of S. dysgalactiae subsp. equisimilis strains causing human infections. IMPORTANCE Our studies addressed a critical knowledge gap in understanding the genomics and virulence of the bacterial pathogen Streptococcus dysgalactiae subsp. equisimilis. S. dysgalactiae subsp. equisimilis strains are responsible for a recent increase in severe human infections in some countries. We determined that certain S. dysgalactiae subsp. equisimilis strains are genetically descended from a common ancestor and that these strains can cause severe infections in a mouse model of necrotizing myositis. Our findings highlight the need for expanded studies on the genomics and pathogenic mechanisms of this understudied subspecies of the Streptococcus family.

Project description:Synthesis of the plasminogen activator streptokinase (SK) by group A streptococci (GAS) has recently been shown to be subject to control by two two-component regulators, covRS (or csrRS) and fasBCA. In independent studies, response regulator CovR proved to act as the repressor, whereas FasA was found to act indirectly as the activator by controlling the expression of a stimulatory RNA, fasX. In an attempt at understanding the regulation of SK production in the human group C streptococcal (GCS) strain H46A, the strongest SK producer known yet, we provide here physical and functional evidence for the presence of the cov and fas systems in GCS as well and, using a mutational approach, compare the balance between their opposing actions in H46A and GAS strain NZ131. Sequence analysis combined with Southern hybridization revealed that the covRS and fasCAX operons are preserved at high levels of primary structure identity between the corresponding GAS and GCS genes, with the exception of fasB, encoding a second sensor kinase that is not a member of the GCS fas operon. This analysis also showed that wild-type H46A is actually a derepressed mutant for SK and streptolysin S (SLS) synthesis, carrying a K102 amber mutation in covR. Using cov and fas mutations in various combinations together with strain constructs allowing complementation in trans, we found that, in H46A, cov and fas contribute to approximately equal negative and positive extents, respectively, to constitutive SK and SLS activity. The amounts of SK paralleled the level of skc(H46A) transcription. The most profound difference between H46A and NZ131 regarding the relative activities of the cov and fas systems consisted in significantly higher activity of a functional CovR repressor in NZ131 than in H46A. In NZ131, CovR decreased SK activity in a Fas(+) background about sevenfold, compared to a 1.9-fold reduction of SK activity in H46A. Combined with the very short-lived nature of covR mRNA (decay rate, 1.39/min), such differences may contribute to strain-specific peculiarities of the expression of two prominent streptococcal virulence factors in response to environmental changes.

Dataset Information

Immunoglobulin Attenuates Streptokinase-Mediated Virulence in Streptococcus dysgalactiae Subspecies equisimilis Necrotizing Fasciitis.

Publications

Immunoglobulin Attenuates Streptokinase-Mediated Virulence in Streptococcus dysgalactiae Subspecies equisimilis Necrotizing Fasciitis.

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