scholarly journals Streptolysin O concentration and activity is central to in vivo phenotype and disease outcome in Group A Streptococcus infection

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Jenny Clarke ◽  
Murielle Baltazar ◽  
Mansoor Alsahag ◽  
Stavros Panagiotou ◽  
Marion Pouget ◽  
...  
Keyword(s):  
Septic Arthritis ◽  
Rapid Development ◽  
Clinical Manifestations ◽  
Disease Outcome ◽  
Haemolytic Activity ◽  
Human Pathogens ◽  
Streptolysin O ◽  
Group A

AbstractGroup A Streptoccocus (GAS) is among the most diverse of all human pathogens, responsible for a range of clinical manifestations, from mild superficial infections such as pharyngitis to serious invasive infections such as necrotising fasciitis and sepsis. The drivers of these different disease phenotypes are not known. The GAS cholesterol-dependent cytolysin, Streptolysin O (SLO), has well established cell and tissue destructive activity. We investigated the role of SLO in determining disease outcome in vivo, by using two different clinical lineages; the recently emerged hypervirulent outbreak emm type 32.2 strains, which result in sepsis, and the emm type 1.0 strains which cause septic arthritis. Using clinically relevant in vivo mouse models of sepsis and a novel septic arthritis model, we found that the amount and activity of SLO was vital in determining the course of infection. The emm type 32.2 strain produced large quantities of highly haemolytic SLO that resulted in rapid development of sepsis. By contrast, the reduced concentration and lower haemolytic activity of emm type 1.0 SLO led to translocation of bacteria from blood to joints. Importantly, sepsis associated strains that were attenuated by deletion or inhibition of SLO, then also translocated to the joint, confirming the key role of SLO in determining infection niche. Our findings demonstrate that SLO is key to in vivo phenotype and disease outcome. Careful consideration should be given to novel therapy or vaccination strategies that target SLO. Whilst neutralising SLO activity may reduce severe invasive disease, it has the potential to promote chronic inflammatory conditions such as septic arthritis.

scholarly journals Streptolysin production and activity is central toin vivopathotype and disease outcome in GAS infections

2019 ◽  
Author(s):  
Jenny Clarke ◽  
Murielle Baltazar ◽  
Mansoor Alsahag ◽  
Stavros Panagiotou ◽  
Marion Pouget ◽  
...  
Keyword(s):  
Septic Arthritis ◽  
Rapid Development ◽  
Clinical Manifestations ◽  
Careful Consideration ◽  
Disease Outcome ◽  
Haemolytic Activity ◽  
Human Pathogens ◽  
Novel Therapy

AbstractStreptococcus pyogenes (GAS) is among the most diverse of all human pathogens, responsible for a range of clinical manifestations, from mild superficial infections such as pharyngitis to serious invasive infections such as necrotising fasciitis and sepsis. The drivers of these different disease phenotypes are not known. The GAS cholesterol-dependent cytolysin, streptolysin O (SLO), has well established cell and tissue destructive activity. We investigated the role of SLO in determining disease outcomein vivo, by using two different clinical lineages; the recently emerged hypervirulent outbreakemmtype 32.2 strains, which result in sepsis, and theemmtype 1.0 strains which cause septic arthritis. Using clinically relevantin vivomouse models of sepsis and a novel septic arthritis model, we demonstrated that the amount and activity of SLO is vital in determining the pathotype of infection. Theemm32.2 strain produced large quantities of highly haemolytic SLO that resulted in rapid development of sepsis. By contrast, the lower levels and haemolytic activity ofemm1.0 SLO led to translocation of bacteria to joints. Importantly, sepsis associated strains that were attenuated by deletion or inhibition of SLO also translocated to the joint, confirming the key role of SLO in determining infection niche. Our findings demonstrate that SLO is key toin vivopathotype and disease outcome. Careful consideration should be given to novel therapy or vaccination strategies that target SLO. Whilst neutralising SLO activity may reduce severe invasive disease, it has the potential to promote chronic inflammatory conditions such as septic arthritis.

scholarly journals Role of NADase in Virulence in Experimental Invasive Group A Streptococcal Infection

2005 ◽  
Vol 73 (10) ◽  
pp. 6562-6566 ◽  
Author(s):  
Angela L. Bricker ◽  
Vincent J. Carey ◽  
Michael R. Wessels
Keyword(s):  
Human Infection ◽  
Host Animal ◽  
Cytotoxic Effects ◽  
Invasive Group ◽  
Streptolysin O ◽  
Group A ◽  
Wild Type Parent

ABSTRACT Group A streptococci (GAS) produce several exoproteins that are thought to contribute to the pathogenesis of human infection. Two such proteins, streptolysin O (SLO) and NAD+-glycohydrolase (NADase), have been shown to interact functionally as a compound signaling toxin. When GAS are bound to the surface of epithelial cells in vitro, SLO forms pores in the cell membrane and delivers NADase to the epithelial cell cytoplasm. In vitro, intoxication of keratinocytes with NADase is associated with cytotoxic effects and induction of apoptosis; however, the importance of NADase during infection of an animal host has not been established. We employed isogenic GAS mutants to assess the contribution of NADase activity to GAS virulence in vivo using mouse models of invasive soft-tissue infection and septicemia. In both models, mutant GAS that lacked NADase activity were significantly attenuated for virulence compared with the isogenic wild-type parent, confirming an important role for NADase in the infection of a host animal. A double mutant lacking SLO and NADase activity had an intermediate virulence phenotype, consistent with the hypothesis that SLO evokes a protective innate immune response. We conclude that NADase and SLO together enhance GAS virulence in vivo.

scholarly journals Downregulation of S100A4 Alleviates Cardiac Fibrosis via Wnt/β -Catenin Pathway in Mice

2018 ◽  
Vol 46 (6) ◽  
pp. 2551-2560 ◽  
Author(s):  
LiJun Qian ◽  
Jian Hong ◽  
YanMei Zhang ◽  
MengLin Zhu ◽  
XinChun Wang ◽  
...  
Keyword(s):  
Calcium Binding ◽  
Cardiac Fibrosis ◽  
Cardiac Fibroblasts ◽  
Group A ◽  
Ischemic Diseases ◽  
Fibrotic Diseases ◽  
Signaling Activation

Background/Aims: Cardiac fibrosis is a pathological change leading to cardiac remodeling during the progression of myocardial ischemic diseases, and its therapeutic strategy remains to be explored. S100A4, a calcium-binding protein, participates in fibrotic diseases with an unclear mechanism. This study aimed to investigate the role of S100A4 in cardiac fibrosis. Methods: Cardiac fibroblasts from neonatal C57BL/6 mouse hearts were isolated and cultured. Myocardial infarction was induced by ligating the left anterior descending coronary artery (LAD). The ligation was not performed in the sham group. A volume of 5×105pfu/g adenovirus or 5 µM/g ICG-001 was intramyocardially injected into five parts bordering the infarction zone or normal region. We used Western blotting, quantitative RT-PCR, immunofluorescence, immunohistochemistry and Masson’s trichrome staining to explore the function of S100A4. Results: We found significant increases of S100A4 level and cardiac fibrosis markers, and β-catenin signaling activation in vitro and in vivo. In addition, knockdown of S100A4 significantly reduced cardiac fibrosis and β-catenin levels. Moreover, the expression of S100A4 decreased after ICG-001 inhibited β-catenin signal pathway. Conclusion: Downregulation of S100A4 alleviates cardiac fibrosis via Wnt/β -catenin pathway in mice. S100A4 may be a therapeutic target of cardiac fibrosis.

Role of Streptolysin O in a Mouse Model of Invasive Group A Streptococcal Disease

2000 ◽  
Vol 68 (11) ◽  
pp. 6384-6390 ◽  
Author(s):  
Brandi Limbago ◽  
Vikram Penumalli ◽  
Brian Weinrick ◽  
June R. Scott
Keyword(s):  
Mouse Model ◽  
Invasive Group ◽  
Streptococcal Disease ◽  
Streptolysin O ◽  
Group A

scholarly journals The Mga Regulon but Not Deoxyribonuclease Sda1 of Invasive M1T1 Group A Streptococcus Contributes toIn VivoSelection of CovRS Mutations and Resistance to Innate Immune Killing Mechanisms

2015 ◽  
Vol 83 (11) ◽  
pp. 4293-4303 ◽  
Author(s):  
Guanghui Liu ◽  
Wenchao Feng ◽  
Dengfeng Li ◽  
Mengyao Liu ◽  
Daniel C. Nelson ◽  
...  
Keyword(s):  
Group A Streptococcus ◽  
Regulatory System ◽  
Innate Immune ◽  
M Protein ◽  
Content Type ◽  
Group A ◽  
Innate Immune Evasion ◽  
Selection Of

ABSTRACTInvasive M1T1 group AStreptococcus(GAS) can have a mutation in the regulatory system CovRS, and this mutation can render strains hypervirulent. Interestingly, via mechanisms that are not well understood, the host innate immune system's neutrophils select spontaneous M1T1 GAS CovRS hypervirulent mutants, thereby enhancing the pathogen's ability to evade immune killing. It has been reported that the DNase Sda1 is critical for the resistance of M1T1 strain 5448 to killing in human blood and provides pressure forin vivoselection of CovRS mutations. We reexamined the role of Sda1 in the selection of CovRS mutations and in GAS innate immune evasion. Deletion ofsda1or all DNase genes in M1T1 strain MGAS2221 did not alter emergence of CovRS mutants during murine infection. Deletion ofsda1in strain 5448 resulted in Δsda1mutants with (5448 Δsda1M+strain) and without (5448 Δsda1M−strain) M protein production. The 5448 Δsda1M+strain accumulated CovRS mutationsin vivoand resisted killing in the bloodstream, whereas the 5448 Δsda1M−strain lostin vivoselection of CovRS mutations and was sensitive to killing. The deletion ofemmand a spontaneous Mga mutation in MGAS2221 reduced and preventedin vivoselection for CovRS mutants, respectively. Thus, in contrast to previous reports, Sda1 is not critical forin vivoselection of invasive M1T1 CovRS mutants and GAS resistance to innate immune killing mechanisms. In contrast, M protein and other Mga-regulated proteins contribute to thein vivoselection of M1T1 GAS CovRS mutants. These findings advance the understanding of the progression of invasive M1T1 GAS infections.

scholarly journals Streptolysin-induced endoplasmic reticulum stress promotes group A streptococcal in vivo biofilm formation and necrotizing fasciitis

2017 ◽  
Author(s):  
Anuradha Vajjala ◽  
Debabrata Biswas ◽  
Kelvin Kian Long Chong ◽  
Wei Hong Tay ◽  
Emanuel Hanski ◽  
...  
Keyword(s):  
Soft Tissue ◽  
Er Stress ◽  
Necrotizing Fasciitis ◽  
Biofilm Formation ◽  
Mammalian Cells ◽  
Chronic Infections ◽  
Group A

AbstractGroup A Streptococcus (GAS) is a human pathogen that causes infections ranging from mild to fulminant and life-threatening. Biofilms have been implicated in acute GAS soft-tissue infections such as necrotizing fasciitis (NF). However, most in vitro models used to study GAS biofilms have been designed to mimic chronic infections and insufficiently recapitulate in vivo conditions and the host-pathogen interactions that might influence biofilm formation. Here we establish and characterize an in vitro model of GAS biofilm development on mammalian cells that simulates microcolony formation observed in a murine model of human NF. We show that on mammalian cells, GAS forms dense aggregates that display hallmark biofilm characteristics including a three-dimensional architecture and enhanced tolerance to antibiotics. In contrast to abiotic-grown biofilms, host-associated biofilms require the expression of secreted GAS streptolysins O and S (SLO, SLS) resulting in the release of a host-associated biofilm promoting-factor(s). Supernatants from GAS-infected mammalian cells or from cells treated with endoplasmic reticulum (ER) stressors restore biofilm formation to an SLO and SLS null mutant that is otherwise attenuated in biofilm formation on cells, together suggesting a role for streptolysin-induced ER stress in this process. In an in vivo mouse model, the streptolysin-null mutant is attenuated in both microcolony formation and bacterial spread, but pre-treatment of softtissue with an ER-stressor restores the ability of the mutant to form wild type like microcolonies that disseminate throughout the soft tissue. Taken together, we have identified a new role of streptolysin-driven ER stress in GAS biofilm formation and NF disease progression.Significance StatementAlthough it is well-accepted that bacterial biofilms are associated with many chronic infections, little is known about the mechanisms by which group A Streptococcus (GAS) biofilms contribute to acute soft tissue-invasive diseases like necrotizing fasciitis (NF). In this study, we establish a physiologically relevant in vitro model to study GAS biofilm formation on mammalian cells and validate our findings in a mouse model that mimics human NF. This study demonstrates a novel role of GAS streptolysin-mediated ER stress in the development and spread of GAS biofilms in acute softtissue infections. We also show that biofilm formation depends on the release of a host-associated factor that promotes microcolony formation and GAS dissemination in vivo.

scholarly journals Mediator complex proximal Tail subunit MED30 is critical for Mediator core stability and cardiomyocyte transcriptional network

PLoS Genetics ◽  
2021 ◽  
Vol 17 (9) ◽  
pp. e1009785
Author(s):  
Changming Tan ◽  
Siting Zhu ◽  
Zee Chen ◽  
Canzhao Liu ◽  
Yang E. Li ◽  
...  
Keyword(s):  
Congenital Heart Defects ◽  
Congenital Heart ◽  
Heart Defects ◽  
Rapid Development ◽  
Core Stability ◽  
Mediator Complex ◽  
Transcriptional Networks ◽  
Adult Cardiomyocytes

Dysregulation of cardiac transcription programs has been identified in patients and families with heart failure, as well as those with morphological and functional forms of congenital heart defects. Mediator is a multi-subunit complex that plays a central role in transcription initiation by integrating regulatory signals from gene-specific transcriptional activators to RNA polymerase II (Pol II). Recently, Mediator subunit 30 (MED30), a metazoan specific Mediator subunit, has been associated with Langer-Giedion syndrome (LGS) Type II and Cornelia de Lange syndrome-4 (CDLS4), characterized by several abnormalities including congenital heart defects. A point mutation in MED30 has been identified in mouse and is associated with mitochondrial cardiomyopathy. Very recent structural analyses of Mediator revealed that MED30 localizes to the proximal Tail, anchoring Head and Tail modules, thus potentially influencing stability of the Mediator core. However, in vivo cellular and physiological roles of MED30 in maintaining Mediator core integrity remain to be tested. Here, we report that deletion of MED30 in embryonic or adult cardiomyocytes caused rapid development of cardiac defects and lethality. Importantly, cardiomyocyte specific ablation of MED30 destabilized Mediator core subunits, while the kinase module was preserved, demonstrating an essential role of MED30 in stability of the overall Mediator complex. RNAseq analyses of constitutive cardiomyocyte specific Med30 knockout (cKO) embryonic hearts and inducible cardiomyocyte specific Med30 knockout (icKO) adult cardiomyocytes further revealed critical transcription networks in cardiomyocytes controlled by Mediator. Taken together, our results demonstrated that MED30 is essential for Mediator stability and transcriptional networks in both developing and adult cardiomyocytes. Our results affirm the key role of proximal Tail modular subunits in maintaining core Mediator stability in vivo.

scholarly journals Pathogenetic Impact of Bacterial–Fungal Interactions

2019 ◽  
Vol 7 (10) ◽  
pp. 459 ◽  
Author(s):  
Filomena Nogueira ◽  
Shirin Sharghi ◽  
Karl Kuchler ◽  
Thomas Lion
Keyword(s):  
Immune System ◽  
Clinical Manifestations ◽  
Antimicrobial Treatment ◽  
Human Pathogens ◽  
Human Fungal Pathogen ◽  
Bacteria And Fungi ◽  
Fungal Interactions ◽  
The Impact

Polymicrobial infections are of paramount importance because of the potential severity of clinical manifestations, often associated with increased resistance to antimicrobial treatment. The intricate interplay with the host and the immune system, and the impact on microbiome imbalance, are of importance in this context. The equilibrium of microbiota in the human host is critical for preventing potential dysbiosis and the ensuing development of disease. Bacteria and fungi can communicate via signaling molecules, and produce metabolites and toxins capable of modulating the immune response or altering the efficacy of treatment. Most of the bacterial–fungal interactions described to date focus on the human fungal pathogen Candida albicans and different bacteria. In this review, we discuss more than twenty different bacterial–fungal interactions involving several clinically important human pathogens. The interactions, which can be synergistic or antagonistic, both in vitro and in vivo, are addressed with a focus on the quorum-sensing molecules produced, the response of the immune system, and the impact on clinical outcome.

scholarly journals In vitro and in vivo replication of influenza A H1N1 WSN33 viruses with different M1 proteins

2013 ◽  
Vol 94 (4) ◽  
pp. 884-895 ◽  
Author(s):  
Zhiguang Ran ◽  
Ying Chen ◽  
Huigang Shen ◽  
Xiaoxiao Xiang ◽  
Qinfang Liu ◽  
...  
Keyword(s):  
Influenza A ◽  
Cultured Cells ◽  
Important Determinant ◽  
Clinical Manifestations ◽  
Structural Protein ◽  
M1 Protein ◽  
Influenza A H1n1

The M1 protein is a major structural protein that has multiple functions in various steps within the life cycle of the influenza A virus (IAV). However, little is currently known about the role of M1 in IAV replication in vivo and the associated pathogenesis. In this study, six isogenic H1N1 WSN33 viruses, constructed to express unique M1 proteins derived from various strains, subtypes or WSN33 itself, were tested to determine in vitro and in vivo functional exchangeability of M1 proteins in the replication and pathogenesis of the WSN33 virus. Despite five chimeric M1 viruses replicating to levels similar to those of the parental WSN33 virus in cell cultures, all M1 chimeras exhibited improved replication and enhanced virulence in mice when compared with the WSN33 virus. Interestingly, M1 proteins derived from swine viruses caused more severe clinical diseases than those from human or quail. These data indicate that the M1 protein is an important determinant of viral replication and pathogenic properties in mice, although the functions of M1 observed in vivo are not adequately reflected in simple infections of cultured cells. Chimeric M1 viruses that are variable in their clinical manifestations described here will aid future understanding of the role of M1 in IAV pathogenesis.

Variable association of complement activation by rituximab and paclitaxel in cancer patients in vivo and in their screening serum in vitro with clinical manifestations of hypersensitivity: a pilot study

2015 ◽  
Vol 7 (4) ◽  
Author(s):  
Gergely Tibor Kozma ◽  
Tamás Mészáros ◽  
Zsóka Weiszhár ◽  
Tamás Schneider ◽  
András Rosta ◽  
...  
Keyword(s):  
Pilot Study ◽  
Cancer Patients ◽  
Anticancer Drugs ◽  
Complement Activation ◽  
Clinical Manifestations ◽  
Hypersensitivity Reactions

AbstractTo explore the role of complement (C) activation in the hypersensitivity reactions (HSRs) to some anticancer drugs, as well as the use of the C activation biomarkers (C

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