共查询到20条相似文献,搜索用时 796 毫秒
1.
Severe invasive streptococcal infection by Streptococcus pyogenes and Streptococcus dysgalactiae subsp. equisimilis
下载免费PDF全文
![点击此处可从《Microbiology and immunology》网站下载免费的PDF全文](/ch/ext_images/free.gif)
Shinya Watanabe Norihiko Takemoto Kohei Ogura Tohru Miyoshi‐Akiyama 《Microbiology and immunology》2016,60(1):1-9
Streptococcus pyogenes, a group A Streptococcus (GAS), has been recognized as the causative pathogen in patients with severe invasive streptococcal infection with or without necrotizing fasciitis. In recent epidemiological studies, Streptococcus dysgalactiae subsp. equisimilis (SDSE) has been isolated from severe invasive streptococcal infection. Complete genome sequence showed that SDSE is the closest bacterial species to GAS, with approximately 70% of genome coverage. SDSE, however, lacks several key virulence factors present in GAS, such as SPE‐B, the hyaluronan synthesis operon and active superantigen against human immune cells. A key event in the ability of GAS to cause severe invasive streptococcal infection was shown to be the acquisition of novel genetic traits such as phages. Strikingly, however, during severe invasive infection, GAS destroys its own covRS two‐component system, which negatively regulates many virulence factor genes, resulting in a hyper‐virulent phenotype. In contrast, this phenomenon has not been observed in SDSE. The present review describes the epidemiology of severe invasive streptococcal infection and the detailed pathogenic mechanisms of GAS and SDSE, emphasizing findings from their genome sequences and analyses of gene expression. 相似文献
2.
Anjuli M. Timmer John C. Timmer Morgan A. Pence Li-Chung Hsu Mariam Ghochani Terrence G. Frey Michael Karin Guy S. Salvesen Victor Nizet 《The Journal of biological chemistry》2009,284(2):862-871
Group A Streptococcus (GAS) is a leading human bacterial pathogen
capable of producing invasive infections even in previously healthy
individuals. As frontline components of host innate defense, macrophages play
a key role in control and clearance of GAS infections. We find GAS induces
rapid, dose-dependent apoptosis of primary and cultured macrophages and
neutrophils. The cell death pathway involves apoptotic caspases, is partly
dependent on caspase-1, and requires GAS internalization by the phagocyte.
Analysis of GAS virulence factor mutants, heterologous expression, and
purified toxin studies identified the pore-forming cytolysin streptolysin O
(SLO) as necessary and sufficient for the apoptosis-inducing phenotype.
SLO-deficient GAS mutants induced less macrophage apoptosis in vitro
and in vivo, allowed macrophage cytokine secretion, and were less
virulent in a murine systemic infection model. Ultrastructural evidence of
mitochondrial membrane remodeling, coupled with loss of mitochondrial
depolarization and cytochrome c release, suggests a direct attack of
the toxin initiates the intrinsic apoptosis pathway. A general caspase
inhibitor blocked SLO-induced apoptosis and enhanced macrophage killing of
GAS. We conclude that accelerated, caspase-dependent macrophage apoptosis
induced by the pore-forming cytolysin SLO contributes to GAS immune evasion
and virulence.Group A Streptococcus
(GAS)4 is a leading
human pathogen that annually infects hundreds of millions of people worldwide
(1). The last 3 decades have
witnessed a marked increase in severe, invasive forms of GAS infection, many
attributable to a single globally disseminated clone of the M1T1 serotype
(2). Invasive GAS infection
defines a capacity of the pathogen to resist host innate defense mechanisms
designed to prevent microbial spread beyond epithelial surfaces.Macrophages are critical host defense cells involved directly in bacterial
clearance and also in alerting other immune system components to invading
pathogens. Macrophage microbicidal activity is accomplished by phagocytic
uptake coupled with the action of reactive oxygen species, enzymatic
proteolysis, and cationic antimicrobial peptides; their role in amplification
of the innate and adaptive immune responses is achieved through release of
soluble factors such as cytokines and nitric oxide. Mice depleted of
macrophages or treated with inhibitors of macrophage phagocytosis cannot clear
GAS infections even at relatively low challenge doses
(3), demonstrating the
essential first line defense function of these immune cells against the
pathogen.We sought to explore the interaction of the highly virulent GAS M1T1 clone
with macrophages to better understand its propensity to produce invasive human
infection. A prominent regulatory feature of macrophage biology in the context
of infectious disease and inflammation is the process of apoptosis, mediated
by caspase family proteases. Although a number of highly adapted intracellular
bacterial pathogens, including Mycobacterium tuberculosis, Legionella
pneumophila, and Brucella spp., have evolved mechanisms to block
macrophage apoptosis and use the host cell as a vehicle for in vivo
dissemination
(4–6),
a recent study of GAS M1T1 interactions with another host phagocytic cell type
suggested a different outcome. In contrast to other prominent Gram-positive
pathogens, including Staphylococcus aureus and Listeria
monocytogenes, GAS induced an accelerated program of apoptosis in human
neutrophils (7), although the
specific virulence factor(s) involved, effects on caspase activation, and
contribution to disease outcome were not studied.Here we report that GAS rapidly induces macrophage apoptosis through
caspase-dependent pathways, promoted by release of cytochrome c and
permeabilization of mitochondrial outer membranes. GAS-induced macrophage
apoptosis is mediated by the cytolysin streptolysin O (SLO), which is both
necessary and sufficient for the phenotype. SLO-mediated macrophage apoptosis
leads to enhanced GAS survival, dampened cytokine responses, and increased
virulence during systemic infection. 相似文献
3.
4.
5.
The Group A Streptococcus serotype M2 pilus plays a role in host cell adhesion and immune evasion
下载免费PDF全文
![点击此处可从《Molecular microbiology》网站下载免费的PDF全文](/ch/ext_images/free.gif)
Jia‐Yun C. Tsai Jacelyn M. S. Loh Fiona Clow Natalie Lorenz Thomas Proft 《Molecular microbiology》2017,103(2):282-298
Group A Streptococcus (GAS), or Streptococcus pyogenes, is a human pathogen that causes diseases ranging from skin and soft tissue infections to severe invasive diseases, such as toxic shock syndrome. Each GAS strain carries a particular pilus type encoded in the variable f ibronectin‐binding, c ollagen‐binding, T antigen (FCT) genomic region. Here, we describe the functional analysis of the serotype M2 pilus encoded in the FCT‐6 region. We found that, in contrast to other investigated GAS pili, the ancillary pilin 1 lacks adhesive properties. Instead, the backbone pilin is important for host cell adhesion and binds several host factors, including fibronectin and fibrinogen. Using a panel of recombinant pilus proteins, GAS gene deletion mutants and Lactococcus lactis gain‐of‐function mutants we show that, unlike other GAS pili, the FCT‐6 pilus also contributes to immune evasion. This was demonstrated by a delay in blood clotting, increased intracellular survival of the bacteria in macrophages, higher bacterial survival rates in human whole blood and greater virulence in a Galleria mellonella infection model in the presence of fully assembled FCT‐6 pili. 相似文献
6.
Ira Jain Jessica L. Danger Cameron Burgess Timsy Uppal Paul Sumby 《Molecular microbiology》2020,113(1):190-207
The group A Streptococcus (GAS) causes diseases that range from mild (e.g. pharyngitis) to severely invasive (e.g. necrotizing fasciitis). Strain- and serotype-specific differences influence the ability of isolates to cause individual diseases. At the center of this variability is the CovR/S two-component system and the accessory protein RocA. Through incompletely defined mechanisms, CovR/S and RocA repress the expression of more than a dozen immunomodulatory virulence factors. Alleviation of this repression is selected for during invasive infections, leading to the recovery of covR, covS or rocA mutant strains. Here, we investigated how RocA promotes CovR/S activity, identifying that RocA is a pseudokinase that interacts with CovS. Disruption of CovS kinase or phosphatase activities abolishes RocA function, consistent with RocA acting through the modulation of CovS activity. We also identified, in conflict with a previous study, that the RocA regulon includes the secreted protease-encoding gene speB. Finally, we discovered an inverse correlation between the virulence of wild-type, rocA mutant, covS mutant and covR mutant strains during invasive infection and their fitness in an ex vivo upper respiratory tract model. Our data inform on mechanisms that control GAS disease potential and provide an explanation for observed strain- and serotype-specific variability in RocA function. 相似文献
7.
8.
Regulatory rewiring confers serotype‐specific hyper‐virulence in the human pathogen group A Streptococcus
下载免费PDF全文
![点击此处可从《Molecular microbiology》网站下载免费的PDF全文](/ch/ext_images/free.gif)
Eric W. Miller Jessica L. Danger Anupama B. Ramalinga Nicola Horstmann Samuel A. Shelburne Paul Sumby 《Molecular microbiology》2015,98(3):473-489
Phenotypic heterogeneity is commonly observed between isolates of a given pathogen. Epidemiological analyses have identified that some serotypes of the group A Streptococcus (GAS) are non‐randomly associated with particular disease manifestations. Here, we present evidence that a contributing factor to the association of serotype M3 GAS isolates with severe invasive infections is the presence of a null mutant allele for the orphan kinase RocA. Through use of RNAseq analysis, we identified that the natural rocA mutation present within M3 isolates leads to the enhanced expression of more than a dozen immunomodulatory virulence factors, enhancing phenotypes such as hemolysis and NAD+ hydrolysis. Consequently, an M3 GAS isolate survived human phagocytic killing at a level 13‐fold higher than a rocA complemented derivative, and was significantly more virulent in a murine bacteremia model of infection. Finally, we identified that RocA functions through the CovR/S two‐component system as levels of phosphorylated CovR increase in the presence of functional RocA, and RocA has no regulatory activity following covR or covS mutation. Our data are consistent with RocA interfacing with the CovR/S two‐component system, and that the absence of this activity in M3 GAS potentiates the severity of invasive infections caused by isolates of this serotype. 相似文献
9.
Nina N. Schommer Jun Muto Victor Nizet Richard L. Gallo 《The Journal of biological chemistry》2014,289(39):26914-26921
Group A Streptococcus (GAS) commonly infects human skin and occasionally causes severe and life-threatening invasive diseases. The hyaluronan (HA) capsule of GAS has been proposed to protect GAS from host defense by mimicking endogenous HA, a large and abundant glycosaminoglycan in the skin. However, HA is degraded during tissue injury, and the functions of short-chain HA that is generated during infection have not been studied. To examine the impact of the molecular mass of HA on GAS infection, we established infection models in vitro and in vivo in which the size of HA was defined by enzymatic digestion or custom synthesis. We discovered that conversion of high molecular mass HA to low molecular mass HA facilitated GAS phagocytosis by macrophages and limited the severity of infection in mice. In contrast, native high molecular mass HA significantly impaired internalization by macrophages and increased GAS survival in murine blood. Thus, our data demonstrate that GAS virulence can be influenced by the size of HA derived from both the bacterium and host and suggest that high molecular mass HA facilitates GAS deep tissue infections, whereas the generation of short-chain HA can be protective. 相似文献
10.
Regulatory gene mutation: a driving force behind group a Streptococcus strain‐ and serotype‐specific variation
下载免费PDF全文
![点击此处可从《Molecular microbiology》网站下载免费的PDF全文](/ch/ext_images/free.gif)
Data from multiple bacterial pathogens are consistent with regulator‐encoding genes having higher mutation frequencies than the genome average. Such mutations drive both strain‐ and type‐ (e.g., serotype, haplotype) specific phenotypic heterogeneity, and may challenge public health due to the potential of variants to circumvent established treatment and/or preventative regimes. Here, using the human bacterial pathogen the group A Streptococcus (GAS; S. pyogenes) as a model organism, we review the types and regulatory‐, phenotypic‐, and disease‐specific consequences of naturally occurring regulatory gene mutations. Strain‐specific regulator mutations that will be discussed include examples that transform isolates into hyper‐invasive forms by enhancing expression of immunomodulatory virulence factors, and examples that promote asymptomatic carriage of the organism. The discussion of serotype‐specific regulator mutations focuses on serotype M3 GAS isolates, and how the identified rewiring of regulatory networks in this serotype may be contributing to a decades old epidemiological association of M3 isolates with particularly severe invasive infections. We conclude that mutation plays an outsized role in GAS pathogenesis and has clinical relevance. Given the phenotypic variability associated with regulatory gene mutations, the rapid examination of these genes in infecting isolates may inform with respect to potential patient complications and treatment options. 相似文献
11.
The group A streptococci (GAS, Streptococcus pyogenes) are important human pathogens which can cause a variety of diseases, ranging from mild infections to very severe invasive diseases. In recent years, evidence has been accumulated that host genetic factors have a major influence on the outcome of streptococcal infections. Variability in the degree of susceptibility of different inbred mouse strains to infection with GAS has demonstrated that the host genetic background largely determines the susceptibility of mice to this pathogen. This information is particularly useful for studying the immune mechanisms underlying disease susceptibility in mice, and provides an entry point for the identification of host defence loci. This paper reviews the recent advances in the characterisation of pathogenic mechanisms associated with the development of GAS-induced septic shock in the mouse model and outlines the current knowledge regarding the genetic control of immune responses to Group A streptococcus in mice. 相似文献
12.
Anna Henningham Masaya Yamaguchi Ramy K. Aziz Kirsten Kuipers Cosmo Z. Buffalo Samira Dahesh Biswa Choudhury Jeremy Van Vleet Yuka Yamaguchi Lisa M. Seymour Nouri L. Ben Zakour Lingjun He Helen V. Smith Keith Grimwood Scott A. Beatson Partho Ghosh Mark J. Walker Victor Nizet Jason N. Cole 《The Journal of biological chemistry》2014,289(46):32303-32315
A recent analysis of group A Streptococcus (GAS) invasive infections in Australia has shown a predominance of M4 GAS, a serotype recently reported to lack the antiphagocytic hyaluronic acid (HA) capsule. Here, we use molecular genetics and bioinformatics techniques to characterize 17 clinical M4 isolates associated with invasive disease in children during this recent epidemiology. All M4 isolates lacked HA capsule, and whole genome sequence analysis of two isolates revealed the complete absence of the hasABC capsule biosynthesis operon. Conversely, M4 isolates possess a functional HA-degrading hyaluronate lyase (HylA) enzyme that is rendered nonfunctional in other GAS through a point mutation. Transformation with a plasmid expressing hasABC restored partial encapsulation in wild-type (WT) M4 GAS, and full encapsulation in an isogenic M4 mutant lacking HylA. However, partial encapsulation reduced binding to human complement regulatory protein C4BP, did not enhance survival in whole human blood, and did not increase virulence of WT M4 GAS in a mouse model of systemic infection. Bioinformatics analysis found no hasABC homologs in closely related species, suggesting that this operon was a recent acquisition. These data showcase a mutually exclusive interaction of HA capsule and active HylA among strains of this leading human pathogen. 相似文献
13.
Group B Streptococcus (GBS) capsular type III is an important agent of life‐threatening invasive infections. It has been previously shown that encapsulated GBS is easily internalized by dendritic cells (DCs) and can persist inside these immune cells. The mechanisms underlying these processes are unknown. Here, colocalization studies and the use of endocytosis inhibitors and caveolin?/? mice, demonstrated that GBS uses multiple endocytosis mechanisms to enter mouse DCs. The capsular polysaccharide (CPS) selectively drives GBS internalization via caveolae‐independent but lipid raft‐dependent pathways. Non‐encapsulated bacteria failed to engage lipid rafts. GBS internalization by DCs also occurs via clathrin‐mediated endocytosis in a process independent of bacterial CPS. Albeit caveolae are not required for GBS internalization, signalling events through caveolin‐1 are involved in production of the inflammatory chemokine CCL2 by DCs infected with encapsulated GBS only. This study addresses for the first time endocytosis pathways implicated in DC internalization of encapsulated GBS and suggests a complex interplay between GBS and DCs, which was selectively modulated by the presence of CPS. 相似文献
14.
High‐density lipoprotein acts as an opsonin to enhance phagocytosis of group A streptococcus by U937 cells
下载免费PDF全文
![点击此处可从《Microbiology and immunology》网站下载免费的PDF全文](/ch/ext_images/free.gif)
Ling Liu Lulei Zhou Yuxin Li Wencheng Bai Na Liu Wenlong Li Yumin Gao Zhi Liu Runlin Han 《Microbiology and immunology》2015,59(7):419-425
15.
Streptolysin O and its Co-Toxin NAD-glycohydrolase Protect Group A Streptococcus from Xenophagic Killing 总被引:1,自引:0,他引:1
Group A Streptococcus (Streptococcus pyogenes or GAS) causes pharyngitis, severe invasive infections, and the post-infectious syndromes of glomerulonephritis and rheumatic fever. GAS can be internalized and killed by epithelial cells in vitro, a process that may contribute to local innate defense against pharyngeal infection. Secretion of the pore-forming toxin streptolysin O (SLO) by GAS has been reported to stimulate targeted autophagy (xenophagy) upon internalization of the bacteria by epithelial cells. Whereas this process was associated with killing of GAS in HeLa cells, studies in human keratinocytes found SLO production enhanced intracellular survival. To reconcile these conflicting observations, we now report in-depth investigation of xenophagy in response to GAS infection of human oropharyngeal keratinocytes, the predominant cell type of the pharyngeal epithelium. We found that SLO expression was associated with prolonged intracellular survival; unexpectedly, expression of the co-toxin NADase was required for this effect. Enhanced intracellular survival was lost upon deletion of NADase or inactivation of its enzymatic activity. Shortly after internalization of GAS by keratinocytes, SLO-mediated damage to the bacteria-containing vacuole resulted in exposure to the cytosol, ubiquitination of GAS and/or associated vacuolar membrane remnants, and engulfment of GAS in LC3-positive vacuoles. We also found that production of streptolysin S could mediate targeting of GAS to autophagosomes in the absence of SLO, a process accompanied by galectin 8 binding to damaged GAS-containing endosomes. Maturation of GAS-containing autophagosome-like vacuoles to degradative autolysosomes was prevented by SLO pore-formation and by SLO-mediated translocation of enzymatically active NADase into the keratinocyte cytosol. We conclude that SLO stimulates xenophagy in pharyngeal keratinocytes, but the coordinated action of SLO and NADase prevent maturation of GAS-containing autophagosomes, thereby prolonging GAS intracellular survival. This novel activity of NADase to block autophagic killing of GAS in pharyngeal cells may contribute to pharyngitis treatment failure, relapse, and chronic carriage. 相似文献
16.
Group A Streptococcus (GAS) is a versatile human pathogen causing diseases ranging from uncomplicated mucosal infections to life-threatening invasive disease. The development of human-relevant animal models of GAS infection and introduction of new technologies have markedly accelerated the pace of discoveries related to GAS host–pathogen interactions. For example, recently investigators have identified pili on the GAS cell surface and learned that they are key components for adherence to eukaryotic cell surfaces. Similarly, the recent development of a transgenic mouse expressing human plasminogen has resulted in new understanding of the molecular processes contributing to invasive infection. Improved understanding of the molecular mechanisms underlying the pathogenesis of GAS pharyngeal, invasive and other infections holds the promise of assisting with the development of novel preventive or therapeutic agents for this prevalent human pathogen. 相似文献
17.
Pathogenic Streptococcus strains employ novel escape strategy to inhibit bacteriostatic effect mediated by mammalian peptidoglycan recognition protein
下载免费PDF全文
![点击此处可从《Cellular microbiology》网站下载免费的PDF全文](/ch/ext_images/free.gif)
Jing Wang Youjun Feng Changjun Wang Swaminath Srinivas Chen Chen Hui Liao Elaine He Shibo Jiang Jiaqi Tang 《Cellular microbiology》2017,19(7)
Pathogenic streptococcal species are responsible for some of the most lethal and prevalent animal and human infections. Previous reports have identified a candidate pathogenicity island (PAI) in two highly virulent clinical isolates of Streptococcus suis type 2, a causative agent of high‐mortality streptococcal toxic shock syndrome. This PAI contains a type‐IVC secretion system C subgroup (type‐IVC secretion system) that is involved in the secretion of unknown pathogenic effectors that are responsible for streptococcal toxic shock syndrome caused by highly virulent strains of S. suis. Both virulence protein B4 and virulence protein D4 were demonstrated to be key components of this type‐IVC secretion system. In this study, we identify a new PAI family across 3 streptococcal species; Streptococcus genomic island contains type‐IV secretion system, which contains a genomic island type‐IVC secretion system and a novel PPIase molecule, SP1. SP1 is shown to interact with a component of innate immunity, peptidoglycan recognition protein (PGLYRP‐1) and to perturb the PGLYRP‐1‐mediated bacteriostatic effect by interacting with protein PGLYRP‐1. Our study elucidates a novel mechanism by which bacteria escape by components of the innate immune system by secretion of the SP1 protein in pathogenic Streptococci, which then interacts with PGLYRP‐1 from the host. Our results provide potential targets for the development of new antimicrobial drugs against bacteria with resistance to innate host immunity. 相似文献
18.
19.
Samantha L. van der Beek Azul Zorzoli Ebru anak Robert N. Chapman Kieron Lucas Benjamin H. Meyer Dimitrios Evangelopoulos Luiz Pedro S. de Carvalho Geert‐Jan Boons Helge C. Dorfmueller Nina M. van Sorge 《Molecular microbiology》2019,111(4):951-964
Biosynthesis of the nucleotide sugar precursor dTDP‐L‐rhamnose is critical for the viability and virulence of many human pathogenic bacteria, including Streptococcus pyogenes (Group A Streptococcus; GAS), Streptococcus mutans and Mycobacterium tuberculosis. Streptococcal pathogens require dTDP‐L‐rhamnose for the production of structurally similar rhamnose polysaccharides in their cell wall. Via heterologous expression in S. mutans, we confirmed that GAS RmlB and RmlC are critical for dTDP‐L‐rhamnose biosynthesis through their action as dTDP‐glucose‐4,6‐dehydratase and dTDP‐4‐keto‐6‐deoxyglucose‐3,5‐epimerase enzymes respectively. Complementation with GAS RmlB and RmlC containing specific point mutations corroborated the conservation of previous identified catalytic residues. Bio‐layer interferometry was used to identify and confirm inhibitory lead compounds that bind to GAS dTDP‐rhamnose biosynthesis enzymes RmlB, RmlC and GacA. One of the identified compounds, Ri03, inhibited growth of GAS, other rhamnose‐dependent streptococcal pathogens as well as M. tuberculosis with an IC50 of 120–410 µM. Importantly, we confirmed that Ri03 inhibited dTDP‐L‐rhamnose formation in a concentration‐dependent manner through a biochemical assay with recombinant rhamnose biosynthesis enzymes. We therefore conclude that inhibitors of dTDP‐L‐rhamnose biosynthesis, such as Ri03, affect streptococcal and mycobacterial viability and can serve as lead compounds for the development of a new class of antibiotics that targets dTDP‐rhamnose biosynthesis in pathogenic bacteria. 相似文献
20.
Group A streptococcus (GAS) causes variety of diseases ranging from common pharyngitis to life-threatening severe invasive diseases, including necrotizing fasciitis and streptococcal toxic shock-like syndrome. The characteristic of invasive GAS infections has been thought to attribute to genetic changes in bacteria, however, no clear evidence has shown due to lack of an intriguingly study using serotype-matched isolates from clinical severe invasive GAS infections. In addition, rare outbreaks of invasive infections and their distinctive pathology in which infectious foci without neutrophil infiltration hypothesized us invasive GAS could evade host defense, especially neutrophil functions. Herein we report that a panel of serotype-matched GAS, which were clinically isolated from severe invasive but not from non-invaive infections, could abrogate functions of human polymorphnuclear neutrophils (PMN) in at least two independent ways; due to inducing necrosis to PMN by enhanced production of a pore-forming toxin streptolysin O (SLO) and due to impairment of PMN migration via digesting interleukin-8, a PMN attracting chemokine, by increased production of a serine protease ScpC. Expression of genes was upregulated by a loss of repressive function with the mutation of csrS gene in the all emm49 severe invasive GAS isolates. The csrS mutants from clinical severe invasive GAS isolates exhibited high mortality and disseminated infection with paucity of neutrophils, a characteristic pathology seen in human invasive GAS infection, in a mouse model. However, GAS which lack either SLO or ScpC exhibit much less mortality than the csrS-mutated parent invasive GAS isolate to the infected mice. These results suggest that the abilities of GAS to abrogate PMN functions can determine the onset and severity of invasive GAS infection. 相似文献