THE TOXIC ACTION OF PREPARATIONS CONTAINING THE OXYGEN-LABILE HEMOLYSIN OF STREPTOCOCCUS PYOGENES

1. The susceptibility of mice to the lethal effect of preparations containing the oxygen-labile hemolysin (streptolysin O) of group A hemolytic streptococci has been studied. Injection of a single sublethal dose of the streptococcal preparation causes the development of resistance to the effect of a lethal dose injected subsequently. 2. Resistance is demonstrable 3 to 6 hours after the injection of the streptococcal preparation, persists for approximately 30 hours, and then disappears. 3. Resistance induced by the streptococcal preparation, although relatively specific, is directed not only against the streptococcal preparation but also against saponin. Mice made refractory to the streptococcal preparation and to saponin exhibit normal susceptibility to a number of other toxic agents, with the possible exception of the alpha toxin of Cl. welchii. 4. Mice injected with a sublethal dose of saponin develop resistance to the effect of a lethal dose of either saponin or the streptococcal preparation. 5. Resistance depends upon processes distinct from those underlying classical antitoxic immunity.

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Prophage exotoxins enhance colonization fitness in epidemic scarlet fever-causing Streptococcus pyogenes

Nature Communications ◽

10.1038/s41467-020-18700-5 ◽

2020 ◽

Vol 11 (1) ◽

Author(s):

Stephan Brouwer ◽

Timothy C. Barnett ◽

Diane Ly ◽

Katherine J. Kasper ◽

David M. P. De Oliveira ◽

...

Keyword(s):

Streptococcus Pyogenes ◽

Scarlet Fever ◽

Global Public Health ◽

Nasopharyngeal Colonization ◽

North East ◽

Streptolysin O ◽

Knockout Mutants ◽

Group A ◽

Bacterial Superantigen

Abstract The re-emergence of scarlet fever poses a new global public health threat. The capacity of North-East Asian serotype M12 (emm12) Streptococcus pyogenes (group A Streptococcus, GAS) to cause scarlet fever has been linked epidemiologically to the presence of novel prophages, including prophage ΦHKU.vir encoding the secreted superantigens SSA and SpeC and the DNase Spd1. Here, we report the molecular characterization of ΦHKU.vir-encoded exotoxins. We demonstrate that streptolysin O (SLO)-induced glutathione efflux from host cellular stores is a previously unappreciated GAS virulence mechanism that promotes SSA release and activity, representing the first description of a thiol-activated bacterial superantigen. Spd1 is required for resistance to neutrophil killing. Investigating single, double and triple isogenic knockout mutants of the ΦHKU.vir-encoded exotoxins, we find that SpeC and Spd1 act synergistically to facilitate nasopharyngeal colonization in a mouse model. These results offer insight into the pathogenesis of scarlet fever-causing GAS mediated by prophage ΦHKU.vir exotoxins.

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Streptolysin O and NAD-Glycohydrolase Prevent Phagolysosome Acidification and Promote Group A Streptococcus Survival in Macrophages

mBio ◽

10.1128/mbio.01690-14 ◽

2014 ◽

Vol 5 (5) ◽

Cited By ~ 47

Author(s):

Benedicte Bastiat-Sempe ◽

John F. Love ◽

Natalie Lomayesva ◽

Michael R. Wessels

Keyword(s):

Streptococcus Pyogenes ◽

Intracellular Survival ◽

Streptococcal Toxic Shock Syndrome ◽

Simple Diffusion ◽

Content Type ◽

Nad Glycohydrolase ◽

Macrophage Phagocytosis ◽

Streptolysin O ◽

Invasive Infections ◽

Group A

ABSTRACTGroup AStreptococcus(GAS,Streptococcus pyogenes) is an ongoing threat to human health as the agent of streptococcal pharyngitis, skin and soft tissue infections, and life-threatening conditions such as necrotizing fasciitis and streptococcal toxic shock syndrome. In animal models of infection, macrophages have been shown to contribute to host defense against GAS infection. However, as GAS can resist killing by macrophagesin vitroand induce macrophage cell death, it has been suggested that GAS intracellular survival in macrophages may enable persistent infection. Using isogenic mutants, we now show that the GAS pore-forming toxin streptolysin O (SLO) and its cotoxin NAD-glycohydrolase (NADase) mediate GAS intracellular survival and cytotoxicity for macrophages. Unexpectedly, the two toxins did not inhibit fusion of GAS-containing phagosomes with lysosomes but rather prevented phagolysosome acidification. SLO served two essential functions, poration of the phagolysosomal membrane and translocation of NADase into the macrophage cytosol, both of which were necessary for maximal GAS intracellular survival. Whereas NADase delivery to epithelial cells is mediated by SLO secreted from GAS bound to the cell surface, in macrophages, the source of SLO and NADase is GAS contained within phagolysosomes. We found that transfer of NADase from the phagolysosome to the macrophage cytosol occurs not by simple diffusion through SLO pores but rather by a specific translocation mechanism that requires the N-terminal translocation domain of NADase. These results illuminate the mechanisms through which SLO and NADase enable GAS to defeat macrophage-mediated killing and provide new insight into the virulence of a major human pathogen.IMPORTANCEMacrophages constitute an important element of the innate immune response to mucosal pathogens. They ingest and kill microbes by phagocytosis and secrete inflammatory cytokines to recruit and activate other effector cells. Group AStreptococcus(GAS,Streptococcus pyogenes), an important cause of pharyngitis and invasive infections, has been shown to resist killing by macrophages. We find that GAS resistance to macrophage killing depends on the GAS pore-forming toxin streptolysin O (SLO) and its cotoxin NAD-glycohydrolase (NADase). GAS bacteria are internalized by macrophage phagocytosis but resist killing by secreting SLO, which damages the phagolysosome membrane, prevents phagolysosome acidification, and translocates NADase from the phagolysosome into the macrophage cytosol. NADase augments SLO-mediated cytotoxicity by depleting cellular energy stores. These findings may explain the nearly universal production of SLO by GAS clinical isolates and the association of NADase with the global spread of a GAS clone implicated in invasive infections.

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Prophage exotoxins enhance colonization fitness in epidemic scarlet fever-causing Streptococcus pyogenes

10.1101/2020.05.17.095000 ◽

2020 ◽

Author(s):

Stephan Brouwer ◽

Timothy C. Barnett ◽

Diane Ly ◽

Katherine J. Kasper ◽

David M.P. De Oliveira ◽

...

Keyword(s):

Streptococcus Pyogenes ◽

Scarlet Fever ◽

Optimal Growth ◽

Global Public Health ◽

Nasopharyngeal Colonization ◽

North East ◽

Streptolysin O ◽

Knockout Mutants ◽

Group A

AbstractThe re-emergence of scarlet fever poses a new global public health threat. The capacity of North-East Asian serotype M12 (emm12) Streptococcus pyogenes (group A Streptococcus, GAS) to cause scarlet fever has been linked epidemiologically to the presence of novel prophages, including prophage ΦHKU.vir encoding the secreted superantigens SSA and SpeC and the DNase Spd1. Here we report the comprehensive molecular characterization of ΦHKU.vir-encoded exotoxins. We demonstrate that streptolysin O (SLO)-induced glutathione efflux from host cellular stores is a previously unappreciated GAS virulence mechanism that promotes SSA release and activity, representing the first description of a thiol-activated bacterial superantigen. Spd1 is required for optimal growth in human blood, confers resistance to neutrophil killing, and degrades neutrophil extracellular traps (NETs). Investigating single, double and triple isogenic knockout mutants of the ΦHKU.vir-encoded exotoxins, we find that SpeC and Spd1 act synergistically to facilitate nasopharyngeal colonization in a mouse model. These results offer insight into the etiology and pathogenesis of scarlet fever-causing GAS mediated by phage ΦHKU.vir exotoxins.

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Hemolytic mutants of group A Streptococcus pyogenes

Journal of Clinical Microbiology ◽

10.1128/jcm.7.2.153-157.1978 ◽

1978 ◽

Vol 7 (2) ◽

pp. 153-157

Author(s):

W Owens ◽

F Henley ◽

B D Barridge

Keyword(s):

Streptococcus Pyogenes ◽

Group A Streptococcus ◽

Nicotinamide Adenine ◽

Streptolysin S ◽

Naturally Occurring ◽

Streptolysin O ◽

Group A ◽

The Dead

Hemolytic mutants of Lancefield strain SS-95 and ATCC 19615 Streptococcus pyogenes were produced by treatment with N-methyl-N'-nitro-N-nitrosoguanidine. These mutants contained the same levels of streptolysin O, nicotinamide adenine dinucleotidase, deoxyribonuclease, and hyaluronidase. The mutants were deficient in streptolysin S, as was the naturally occurring nonhemolytic Lowry strain. The mutants retained their pathogenicity for mice and, when reisolated from the dead animals, produced the mutant hemolytic pattern.

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Signaling Peptide SpoV Is Essential for Streptococcus pyogenes Virulence, and Prophylaxis with Anti-SpoV Decreases Disease Severity

Microorganisms ◽

10.3390/microorganisms9112321 ◽

2021 ◽

Vol 9 (11) ◽

pp. 2321

Author(s):

Andrea L. Herrera ◽

Michael S. Chaussee

Keyword(s):

Streptococcus Pyogenes ◽

Therapeutic Potential ◽

Group A Streptococcus ◽

Ex Vivo ◽

Invasive Disease ◽

Human Model ◽

Streptolysin S ◽

Streptolysin O ◽

Group A ◽

Specific Peptide

Streptococcal peptide of virulence (SpoV) is a Streptococcus pyogenes (group A streptococcus (GAS))-specific peptide that is important for GAS survival in murine blood, and the expression of the virulence factors streptolysin O (slo) and streptolysin S (sagA). We used a spoV mutant in isolate MGAS315 to assess the contribution of the SpoV peptide to virulence by using a murine model of invasive disease and an ex vivo human model (Lancefield assay). We then used antibodies to SpoV in both models to evaluate their ability to decrease morbidity and mortality. Results showed that SpoV is essential for GAS virulence, and targeting the peptide has therapeutic potential.

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Unfolded protein response inhibitors cure group A streptococcal necrotizing fasciitis by modulating host asparagine

Science Translational Medicine ◽

10.1126/scitranslmed.abd7465 ◽

2021 ◽

Vol 13 (605) ◽

pp. eabd7465

Author(s):

Aparna Anand ◽

Abhinay Sharma ◽

Miriam Ravins ◽

Debabrata Biswas ◽

Poornima Ambalavanan ◽

...

Keyword(s):

Necrotizing Fasciitis ◽

Unfolded Protein Response ◽

Mammalian Cells ◽

Lethal Dose ◽

Sublethal Dose ◽

Effective Vaccine ◽

Antibiotic Administration ◽

Unfolded Protein ◽

Group A ◽

Protein Response

Group A streptococcus (GAS) is among the top 10 causes of mortality from an infectious disease, producing mild to invasive life-threatening manifestations. Necrotizing fasciitis (NF) is characterized by a rapid GAS spread into fascial planes followed by extensive tissue destruction. Despite prompt treatments of antibiotic administration and tissue debridement, mortality from NF is still high. Moreover, there is no effective vaccine against GAS, and early diagnosis of NF is problematic because its clinical presentations are not specific. Thus, there is a genuine need for effective treatments against GAS NF. Previously, we reported that GAS induces endoplasmic reticulum (ER) stress to gain asparagine from the host. Here, we demonstrate that GAS-mediated asparagine induction and release occur through the PERK-eIF2α-ATF4 branch of the unfolded protein response. Inhibitors of PERK or integrated stress response (ISR) blocked the formation and release of asparagine by infected mammalian cells, and exogenously added asparagine overcame this inhibition. Moreover, in a murine model of NF, we show that the inhibitors minimized mortality when mice were challenged with a lethal dose of GAS and reduced bacterial counts and lesion size when mice were challenged with a sublethal dose. Immunohistopathology studies demonstrated that PERK/ISR inhibitors protected mice by enabling neutrophil infiltration into GAS-infected fascia and reducing the pro-inflammatory response that causes tissue damage. Inhibitor treatment was also effective in mice when started at 12 hours after infection. We conclude that host metabolic alteration induced by PERK or ISR inhibitors is a promising therapeutic strategy to treat highly invasive GAS infections.

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Tonsillar Inflammation, a Rare Cause of Bradycardia and Hypotension

Medical & Clinical Research ◽

10.33140/mcr.03.03.03 ◽

2018 ◽

Vol 3 (3) ◽

Keyword(s):

Streptococcus Pyogenes ◽

Fusobacterium Necrophorum ◽

Outpatient Setting ◽

Peritonsillar Abscess ◽

The Other ◽

Streptococcus Group ◽

Other Hand ◽

Group A

Tonsillitis is a frequently encountered pathology in the outpatient setting, usually caused by viruses [1]. When bacterial, the most common causatory microbe is streptococcus group A [1]. Tonsillar and peritonsillar abscess (PTA) on the other hand are never viral, and are usually caused by streptococcus pyogenes, Streptococcus melleri, fusobacterium necrophorum and staphylococci [1,2]. The overall incidence of PTA is suggested to be 37/100,000 patients, with the highest incidence between ages 14-21 at 124/100,000 [3].

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Etiology, clinical presentation, laboratory diagnostics, pathogenesis of impetigo and treatment methods

Terapevt (General Physician) ◽

10.33920/med-12-2003-07 ◽

2020 ◽

pp. 64-70

Author(s):

Anastasiya Laknitskaya

Keyword(s):

Streptococcus Pyogenes ◽

Skin Diseases ◽

Group A Streptococcus ◽

Antibiotic Sensitivity ◽

Antioxidant Defense System ◽

Laboratory Diagnostics ◽

Treatment Methods ◽

Group A ◽

The Individual

Currently, one of the priority medical and social problems is the optimization of treatment methods for pyoderma associated with Streptococcus pyogenes — group A streptococcus (GAS). To date, the proportion of pyoderma, the etiological factor of which is Streptococcus pyogenes, is about 6 % of all skin diseases and is in the range from 17.9 to 43.9 % of all dermatoses. Role of the bacterial factor in the development of streptococcal pyoderma is obvious. Traditional treatment complex includes antibacterial drugs selected individually, taking into account the antibiotic sensitivity of pathognomonic bacteria, and it is not always effective. Currently implemented immunocorrection methods often do not take into account specific immunological features of the disease, the individual, and the fact that the skin performs the function of not only a mechanical barrier, but it is also an immunocompetent organ. Such an approach makes it necessary to conduct additional studies clarifying the role of factors of innate and adaptive immunity, intercellular mediators and antioxidant defense system, that allow to optimize the treatment of this pathology.

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Streptococcus pyogenes Infective Endocarditis – Association with Injection Drug Use: Case Series and Review of the Literature

Open Forum Infectious Diseases ◽

10.1093/ofid/ofab240 ◽

2021 ◽

Author(s):

Melanie T Rebechi ◽

Emily L Heil ◽

Paul M Luethy ◽

Sarah A Schmalzle

Keyword(s):

Infective Endocarditis ◽

Streptococcus Pyogenes ◽

People Who Inject Drugs ◽

Local Population ◽

Case Series ◽

Duke Criteria ◽

Group A ◽

Polymicrobial Bacteremia ◽

Predominantly Female ◽

Living With Hiv

Abstract Background Streptococcus pyogenes, or Group A Strep (GAS), is not considered a typical cause of infective endocarditis (IE), but has anecdotally been observed in unexpectedly high rates in people who inject drugs (PWID) at our institution. Methods All cases of possible or definite GAS IE per Modified Duke Criteria in adults at an academic hospital between 11/15/2015 and 11/15/2020 were identified. Medical records were reviewed for demographics, comorbidities, treatment, and outcomes related to GAS IE. Literature on cases of GAS IE was reviewed. Results 18 cases of probable (11) or definite (7) GAS IE were identified; mean age was 38 years, and the population was predominantly female (56%) and Caucasian (67%), which is inconsistent with local population demographics. Sixteen cases were in people who inject drugs (PWID) (89%), 14 were also homeless, six were also living with HIV (33%), and two were also pregnant. Antibiotic regimens were variable due to polymicrobial bacteremia (39%). One patient underwent surgical valve replacement. Four patients (22%) died due to complications of infection. Literature review revealed 42 adult cases of GAS IE, only 17 of which were in PWID (24%). Conclusions The 16 cases of possible and definite GAS IE in PWID over a five-year period in a single institution reported nearly doubles the number of cases in PWID from all previous reports. This suggests a potential increase in GAS IE particularly in PWID and PLWH, which warrants further epidemiologic investigation.

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