Motion Picture Study of the Toxic Action of Streptolysins on Leucocytes

Hirsch, James G.; Bernheimer, Alan W.; Weissmann, Gerald

doi:10.1084/jem.118.2.223

Cited by 106 publications

(53 citation statements)

References 7 publications

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“…PMN degranulation in response to SLS exposure was similar to that seen after incubation with SLO, but the effect was delayed. Changes in the cell surface and nuclear fusion in response to SLS were less pronounced than the changes in response to SLO (18). …”

Section: Discussionmentioning

confidence: 69%

“…Over 30 years ago, Hirsch and colleagues analyzed the cytopathic effects of purified SLO and SLS preparations on rabbit PMNs by motion picture analysis (18). Exposure to SLO induced a series of changes in PMN morphology characterized by initial disruption of cytoplasmic granules, followed by the development of filamentous processes on the cell surface and eventual cytoplasmic and nuclear liquefaction.…”

Section: Discussionmentioning

confidence: 99%

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Cytotoxic Effects of Streptolysin O and Streptolysin S Enhance the Virulence of Poorly Encapsulated Group A Streptococci

et al. 2003

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Although the toxicity of streptolysin O (SLO) and streptolysin S (SLS) in purified group A streptococci (GAS) has been established, the effect of these molecules in natural infection is not well understood. To identify whether biologically relevant concentrations of SLO and SLS were cytotoxic to epithelial and phagocytic cells that the bacteria would typically encounter during human infection and to characterize the influence of cell injury on bacterial pathogenesis, we derived GAS strains deficient in SLO or SLS in the background of an invasive GAS M3 isolate and determined their virulence in in vitro and in vivo models of human disease. Whereas bacterial production of SLO resulted in lysis of both human keratinocytes and polymorphonuclear leukocytes, GAS expression of SLS was associated only with keratinocyte injury. Expression of SLO but not SLS impaired polymorphonuclear leukocyte killing of GAS in vitro, but this effect could only be demonstrated in the background of acapsular organisms. In mouse invasive soft-tissue infection, neither SLO or SLS expression significantly influenced mouse survival. By contrast, in a mouse model of bacterial sepsis after intraperitoneal inoculation of GAS, SLO expression enhanced the virulence of both encapsulated and acapsular GAS, whereas SLS expression increased the virulence only of acapsular GAS. We conclude that the cytotoxic effects of SLO protect GAS from phagocytic killing and enhance bacterial virulence, particularly of strains that may be relatively deficient in hyaluronic acid capsule. Compared to SLO, SLS in this strain background has a more modest influence on GAS pathogenicity and the effect does not appear to involve bacterial resistance to phagocytosis.Group A streptococci (GAS) are important human pathogens. Millions of children each year develop GAS pharyngitis. Although throat infection is typically benign, it can be complicated by the development of acute and chronic rheumatic heart disease. Invasive GAS infection occurs less frequently than pharyngitis but causes significantly more morbidity. The incidence of severe invasive GAS disease associated with shock and organ failure appears to be increasing (14,38,40).GAS produce two hemolysins that may contribute to pathogenesis. Streptolysin O (SLO) is a well-characterized oxygenlabile prototype of a cholesterol-binding bacterial exotoxin. When cultured in broth, GAS express SLO during exponentialphase and early stationary-phase growth (1). Streptolysin S (SLS) is an oxygen-stable oligopeptide primarily responsible for the characteristic zone of beta-hemolysis surrounding GAS colonies grown on blood-agar medium (17). SLS production occurs when cells are in stationary-phase growth conditions in broth culture (9).Early studies of purified SLO and SLS demonstrated that these hemolysins were toxic to a variety of human cells in vitro and in vivo (3,10,16,19,20). In rabbits, injection of SLO caused blood vessel contraction, increased capillary permeability, massive intravascular thrombosis, dermal necrosis, cardio...

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Section: Discussionmentioning

confidence: 69%

Section: Discussionmentioning

confidence: 99%

Cytotoxic Effects of Streptolysin O and Streptolysin S Enhance the Virulence of Poorly Encapsulated Group A Streptococci

et al. 2003

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“…The zebrafish infection experiments suggest that SLS is involved in reducing the number of PMNs present at the site of streptococcal multiplication. This could be due to the ability of SLS to kill PMNs (28,35,53) or to an effect on local host cells that inhibits their ability to express chemotactic alarm molecules. To distinguish between these possibilities, we adapted an in vitro transepithelial PMN migration assay that has been used to assess how the interactions between several pathogens and a polarized epithelium can lead to the recruitment of PMNs (reviewed in reference 51).…”

Section: Slsmentioning

confidence: 99%

“…A prominent example is streptolysin S (SLS), a potent cytolysin that has been reported to possess both proinflammatory (26) and anti-inflammatory activities (35,53,57) and whose contribution to virulence in a number of animal models of S. pyogenes disease has been the subject of several conflicting reports (for a review, see references 25 and 75). A difficulty in studying SLS has been its intrinsic instability, which has made its biochemical characterization difficult.…”

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confidence: 99%

Streptolysin S Inhibits Neutrophil Recruitment during the Early Stages ofStreptococcus pyogenesInfection

Lin¹,

Loughman

Zinselmeyer³

et al. 2009

Infect Immun

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In contrast to infection of superficial tissues, Streptococcus pyogenes infection of deeper tissue can be associated with a significantly diminished inflammatory response, suggesting that this bacterium has the ability to both promote and suppress inflammation. To examine this, we analyzed the behavior of an S. pyogenes mutant deficient in expression of the cytolytic toxin streptolysin S (SLS ؊ ) and evaluated events that occur during the first few hours of infection by using several models including injection of zebrafish (adults, larvae, and embryos), a transepithelial polymorphonuclear leukocyte (PMN) migration assay, and two-photon microscopy of mice in vivo. In contrast to wild-type S. pyogenes, the SLS ؊ mutant was associated with the robust recruitment of neutrophils and significantly reduced lethal myositis in adult zebrafish. Similarly, the mutant was attenuated in embryos in its ability to cause lethality. Infection of larva muscle allowed an analysis of inflammation in real time, which revealed that the mutant had recruited PMNs to the infection site. Analysis of transepithelial migration in vitro suggested that SLS inhibited the host cells' production of signals chemotactic for neutrophils, which contrasted with the proinflammatory effect of an unrelated cytolytic toxin, streptolysin O. Using two-photon microscopy of mice in vivo, we showed that the extravasation of neutrophils during infection with SLS ؊ mutant bacteria was significantly accelerated compared to infection with wild-type S. pyogenes. Taken together, these data support a role for SLS in the inhibition of neutrophil recruitment during the early stages of S. pyogenes infection.

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“…Slo is a secreted protein produced by nearly all clinical GAS isolates tested (1,26,36) and is the best characterized of a family of oxygen-sensitive, thiol-activated toxins that includes such established virulence factors as perfringolysin (theta toxin), pneumolysin, and listeriolysin O (2,5,10). Slo interacts with cholesterol in target cells to form multisubunit pores and is active on a number of eukaryotic cell types, including erythrocytes, leukocytes, macrophages, platelets, and various cell culture lines (16,23).…”

mentioning

confidence: 99%

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

et al. 2000

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Many of the virulence factors that have been characterized for group A streptococci (GAS) are not expressed in all clinical isolates. One putative virulence factor that is present among most is streptolysin O (Slo), a protein with well-characterized cytolytic activity for many eukaryotic cells types. In other bacterial pathogens, proteins homologous to Slo have been shown to be essential for virulence, but the role of Slo in GAS had not been previously examined. To investigate the role of Slo in GAS virulence, we examined both revertible and stable slo mutants in a mouse model of invasive disease. When the revertible slo mutant was used to infect mice, the reversion frequency of bacteria isolated from the wounds and spleens of infected animals was more than 100 times that of the inoculum, indicating that there was selective pressure in the animal for Slo ؉ GAS. Experiments with the stable slo mutant demonstrated that Slo was not necessary for the formation of necrotic lesions, nor was it necessary for escape from the lesion to cause disseminated infection. Bacteria were present in the spleens of 50% of the mice that survived infection with the stable slo mutant, indicating that dissemination of Slo ؊ GAS does not always cause disease. Finally, mice infected with the stable slo mutant exhibited a significant decrease in mortality rates compared to mice infected with wild-type GAS (P < 0.05), indicating that Slo plays an important role in GAS virulence.

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Motion Picture Study of the Toxic Action of Streptolysins on Leucocytes

Cited by 106 publications

References 7 publications

Cytotoxic Effects of Streptolysin O and Streptolysin S Enhance the Virulence of Poorly Encapsulated Group A Streptococci

Cytotoxic Effects of Streptolysin O and Streptolysin S Enhance the Virulence of Poorly Encapsulated Group A Streptococci

Streptolysin S Inhibits Neutrophil Recruitment during the Early Stages ofStreptococcus pyogenesInfection

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

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