Group B streptococcal b-hemolysin induces NO synthase in macrophages in vitro and multiorgan injury and death in vivo [abstract 26 (original) (raw)
Related papers
Group B Streptococcal β‐Hemolysin Induces Mortality and Liver Injury in Experimental Sepsis
The Journal of Infectious Diseases, 2002
New Zealand White rabbits were challenged with the wild-type (wt) group B streptococci (GBS) serotype III strain (COH1) and its isogenic nonhemolytic (NH) and hyperhemolytic (HH) mutants. Mortality differed significantly between rabbits infected with the HH mutant IN40 (67%), compared with rabbits infected with the wt COH1 strain (27%) and the NH strains COH1-20 and COH1:cyl EDcat (13% and 0%, respectively; P , :05). Histopathologically, disseminated septic microabscesses surrounded by necrotic foci were found exclusively in the livers of HH mutant IN40-infected animals. Serum transaminase levels were 20-fold higher in the HH-infected group, compared with rabbits infected with the other strains. Positive TUNEL (in situ terminal deoxynucleotide transferase-mediated dUTP nick end labeling) staining and activation of caspase-3 in hepatocytes were more frequent in HH-infected than in wt-infected animals and absent in the NH mutant COH1-20-infected group, indicating that GBS b-hemolysin triggers apoptotic pathways in hepatocytes. This work provides the first evidence that GBS b-hemolysin plays a crucial role in the pathophysiology of GBS sepsis by inducing liver failure and high mortality.
Group B Streptococcal �-Hemolysin Induces Nitric Oxide Production in Murine Macrophages
J Infec Dis, 2000
Group B streptococcus (GBS) is the leading cause of sepsis in neonates. Nitric oxide (NO) release plays a role in the hypotension that characterizes septic shock. To examine the role of the GBS b-hemolysin in NO production, the murine macrophage line RAW 264.7 was exposed to a wild-type (WT) GBS isolate and to hyperhemolytic (HH) and nonhemolytic (NH) transposon mutants derived from that isolate. After activation of macrophages by the WT strain, the HH mutant, or cell-free extracts of b-hemolysin, nitrite release into the supernatant increased 110-fold and inducible NO synthase (iNOS) levels in cell lysates increased up to 10-fold compared with treatment with the NH mutant or extracts from that mutant. Hemolysin-induced NO production was dependent on protein tyrosine kinases and NF-kB, but not on extracellular signal-related kinase-1/2-mitogen-activated kinases or protein kinase A. These results indicate that GBS b-hemolysin induces murine macrophage iNOS via intracellular pathways similar to those that mediate lipopolysaccharide-induced iNOS activation. Group B streptococcus (GBS; Streptococcus agalactiae) is the leading cause of pneumonia, meningitis, and septic shock in newborns, particularly those born prematurely [1]. All clinical isolates are encapsulated, and 98%-99% are b-hemolytic [2]. The GBS capsular polysaccharide contributes to virulence by virtue of its antiphagocytic property [3]. The GBS b-hemolysin, a potent membrane cytotoxin that injures lung epithelial [4] and endothelial [5] and brain endothelial [6] cells, may contribute to the pathogenesis of neonatal pneumonia and meningitis. Crude b-hemolysin preparations from GBS cultures induce cardiotoxicity and hypotension after intravenous administration to rabbits or rats, suggesting a role in septic shock [7]; however, the molecular mechanisms by which the GBS b-hemolysin may contribute to the pathogenesis of septic shock have not been delineated. The hypotension of septic shock is thought to be due in part to an excess production of nitric oxide (NO), as elevated NO levels are found in septic patients [8, 9]. Three isoforms of NO synthases (NOS) are present in mammals: the high-output in
Group B Streptococcal b-Hemolysin Induces Nitric Oxide Production
2015
Group B streptococcus (GBS) is the leading cause of sepsis in neonates. Nitric oxide (NO) release plays a role in the hypotension that characterizes septic shock. To examine the role of the GBS b-hemolysin in NO production, the murine macrophage line RAW 264.7 was exposed to a wild-type (WT) GBS isolate and to hyperhemolytic (HH) and nonhemolytic (NH) transposon mutants derived from that isolate. After activation of macrophages by the WT strain, the HH mutant, or cell-free extracts of b-hemolysin, nitrite release into the su-pernatant increased 110-fold and inducible NO synthase (iNOS) levels in cell lysates increased up to 10-fold compared with treatment with the NH mutant or extracts from that mutant. Hemolysin-induced NO production was dependent on protein tyrosine kinases and NF-kB, but not on extracellular signal-related kinase-1/2±mitogen-activated kinases or protein kinase A. These results indicate that GBS b-hemolysin induces murine macrophage iNOS via intra-cellular pathway...
Group B Streptococcal β‐Hemolysin Induces Nitric Oxide Production in Murine Macrophages
The Journal of Infectious Diseases, 2000
Group B streptococcus (GBS) is the leading cause of sepsis in neonates. Nitric oxide (NO) release plays a role in the hypotension that characterizes septic shock. To examine the role of the GBS b-hemolysin in NO production, the murine macrophage line RAW 264.7 was exposed to a wild-type (WT) GBS isolate and to hyperhemolytic (HH) and nonhemolytic (NH) transposon mutants derived from that isolate. After activation of macrophages by the WT strain, the HH mutant, or cell-free extracts of b-hemolysin, nitrite release into the supernatant increased 110-fold and inducible NO synthase (iNOS) levels in cell lysates increased up to 10-fold compared with treatment with the NH mutant or extracts from that mutant. Hemolysin-induced NO production was dependent on protein tyrosine kinases and NF-kB, but not on extracellular signal-related kinase-1/2-mitogen-activated kinases or protein kinase A. These results indicate that GBS b-hemolysin induces murine macrophage iNOS via intracellular pathways similar to those that mediate lipopolysaccharide-induced iNOS activation. Group B streptococcus (GBS; Streptococcus agalactiae) is the leading cause of pneumonia, meningitis, and septic shock in newborns, particularly those born prematurely [1]. All clinical isolates are encapsulated, and 98%-99% are b-hemolytic [2]. The GBS capsular polysaccharide contributes to virulence by virtue of its antiphagocytic property [3]. The GBS b-hemolysin, a potent membrane cytotoxin that injures lung epithelial [4] and endothelial [5] and brain endothelial [6] cells, may contribute to the pathogenesis of neonatal pneumonia and meningitis. Crude b-hemolysin preparations from GBS cultures induce cardiotoxicity and hypotension after intravenous administration to rabbits or rats, suggesting a role in septic shock [7]; however, the molecular mechanisms by which the GBS b-hemolysin may contribute to the pathogenesis of septic shock have not been delineated. The hypotension of septic shock is thought to be due in part to an excess production of nitric oxide (NO), as elevated NO levels are found in septic patients [8, 9]. Three isoforms of NO synthases (NOS) are present in mammals: the high-output in
The Journal of Infectious Diseases, 2002
Group B streptococcus (GBS) is the leading cause of sepsis in neonates. Nitric oxide (NO) release plays a role in the hypotension that characterizes septic shock. It has been shown that GBS b-hemolysin/cytolysin (b-h/c) stimulates the transcription of inducible NO synthase (iNOS) in murine macrophages via intracellular pathways similar to those that mediate lipopolysaccharide-induced iNOS activation. Here, it is demonstrated that the GBS cell wall and b-h/c act synergistically to induce iNOS in interferon (IFN)-a-primed RAW 264.7 murine macrophages. In nonprimed macrophages, combined activation by the GBS cell wall plus bh/c is necessary to induce an NO response, which indicates that both virulence factors cooperate to substitute for the priming signal typically provided by IFN-a. Group B streptococcus (GBS) is the leading cause of pneumonia, meningitis, and septic shock in newborns, particularly those born prematurely. All clinical isolates are encapsulated, and 98%-99% are b-hemolytic [1]. GBS b-hemolytic activity is mediated by a pore-forming cytotoxin, the genetic basis of which has recently been elucidated [2]. In vitro, the GBS b-hemolysin/cytolysin (b-h/c) is associated with injury to lung epithelial, lung endothelial, and brain endothelial cells and is thus speculated to contribute to GBS penetration of host cellular barriers. Very recently, we reported that b-h/c is responsible for high mortality and liver injury in a rabbit model of GBS septic shock [3]. The hypotension of septic shock is thought to be due, in part, to an excess production of nitric oxide (NO), because elevated NO levels are found in patients with sepsis. Three isoforms of NO synthases (NOS) are present in mammals, the high-output inducible NOS (iNOS) and 2 constitutive isoforms, one originally identified in neurons and the other in endothelial cells. Activated macrophages constitute a major source of NO production. The inflammatory activation of macrophages is thought to involve 2 sequential steps, priming and triggering [4]. Priming is initiated by binding of interferon (IFN)-a to its specific receptor, which results in a number of biochemical and functional alterations that render the macrophages sensitive to triggering agents such as proinflammatory cytokines, lipopolysaccharide (LPS) [4],
Mechanisms of Group B Streptococcal-Induced Apoptosis of Murine Macrophages
The Journal of Immunology, 2005
Apoptosis of murine and human macrophages induced by group B Streptococcus agalactiae (GBS) is likely an important virulence mechanism that is used by the bacteria to suppress the host immune response and to persist at sites of infection. The mechanisms by which GBS induces apoptosis are, however, largely unknown. In this study, we report that in murine macrophages GBS induces unique changes in the regulation and localization of the apoptotic regulators Bad, 14-3-3, and Omi/high-temperature requirement A2 and leads to the release of cytochrome c and the activation of caspase-9 and caspase-3. Furthermore, inhibition of caspase-3 impaired GBS-induced apoptosis of macrophages. The ability to modulate the activity of effector caspases may therefore represent an unexploited avenue for therapeutic intervention in GBS infections.
Molecular basis for group B beta-hemolytic streptococcal disease
Proceedings of the National Academy of Sciences, 1987
Group B j3-hemolytic Streptococcus (GBS) is a major pathogen affecting newborns. We have investigated the molecular mechanism underlying the respiratory distress induced in sheep after intravenous injection of a toxin produced by this organism. The pathophysiological response is characterized by pulmonary hypertension, followed by granulocytopenia and increased pulmonary vascular permeability to protein. 31P NMR studies of GBS toxin and model components before and after reductive alkaline hydrolysis demonstrated that phosphodiester residues are an integral part of the GBS toxin. Reductive alkaline treatment cleaves phosphate esters from secondary and primary alcohols and renders GBS toxin nontoxic in the sheep model and inactive as a mediator of elastase release in vitro from isolated human granulocytes. We propose that the interaction of cellular receptors with mannosyl phosphodiester groups plays an essential role in the pathophysiological response to GBS toxin.
Severity of Group B Streptococcal Arthritis Is Correlated with β‐Hemolysin Expression
Journal of Infectious Diseases, 2000
nates and adults. To examine the potential role of GBS b-hemolysin in joint injury, mice were infected with 2 wild-type strains or with nonhemolytic (NH) or hyperhemolytic (HH) variants derived by transposon mutagenesis. Compared with mice infected with the parent strains, mice infected with the NH mutants had decreased mortality and bacterial proliferation. A reduced LD 50 and a higher microbial load were obtained in mice infected with the HH mutants. Greater degrees of joint inflammation and damage were observed in the HH mutant-infected animals than in those infected with the parental strains. NH mutant-infected mice manifested only a mild and transient arthritis. Systemic and local levels of interleukin-6 mirrored the observed differences in virulence and severity of arthritis. These data support a direct correlation of GBS b-hemolysin expression with mortality and severity of articular lesions.