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PubMed1989

Quantification and toxicity of group A streptococcal pyrogenic exotoxins in an animal model of toxic shock syndrome-like illness.

Toxic shock-like syndrome isolates of group A streptococci were evaluated for production of pyrogenic exotoxins (also called SPEs, scarlet fever toxins, and erythrogenic toxins). The isolates were consecutively obtained during 1987 and 1988. Of these isolates, 23 of 26 made SPE type A, 10 of 26 made SPE B, and 8 of 26 made SPE C. SPE A was produced in significantly greater amounts than SPEs B and C (3.2 micrograms/ml of culture fluid compared with 0.7 and 0.6 microgram/ml, respectively). SPE A, administered in miniosmotic pumps implanted subcutaneously in rabbits, was significantly more toxic than SPE C; seven of eight rabbits succumbed after challenge with 150 or 300 micrograms of SPE A, compared with one of six after challenge with SPE C.

Animals↗
PubMed1992

Streptococcus pyogenes pharyngitis: characterization of strains by multilocus enzyme genotype, M and T protein serotype, and pyrogenic exotoxin gene probing.

Multilocus enzyme electrophoresis, serological characterization of M and T proteins, and probing for pyrogenic exotoxin A and C genes were used to investigate the bacteriologic epidemiology of strains of Streptococcus pyogenes recovered primarily from patients with recurrent pharyngitis. A total of 164 strains recovered from individuals living in nine states of the United States was analyzed. Two-thirds of the patients in our sample were infected with the homologous strain following antibiotic therapy and presumably represented treatment failures, whereas the other one-third of the patients were infected with a heterologous strain after therapy and probably represented reinfections. Multilocus enzyme electrophoresis was as efficacious in strain discrimination as serologic typing techniques were and, in addition, successfully characterized all organisms that were serologically nontypeable. Two clones of S. pyogenes responsible for most of the episodes of toxic shock-like syndrome in the United States are geographically widespread, but they vary by locality in the frequency of their occurrence. Compared with a sample of strains cultured from patients whose pharyngeal infections were eliminated by antimicrobial therapy, these two clones were statistically overrepresented among organisms that cause recurrent pharyngitis.

Antigens, Bacterial↗
PubMed1998

Diagnosis of group A streptococcal necrotizing fasciitis by using PCR to amplify the streptococcal pyrogenic exotoxin B gene.

This study evaluated a PCR assay for detection of the streptococcal pyrogenic exotoxin B (speB) gene from tissue biopsy specimens of patients with necrotizing fasciitis. speB was detected in specimens from all 10 patients with necrotizing fasciitis due to group A streptococcus. The assay was negative for all 11 patients without culture or serologic evidence of streptococcal infection. These results suggest that the detection of speB by PCR may be useful for confirming group A streptococcal infection when cultures are negative or not available.

Bacterial Proteins↗
PubMed2003

Prevalence of genes encoding pyrogenic toxin superantigens and exfoliative toxins among strains of Staphylococcus aureus isolated from blood and nasal specimens.

A total of 429 different Staphylococcus aureus isolates encompassing 219 blood isolates and 210 isolates taken from anterior nares were systematically searched by two multiplex PCR-DNA enzyme immunoassays (PCR-DEIA) for exfoliative toxin (ET) genes eta and etb, as well as for the classical members of the pyrogenic toxin superantigen (PTSAg) gene family comprising the staphylococcal enterotoxin (SE) genes sea-see and the toxic shock syndrome toxin 1 gene tst. In addition, a third PCR-DEIA was established to investigate the possession of four recently described SE genes, viz. seg-sej. The most frequent PTSAg/ET genes amplified were seg and sei, which were found strictly in combination in 55.0% of the S. aureus isolates tested. Other frequently detected toxin genes were tst (20.3%), sea (15.9%), and sec (11.2%). Only five isolates harbored ET genes. Regarding the origin of the S. aureus isolates, a significant difference (P = 0.037) was found for the possession of the sed/sej gene combination (10.5% of blood isolates versus 3.3% of nasal strains). Overall, about half of S. aureus isolates tested harbored genes of the classical members of the PTSAg family and ETs (50.8%), whereas 73.0% of S. aureus isolates were toxin gene positive if the recently described SE genes were included. This notable higher prevalence indicates that the possession of PTSAg genes in particular seems to be a habitual feature of S. aureus. Moreover, mainly due to the fixed combinations of seg plus sei, as well as sed plus sej, the possession of multiple PTSAg genes (62.9%) is more frequent than assumed so far.

Bacteremia↗
PubMed2005

Cytotoxin and pyrogenic toxin superantigen gene profiles of Staphylococcus aureus associated with subclinical mastitis in dairy cows and relationships with macrorestriction genomic profiles.

A set of 84 Staphylococcus aureus isolates collected from the milk of cows with subclinical mastitis in Asturias (a cattle region of Spain) and six control strains were tested for sequences of genes encoding hemolysins (hla, hlb, hld, hlg, and hlg-2), leukotoxins (lukPV, lukM, and lukED), toxic shock syndrome toxin (tst), and enterotoxins (sea to see, seg to ser, and seu) by conventional and multiplex PCR. It was found that 84, 83, 11, and 39 isolates carried some type of hl, luk, tst, or se gene, respectively, which were arranged in 14 exotoxin genotypes. All of the isolates were negative for lukPV, hlg, sea, sed, see, sej, sek, sep, seq, and ser. Two gene groupings could be related with pathogenicity islands-[lukED, seg, sei, sem, sen, seo +/- seu] with Sabeta-1 and [tst, sec, sel] with SaPIbov, present in 45 and 13.1% of the isolates, respectively-while 11.9% of them carried both islands. Only one contained seb (together with upsilonSabeta-1), and another contained seh (together with lukED). The isolates were also analyzed by pulsed-field gel electrophoresis performed with SmaI. Thirty-nine SmaI profiles (similarity coefficient [S] = 0.94 to 0.21) were differentiated; 12, 1, and 10 of these, respectively, were generated by isolates presumptively carrying Sabeta-1, SaPIbov, or both. Five SmaI profiles (S > or = 0.8) formed a cluster, which contained 20 and 10 isolates carrying one (upsilonSabeta-1) or both islands. These data show the high frequency of genes encoding cytotoxins and pyrogenic toxin superantigens, their relationship with pathogenicity islands, and their distribution among a diversity of genetic types of S. aureus related to subclinical mastitis.

Animals↗
PubMed1994

Cysteine protease activity of streptococcal pyrogenic exotoxin B.

Streptococcal pyrogenic exotoxin B (SPE B) was purified and its protease and mitogenic activities were investigated. The apparent molecular mass of SPE B purified in the presence of iodoacetic acid was 42 kDa, whereas 29-kDa SPE B was predominant without the reagent. A polyclonal antibody raised against the 29-kDa species reacted with both species, indicating that the 42-kDa species was a precursor of the 29-kDa entity. Both the 42- and 29-kDa species enhanced [3H]thymidine incorporation into human peripheral blood mononuclear cells, whereas neither had any effect on T cell depleted mononuclear cells. The 29-kDa SPE B possessed caseinolytic activity, with an optimal pH of 8, and the activity was specifically suppressed by the antibody. A group of cysteine protease inhibitors, but no serine-, metallo-, or acidic-protease inhibitors, limited the protease activity, whereas dithiothreitol increased the activity. The DNA sequence around a putative active cysteine residue was identical among the speB genes from Streptococcus pyogenes R70, NY-5, and T19. Taken together, these results indicate that SPE B is identical to a cysteine protease, streptopain (EC 3.4.22.10).

Amino Acid Sequence↗
PubMed1996

Expression of T-cell receptor V beta 2 and type 1 helper T-cell-related cytokine mRNA in streptococcal pyrogenic exotoxin-C-activated human peripheral blood mononuclear cells.

Streptococcal pyrogenic exotoxin type C (SPE C) is a member of the bacterial superantigens that are potent stimulants of T cells. We expressed SPE C in Escherichia coli and characterized its selective stimulation properties on human T cells bearing specific V beta chains of T-cell receptors (TCRs). Cytokine profiles induced by SPE C were also examined. Recombinant SPE C significantly enhanced proliferation of human peripheral blood mononuclear cells (PBMCs) at concentrations as low as 10(-12)-10(-14)M. Reverse transcription of RNA, from SPE-C-stimulated PBMCs followed by polymerase chain reaction, revealed selective induction of TCR V beta 2 chain expression. SPE C raised the mRNA level of type 1 helper T cell (TH1) related cytokines, such as interferon gamma (IFN-gamma), interleukin 2 (IL-2), and tumor necrosis factor beta (TNF beta). The expression of TNF alpha was also increased. In contrast, the increase in mRNA levels of the p35 small fragment of IL-12 and type 2 helper T cell (TH2) related cytokines (i.e., IL-4 and IL-10) was not significantly affected by SPE C. The mRNA level of proinflammatory cytokine IL-6 was increased marginally. Consistent with the mRNA accumulation, protein concentrations of IFN gamma, IL-2, and TNF were increased in SPE-C-stimulated PBMCs, but IL-4 was not. From these results, we conclude that the stimuli of SPE C preferentially causes the TH1 responses in human T cells bearing TCR V beta 2.

Bacterial Proteins↗
PubMed1989

Pyrogenic and thermogenic effects of interleukin 1 beta in the rat.

Single injections of recombinant human interleukin 1 beta (IL-1 beta) caused large (up to 2 degrees C) and sustained (3 h) increases in body temperature in conscious rats. Intracerebroventricular injections (10-100 ng) were much more effective and elicited greater responses than intravenous injections (0.1-1 microgram). IL-1 beta increased resting oxygen consumption by 25-49% in a dose-dependent manner. The activity of the thermogenic proton conductance pathway in brown adipose tissue (BAT) mitochondria was assessed from purine nucleotide (GDP) binding and was elevated by 40 and 86% 1 h after intravenous (1 microgram) or intracerebroventricular (100 ng) injection of IL-1 beta, respectively. Regional tissue blood flow was determined in anesthetized rats from the distribution of radiolabeled microspheres. Blood flow to liver (hepatic arterial), testes, skin, and white adipose tissue was unaffected by IL-1 beta injection. Blood flow to brain and kidney was increased (142 and 50%) but reduced (58%) to skeletal muscle after intravenous but not intracerebroventricular injection of interleukin. In contrast, blood flow to BAT was markedly elevated after intravenous (288%) or intracerebroventricular (382%) injection of IL-1 beta. Severing the sympathetic nerves supplying the interscapular BAT depot prevented the increase in blood flow. These data indicate that the potent pyrogenic effects of IL-1 beta in the rat are due largely to a central action. Fever is associated with increases in metabolic rate and BAT activity, and these results provide support for the involvement of brown fat in thermogenesis associated with fever.

Adipose Tissue, Brown↗
PubMed2006

Exercise can be pyrogenic in humans.

Exercise increases mean body temperature (T(body)) and cytokine concentrations in plasma. Cytokines facilitate PG production via cyclooxygenase (COX) enzymes, and PGE(2) can mediate fever. Therefore, we used a COX-2 inhibitor to test the hypothesis that PG-mediated pyrogenicity may contribute to the raised T(body) in exercising humans. In a double-blind, cross-over design, 10 males [age: 23 yr (SD 5), Vo(2 max): 53 ml x kg(-1) x min(-1) (SD 5)] consumed rofecoxib (50 mg/day; NSAID) or placebo (PLAC) for 6 days, 2 wk apart. Exercising thermoregulation was measured on day 6 during 45-min running ( approximately 75% Vo(2 max)) followed by 45-min cycling and 60-min seated recovery (28 degrees C, 50% relative humidity). Plasma cytokine (TNF-alpha, IL-10) concentrations were measured at rest and 30-min recovery. T(body) was similar at rest in PLAC (35.59 degrees C) and NSAID (35.53 degrees C) and increased similarly during running, but became 0.33 degrees C (SD 0.26) lower in NSAID during cycling (37.39 degrees C vs. 37.07 degrees C; P = 0.03), and remained lower throughout recovery. Sweating was initiated at T(body) of approximately 35.6 degrees C in both conditions but ceased at higher T(body) in PLAC than NSAID during recovery [36.66 degrees C (SD 0.36) vs. 36.39 degrees C (SD 0.27); P = 0.03]. Cardiac frequency averaged 6 x min(-1) higher in PLAC (P < 0.01), whereas exercising metabolic rate was similar (505 vs. 507 W x m(-2); P = 0.56). A modest increase in both cytokines across exercise was similar between conditions. COX-2 specific NSAID lowered exercising heat and cardiovascular strain and the sweating (offset) threshold, independently of heat production, indicating that PGE-mediated inflammatory processes may contribute to exercising heat strain during endurance exercise in humans.

Adult↗
PubMed1986

Rat endogenous pyrogen and fever.

Rat endogenous pyrogen (EP), prepared from the white blood cells of lipopolysaccharide-pretreated rats, produced a fever in both rabbits and rats. The effects of human, rabbit, and rat EP on the body temperatures of rabbits and rats were investigated to clarify differences in the febrile response to each kind of EP. The latency to fever onset and the time to peak fever induced by rat EP in rabbits and rats were significantly greater than those induced by human and rabbit EP. The maximum elevation of the body temperature induced by rat EP in both animals was almost identical to that induced by human and rabbit EP. In a comparison of the febrile responses to various EPs between rabbits and rats, the latency to fever onset, the time to peak, and the maximum elevation of fever in rats were approximately half those observed for rabbits. Furthermore, the threshold dosage to induce a fever response in rats was greater than that necessary for rabbits. It is concluded that rat EP could be obtained by in vitro techniques and that rats have the physiological mechanisms to develop a fever through production of EP.

Animals↗
PubMed1986

Dehydration enhances endotoxin fever by increased production of endogenous pyrogen.

The febrile responses in rats to an intravenous injection of the bacterial endotoxin Salmonella typhosa were investigated under normally hydrated and dehydrated conditions. When endotoxin was injected intravenously into the dehydrated rats, a biphasic-patterned fever resulted, whereas in normal rats an intravenous injection of endotoxin did not induce fever. No significant differences in febrile responses to the intravenous endogenous pyrogen (EP), prostaglandin E2, and intracerebroventricular prostaglandin E2 between normal and dehydrated rats were observed. When the blood plasma obtained from rats with endotoxin-induced fever under dehydrated conditions was transferred to the normal rats, a significant rise in the body temperature was induced. The effect of hydration by an administration of the hypotonic solution after dehydration was examined in endotoxin-induced fever and in changes of the basic blood parameters. It is concluded that febrile responses to endotoxin during dehydrated condition are caused by an increased production of EP. The migration of leukocytes from circulation to any other tissue will be an important factor in producing EP under dehydrated conditions. Furthermore, under dehydrated condition, EP may be produced by numerous macrophages in tissues in vivo, where many kinds of leukocytes migrate and exchange signals with each other in developing an immune response.

Animals↗
PubMed1990

Somnogenic, pyrogenic, and hematologic effects of bacterial peptidoglycan.

Bacterial infections and certain muramyl peptides elicit a variety of pathophysiological effects including increases in body temperature and slow-wave sleep. Bacterial cell wall peptidoglycan is composed of muramyl peptides. To investigate the ability of isolated bacterial cell walls to enhance slow-wave sleep, rabbits were injected intravenously with cell walls isolated from Staphylococcus aureus or with soluble peptidoglycan prepared from Neisseria gonorrhoeae. These injections increased slow-wave sleep, electroencephalographic delta-wave amplitudes, and body temperature, reduced rapid-eye-movement sleep, and induced neutrophilia and lymphopenia. The somnogenic and pyrogenic effects of S. aureus cell walls developed within 1 h and persisted throughout the recording period. Injections of N. gonorrhoeae peptidoglycan induced similar effects but of larger magnitude and shorter duration. We conclude that peptidoglycan is a bacterial component that mediates the increased sleep observed during infectious disease.

Animals↗
PubMed1978

Pyrogenic renal hyperemia: the role of prostaglandins.

The intravenous administration of triple typhoid vaccine to anesthetized dogs resulted in a significant increase in renal blood flow accompanied by a modest decline in systemic blood pressure. This renal hyperemia was associated with elevated renal secretory rates of renin and prostaglandin E and F. Measurements of the intracortical distribution of radiolabeled microspheres revealed a progressive decrease in outer cortical blood flow rates and a progressive increase in inner cortical flow rates. When meclofenamate, an inhibitor of prostaglandin synthetase, was administered concomitantly with triple typhoid vaccine renal hyperemia did not develop. The renal renin secretory rate increased modestly and intracortical renal blood flow was not redistributed. The increased renal blood flow after triple typhoid vaccine administration to unanesthetized dogs was also reversed by meclofenamate. The marked increase in prostaglandin secretion by the kidney during renal hyperemia following triple typhoid vaccine administration (pyrogen), and the effect of meclofenamate, is consonant with a role for increased renal synthesis and release of prostaglandins.

Animals↗
PubMed1985

Effect of age on the febrile response of rats to endogenous pyrogen.

Mechanisms underlying the decreased febrile response in the elderly have not been elucidated. One hypothesis is that elderly persons have a decreased response at the hypothalamic or peripheral effector level to endogenous pyrogen (EP). We studied the response to human monocyte-derived EP in young adult and aged Fischer 344 rats, a strain known to have an age-dependent decrease in the febrile response to endotoxin. EP was given intraperitoneally to aged and young adult rats kept at 26 degrees C (thermoneutral zone) or at 15 degrees C (a mild cold stress), in order to accentuate possible peripheral thermoeffector defects. At 26 degrees C, the febrile response in aged rats was similar to that in young adult rats. At 15 degrees C, the febrile response was lower in both groups, but the aged rats did not differ from the young adult rats. When EP was given by intracerebroventricular injection to aged and young adult rats, at 26 or at 15 degrees C, no differences in the febrile responses were noted. Thus, it appears that in aged Fischer rats the hypothalamic response and the peripheral effector response to EP are intact. Further studies on the production and release of EP by rat monocytes are needed to explain the diminished febrile response to endotoxin in the aged rat.

Aging↗
PubMed2006

Pulmonary toxicity screening studies in male rats with TiO2 particulates substantially encapsulated with pyrogenically deposited, amorphous silica.

The aim of this study was to evaluate the acute lung toxicity in rats of intratracheally instilled TiO2 particles that have been substantially encapsulated with pyrogenically deposited, amorphous silica. Groups of rats were intratracheally instilled either with doses of 1 or 5 mg/kg of hydrophilic Pigment A TiO2 particles or doses of 1 or 5 mg/kg of the following control or particle-types: 1) R-100 TiO2 particles (hydrophilic in nature); 2) quartz particles, 3) carbonyl iron particles. Phosphate-buffered saline (PBS) instilled rats served as additional controls. Following exposures, the lungs of PBS and particle-exposed rats were evaluated for bronchoalveolar lavage (BAL) fluid inflammatory markers, cell proliferation, and by histopathology at post-instillation time points of 24 hrs, 1 week, 1 month and 3 months. The bronchoalveolar lavage results demonstrated that lung exposures to quartz particles, at both concentrations but particularly at the higher dose, produced significant increases vs. controls in pulmonary inflammation and cytotoxicity indices. Exposures to Pigment A or R-100 TiO2 particles produced transient inflammatory and cell injury effects at 24 hours postexposure (pe), but these effects were not sustained when compared to quartz-related effects. Exposures to carbonyl iron particles or PBS resulted only in minor, short-term and reversible lung inflammation, likely related to the effects of the instillation procedure. Histopathological analyses of lung tissues revealed that pulmonary exposures to Pigment A TiO2 particles produced minor inflammation at 24 hours postexposure and these effects were not significantly different from exposures to R-100 or carbonyl iron particles. Pigment A-exposed lung tissue sections appeared normal at 1 and 3 months postexposure. In contrast, pulmonary exposures to quartz particles in rats produced a dose-dependent lung inflammatory response characterized by neutrophils and foamy (lipid-containing) alveolar macrophage accumulation as well as evidence of early lung tissue thickening consistent with the development of pulmonary fibrosis. Based on our results, we conclude the following: 1) Pulmonary instillation exposures to Pigment A TiO2 particles at 5 mg/kg produced a transient lung inflammatory response which was not different from the lung response to R-100 TiO2 particles or carbonyl iron particles; 2) the response to Pigment A was substantially less active in terms of inflammation, cytotoxicity, and fibrogenic effects than the positive control particle-type, quartz particles. Thus, based on the findings of this study, we would expect that inhaled Pigment A TiO2 particles would have a low risk potential for producing adverse pulmonary health effects.

Journal Article↗
PubMed1998

Transient low T cell response to streptococcal pyrogenic exotoxin-C in patients with Kawasaki disease.

Superantigens (SAs) are known to induce transient anergy followed by T cell activation. Recent reports have suggested that SAs are involved in the pathogenesis of Kawasaki disease (KD). In the present study, we investigated the peripheral T cell response to SAs by measuring proliferation and IL-2 production to determine whether the T cell anergy is induced by SAs in patients with KD. T cells were obtained from 45 Japanese patients with KD in different stages of the disease and were stimulated by streptococcal pyrogenic exotoxin (SPE)-A, SPE-C, and toxic shock syndrome toxin-1 (TSST-1). T cells from patients with KD in the acute or convalescent stage up to 2 mo showed significantly lower proliferation and IL-2 production than did T cells from healthy control subjects stimulated by SPE-C, but not SPE-A or TSST-1. The T cell response to SPE-C normalized within 1 y. The low T cell response to SPE-C in the acute stage correlated with a peak platelet count and the C-reactive protein-positive period. These findings suggest that the transient low T cell response to SPE-C in patients with KD may have been related to SA-induced anergy or disappearance of SPE-C-responding cells from the circulation. The present results suggested that SPE-C may be involved in the pathogenesis of KD.

Acute Disease↗
PubMed2003

Relation of streptococcal pyrogenic exotoxin C as a causative superantigen for Kawasaki disease.

We previously reported that the frequency of TCRBV2 and TCRBV6S5-bearing T-cells was high in patients in the acute phase of Kawasaki disease (KD) and that streptococcal pyrogenic exotoxin C (SPE-C) was a potent stimulator of these TCRBV-bearing T-cells. To further elucidate the pathogenesis of KD, we examined the T-cell receptor (TCR) repertoire, human leukocyte antigen (HLA)-DRB1 genotype, and antibody responses to recombinant(r) SPE-C in patients with KD. We also performed in vitro stimulation with rSPE-A and rSPE-C of peripheral blood mononuclear cells from healthy donors and characterized the reacting T-cells. The percentage of T-cells bearing TCRBV2 and TCRBV6S5 was high in patients in the acute stage of KD. rSPE-C stimulation of PBMC from healthy donors induced expansion of TCRBV2 and TCRBV6S5-bearing T-cells. Furthermore, serum levels of anti-SPEC antibodies, which did not display antimitogenic activity, were higher in patients with acute KD than in age-matched controls. The frequencies of the DRB1*04051, 0406, and 0901 were high, whereas that of the DRB1*1101 was low among patients with KD as compared with the healthy adults.

Antibodies, Bacterial↗
PubMed2001

[Cloning of group A streptococcal pyrogenic exotoxin-B gene and its recombinant protein expression in culture supernatant].

Streptococcal pyrogenic exotoxin B, a conserved cysteine protease (SPE B/SCP) released by group A Streptococcus (GAS) strains, is considered to be an important virulence factor of this bacterium. This paper reports the cloning of gene encoding SPE B/SCP. For production of recombinant SPE B/SCP (rSPE B/SCP), the primers specific for the SPE B/SCP gene (spe b) were designed based on its nucleotide sequence. Polymerase chain reaction (PCR) was performed with the genomic DNA of GAS strain NZ131 as a template. The amplified PCR products were purified and cloned into the pBluescript II SK(+) plasmid vector. The vector was transformed into Escherichia coli (E. coli) JM109. The rSPE B/SCP and its recombinant proenzyme (rzym) were secreted in the culture supernate of the transformant. The rSPE B/SCP was purified from the supernatant by sequential chromatography on DEAE-Sepharose, matrix gel Red A and Sephadex G-50 columns. The purified rzym and rSPE B/SCP, respectively, gave a single band with a molecular weight approximately 40 kDa and 27 kDa on SDS-polyacrylamide gel electrophoresis, and reacted with anti-SPE B/SCP antibodies in Western Blot analysis. This is the first report in which rSPE B/SCP was obtained from the culture supernate of the transformant.

Bacterial Proteins↗