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PubMed2000

Structural evidence for the evolution of pyrogenic toxin superantigens.

Pathogenic bacteria have evolved a wide variety of toxins to invade and attack host organisms. In particular, strains of the bacteria Staphylococcus aureus and Streptococcus pyogenes produce a family of pyrogenic toxin superantigens (PTSAgs) that can cause illness, e.g., toxic shock syndrome, or synergize with a number of other immune system disorders. The PTSAgs are all similar in size and have a conserved two-domain tertiary fold despite minimal amino acid sequence identity. The tertiary structure of PTSAg domain 1 is similar to the immunoglobulin binding motif of streptococcal proteins G and L. PTSAg domain 2 resembles members of the oligosaccharide/oligonucleotide binding fold family that includes the B subunits of the AB(5) heat-labile enterotoxins, cholera toxin, pertussis toxin, and verotoxin. The strong structural homology between the pyrogenic toxins and other bacterial proteins suggests that the PTSAgs evolved through the recombination of two smaller beta-strand motifs.

Amino Acid Motifs↗
PubMed1983

Outbreak of pyrogenic reactions at a dialysis center. Association with infusion of heparinized saline solution.

Twenty-three pyrogenic reactions occurred in 16 patients undergoing hemodialysis at a private dialysis center in the south central United States between November 23 and December 2, 1978. No deaths were attributed to reactions; however, 10 patients were hospitalized for observation after experiencing a reaction. Cultures of all blood specimens obtained from the patients gave negative results. Chills (75 percent), nausea and/or vomiting (30 percent), and fever (90 percent) were the most common signs and symptoms, with mean times of onset after starting dialysis of 1.1, 1.6, and 3.6 hours, respectively. An epidemiologic and laboratory investigation documented that reactions occurred only in patients who had anticoagulation with a dilute solution of heparin. Analyses of heparinized saline solution used during the outbreak revealed a bacterial count of 7.4 X 10(5)/ml and a bacterial endotoxin level of 1,300 ng/ml. Acinetobacter calcoaceticus var. Iwoffi was isolated from the solution. Diluted heparin solution was prepared at the dialysis center by adding commercially supplied sodium heparin to 0.9 percent sodium chloride infusion fluid. Bacteria and endotoxin were not detected in vials of stock heparin and bags of unopened 0.9 percent sodium chloride infusion fluid. We concluded that contamination of the solution occurred at the dialysis center. After changes in the preparation and use of heparin were instituted on December 4, 1978, no pyrogenic reactions occurred in more than 400 subsequent dialyses.

Acinetobacter↗
PubMed1993

Interleukin-6 and tumor necrosis factor in cerebrospinal fluid: changes during pyrogen fever.

Several peptides (cytokines), viz., interleukin-1 (IL-1), interferon-alpha (IFN-alpha), interleukin-6 (IL-6), tumor necrosis factor (TNF), are formed in response to conditions causing tissue inflammation or damage and are implicated in reactive changes of the host, including fever, while IL-1 has been considered an important mediator of fever, the other cytokines, specifically IL-6 and TNF, have recently acquired prominence. The present study extends earlier research on IL-1 and addresses the question of the role of IL-6 and TNF in the genesis of fever. Experiments were conducted in the conscious cat, and IL-6 and TNF were assayed concomitantly in cerebrospinal fluid (CSF) from the third ventricle using specific bioassays. In the absence of fever, IL-6 was usually below the threshold of the assay (4-32 pg/ml), while TNF appeared measurable (424 +/- 57 pg/ml) in most experiments. A single intravenous injection of endotoxin (bolus) or continuous infusion of IL-1 at doses eliciting a sustained fever increased CSF levels of IL-6, but had no effect on concentrations of TNF. Intracerebroventricular injection of a pyrogenic dose of endotoxin led to an elevation of TNF and IL-6 and, in either case, the effect was manifest during the latent period before the fever. In addition, by the same route, IL-1 caused a rise in IL-6. We conclude that brain is intrinsically capable of producing both IL-6 and TNF depending on the site of challenge. However, since IL-6 CSF levels are elevated regardless of the site of pyrogen injection, IL-6 lends itself better to a role in the pathogenesis of fever.

Animals↗
PubMed1995

Response of newborn and adult sheep to pyrogens: relation between fever and brain eicosanoid changes.

We investigated whether the weak febrile response to pyrogens in newborns is due to a diminished activation of the putative pyrogen mediator, prostaglandin (PG)E2. Indwelling cannulas in the third ventricle of lambs (age, 5-31 days) and adult ewes were used to collect cerebrospinal fluid (CSF) for radioimmunoassay of PGE2. Intravenous (i.v.) endotoxin caused a smaller increase in body temperature but a larger increase in CSF PGE2 in lambs compared to adults. PGE2 by intracarotid infusion raised body temperature in 5 of 7 trials in 3 lambs and in 4 of 4 trials in 1 adult. Endotoxin given intracerebroventricularly (i.c.v.) induced a rise in temperature and CSF PGE2 in the lamb but, in the adult, these responses were delayed and smaller. Interleukin-1 i.c.v. and PGE2 i.c.v. were weak pyretic agents at both ages. We conclude that the lamb's diminished febrile response to endotoxin i.v. is not caused by a lesser rise in CSF PGE2, rather it may be due, at least in part, to reduced responsiveness to this putative mediator. Regardless of age, the sheep differs from other species in that pyrogen/PGE2 coupling occurs primarily at a site in brain that is better accessible from blood than CSF.

Animals↗
PubMed1994

Effect of dialyser membranes on extracellular and intracellular granulocyte and monocyte activation in ex vivo pyrogen-free conditions.

This study examined effects of blood-contacting materials on the monocyte reaction following the first contact of human blood with hollow fibre dialyser membranes under pyrogen-free conditions. Membrane materials were the unchanged regenerated cellulose, the synthetic polysulphone (PS), a positively charged diethylaminoethyl cellulose (DEAE-C), the negatively charged carboxymethyl cellulose (CMC) and acrylonitrile copolymer (AN). The experimental system involved perfusion with human fresh venous blood through different modules containing the materials in the form of hollow fibre membranes. Extracellular and intracellular aspects of blood reactions after the first contact with the materials were investigated in Ficoll-separated granulocytes and peripheral blood mononuclear cells. Investigations were done by release reactions of platelet activating factor (PAF), oxygen radical (O2-), leukotriene B4, prostaglandin E2 (PGE2) and cytokines (IL-1 beta, TNF-alpha, IL-6). The intracellular activation of peripheral blood mononuclear cells was done by mRNA transcription of IL-1 beta, TNF-alpha, IL-6, IL-8 and beta 2-microglobulin (beta 2-MG). From the set of parameters, release reactions were only measurable for PAF, PGE2 and O2- if a second stimulus (phorbol myristate acetate, lipopolysaccharide, zymosan and calcium ionophore) was used after blood-membrane interaction. Although the extent of the release reaction was weak, negatively charged membranes were, in general, more active. All dialysers exhibited the same increase in beta 2-MG mRNA transcription, suggesting that all blood-contacting membranes initiate the gene expression of beta 2-MG at the same level. TNF-alpha, IL-6, IL-1 beta and IL-8 mRNAs were demonstrated in the AN and CMC membranes rather than the other materials, which exhibit a lower transcription than the tubing set. As has been found, an enhanced generation of PGE2 for both CMC and AN membranes supports, therefore, the concept of an effect of the negative charges of the materials in the gene expression of cytokines. However, this initiation does not lead to the generation of cytokines, even after stimulation with pyrogens.

Animals↗
PubMed1990

Comparison of the effect of prazosin with that of dihydrobenzperidol and nifidepine on thermoregulatory responses produced by pyrogen in rabbits.

1. Thermal responses to prazosin (0.75 mg/kg; i.v.), dihydrobenzperidol (0.75 mg/kg or 2.25 mg/kg; i.v.), nifidepine (0.05 mg/kg or 0.16 mg/kg; i.v.) administered in the form of bolus injection or infusion were investigated in febrile rabbits. 2. Pyrogen (Escherichia coli lipopolysaccharide, LPS, 1 mcg/kg; i.v.) produced a fever reaction resulting from stimulation of the metabolic rate and heat conservation responses. 3. Prazosin (PRA) and dihydrobenzperidol (DHBP) reduced the pyretic as well as metabolic activity of pyrogen. The former drug enhanced heat elimination from the ear. 4. Nifidepine (ADA) did not significantly affect postpyrogen thermoregulatory parameters. 5. It is suggested that alpha-adrenergic receptor blockade might be responsible for the antipyretic activity of PRA and DHBP.

Animals↗
PubMed1998

Somnogenic and pyrogenic effects of interleukin-1beta and lipopolysaccharide in intact and vagotomized rats.

The vagus nerve appears to serve a role in mediating peripheral immunologic influences on CNS processes. Previous work demonstrates that subdiaphragmatic vagotomy prevents or attenuates many of the behavioral and physiological responses to exogenous interleukin-1 (IL-1) or lipopolysaccharide (LPS). We determined whether the somnogenic effects of IL-1 and LPS were altered in vagotomized rats, and whether the effects of vagotomy on IL-1- and LPS-induced alterations in sleep would vary as a function of circadian phase. The data indicate that vagotomy does not influence the normal circadian patterns of sleep and wakefulness in untreated rats, or modify the pyrogenic or somnogenic effects of intracerebroventricular administration of IL-1. However, in unchallenged animals vagotomy reduces basal brain temperatures, increases delta wave amplitudes during slow-wave sleep (SWS), and induces a reduced rate of weight gain, gastric distension, and adrenal hypoplasia. Vagotomy attenuates the febrile effects of IL-1 during both light and dark phases, attenuated IL-1-induced sleep enhancement during the dark phase, and attenuated IL-1-induced increases in delta wave amplitudes within SWS during the light period. In LPS-treated rats, vagotomy attenuates the febrile and SWS responses to LPS after administration at light onset, but not after administration at dark onset. These results indicate that subdiaphragmatic vagotomy attenuates several of the somnogenic and pyrogenic effects of IL-1beta and LPS, although the effectiveness of the vagal transection in modulating these responses is influenced by circadian factors.

Animals↗
PubMed1976

A surface antigen influenza vaccine. 2. Pyrogenicity and antigenicity.

Conventional influenza vaccine containing whole virus particles purified on a zonal centrifuge is pyrogenic and can cause systemic and local adverse side effects. An improved vaccine was therefore prepared which contained only the surface antigens of the virus adsorbed to aluminium hydroxide. The antigenicity of this vaccine was compared with conventional vaccine in chickens. Both vaccines induced similar titres of serum haemagglutination-inhibition and neuraminidase inhibition antibody. The dose response curves, however, were different. The surface antigens at vaccine strength without aluminium hydroxide were of negligible pyrogenicity in rabbits.

Animals↗
PubMed1999

Do only circulating pyrogenic cytokines act as mediators in the febrile response? A hypothesis.

The classical model of the pathogenesis of fever suggests that pyrogenic cytokines, produced by leucocytes in the bloodstream in response to exogenous pyrogens, represent the distal mediators of the febrile response. They are recognized at the level of the organum vasculosum of the lamina terminalis in the central nervous system, where they induce synthesis of prostaglandins representing the central mediators of the coordinated responses leading to fever. This classical model is challenged by studies showing inconsistencies between the febrile response and the cytokine pattern, as well as by data demonstrating paradoxical hyperfebrile reactions in knock-out mice lacking cytokines or cytokine receptors. Moreover, no measurable cytokine concentrations are to be found in a variety of specific patients groups with febrile conditions. There are recent data in the literature suggesting that alternative pathways may be involved in the induction of fever, ranging from the use of vagal fibres to transmit the signals leading to fever, to local production of cytokines at the level of the hypothalamus, or the use of membrane-bound cytokines as mediators. A multipathway mechanism for the induction of fever is suggested.

Animals↗
PubMed1981

Febrile and plasma iron responses of rabbits injected with endogenous pyrogen from malnourished patients.

The ability of human endogenous pyrogen (EP) harvested from malnourished patients (marasmic or kwashiorkor-like) to induce fever and a simultaneous hypoferremia in rabbits is described. Human peripheral blood leukocytes were obtained from malnourished adult patients before total parenteral nutrition support, and after 1 and 7 days on this therapeutic regime; the leukocytes were stimulated to produce EP in vitro and EP was injected into each rabbit. EP obtained from the leukocytes of patients with predominant protein deprivation syndromes (kwashiorkor) before nutritional support produced an attenuated fever (0.23 degrees C over 4 h) and a relatively unchanged plasma iron concentration (delta Fe = -15 microgram/100 ml over 4 h) in the rabbits. When EP was harvested from these same patients after 7 days of nutritional support therapy and was injected into rabbits, normal 4 h fevers (1.10 degrees C) and reduction in plasma iron levels (delta Fe = -97 micrograms/100 ml) occurred in the rabbits. Human EP obtained from patients with marasmus (predominant calorie deprivation syndromes) produced relatively normal fevers and changes in plasma iron levels in the rabbits, regardless of whether the samples were taken pre-total parenteral nutrition or after 1 and 7 days of total parenteral nutrition. These observations suggest that the synthesis of endogenous pyrogen by human peripheral leukocytes is sensitive to the availability of key substrates and that nutritional support therapy restores the capacity of these cells to produce EP in vitro.

Adult↗
PubMed1995

[Distribution of the genes of streptococcal pyrogenic exotoxin among clinical isolates of Streptococcus pyogenes from the pharynx].

The distribution of the genes of streptococcal pyrogenic exotoxin (speA, B and C) among the 400 clinical isolates of Streptococcus pyogenes from Japanese pharnyx was detected by the PCR method (Nihonrinsho 50: 326, 1992). Sixty, 399 and 303 isolates were positive for the speA, B and C genes, respectively. However, only one isolate had none of these genes. Several isolates possessed two or three genes, i.e., both speB & C, speA & B or speA, B & C were found in 258, 30 and 30 isolates, respectively. No isolate possessing both speA & C without speB was found in this study. We concluded that the PCR method is much more useful for the epidemiological study on streptococcal pyrogenic exotoxins (SPE) of S. pyogenes isolates because of specificity, rapidity and sensitivity of this method compared with the conventional SPE identification method.

Exotoxins↗
PubMed1980

Relative potencies of four reference endotoxin standards as measured by the Limulus amoebocyte lysate and USP rabbit pyrogen tests.

Four commonly used reference endotoxin standards, Escherichia coli O113:H10:K0, E. coli O55:B5, Salmonella abortusequi, and Shigella dysenteriae were compared by the USP rabbit pyrogen and the Limulus amoebocyte lysate tests. By the rabbit pyrogen test, S. abortus equi was identified as the most potent endotoxin, followed closely by E. coli O113:H10:K0 and E. coli O55:B5.

Animals↗
PubMed1996

A new procedure for the purification of streptococcal pyrogenic exotoxin A from Streptococcus pyogenes supernatant.

An important role in the pathogenesis of invasive group A streptococcal disease has been ascribed to the production of streptococcal pyrogenic exotoxin A. We present a new technique for the purification of streptococcal pyrogenic exotoxin A from Streptococcus pyogenes NY-5 supernate, which is highly efficient with respect to yield (35%), purity (> or = 99%), and time.

Bacterial Proteins↗
PubMed1979

Natural phosphorylation of group A streptococcal pyrogenic exotoxin type C.

Group A streptococcal pyrogenic exotoxin (SPE) type C, produced by strain T18P grown in the presence of 32P, was separated from culture supernatant fluids by using alcohol precipitation. The resulting toxin (EtOH-1) contained 3 X 10(6) to 5 X 10(6) cpm of 32P per milligram of protein. The radiolabel migrated with SPE C during isoelectric focusing in polyacrylamide gels (pI 6.7) and double immunodiffusion, in which the toxin formed a line of identity with highly purified SPE C when reacted with hyperimmune antisera raised against SPE C. The EtOH-1 radiolabeled toxin was pyrogenic and had the capacity to enhance host susceptibility to lethal endotoxin shock. EtOH-1 toxin lost both radiolabel and biological activity after being treated with alkaline phosphatase. The nonspecific lymphocyte mitogenicity of purified unlabeled SPE C was stimulated by adenosine monophosphate but not adenosine, adenosine diphosphate, or adenosine triphosphate. Adenosine monophosphate may function as a cofactor of SPE C and contribute the phosphate group required for biological activity.

Adenosine Monophosphate↗
PubMed1988

Nucleotide sequence of streptococcal pyrogenic exotoxin type C.

The nucleotide sequence of the gene speC, encoding streptococcal pyrogenic exotoxin type C (SPE C), was determined. The gene encoded a mature protein of 208 amino acids, with a calculated molecular weight of 24,354. The mature amino acid sequence of SPE C was analyzed for homology with the amino acid sequences of streptococcal pyrogenic exotoxin type A, the staphylococcal enterotoxins, and toxic shock syndrome toxin-1. Of these, SPE C shared the greatest amount of homology with streptococcal exotoxin type A.

Amino Acid Sequence↗
PubMed1991

Cell and receptor requirements for streptococcal pyrogenic exotoxin T-cell mitogenicity.

Streptococcal pyrogenic exotoxins (SPEs) A, B, and C, like other members of the pyrogenic toxin family, are able to cause toxic shock-like syndromes. One of the major properties of these toxins is the ability to induce T-cell proliferation. Characterization of T cell mitogenicity associated with SPEs A, B, and C was undertaken. SPEs A, B, and C were mitogenic for C57BL10/SnJ and BALB/cWAT T cells, with activities differing in intensity depending on the mouse strain and toxin employed. SPE-induced, T-cell-proliferative activity was dependent on class II major histocompatibility complex molecules expressed on antigen-presenting cells. The abilities of SPEs A, B, and C to preferentially stimulate murine cells with certain T-cell receptor V beta s were investigated by fluorescence-activated cell sorter analysis. SPE A preferentially activated T cells expressing V beta 8 but not V beta 3, 6, or 11, while SPEs B and C preferentially stimulated T cells which did not express any of the tested V beta s.

Animals↗
PubMed1995

Revised sequence of the Porphyromonas gingivalis prtT cysteine protease/hemagglutinin gene: homology with streptococcal pyrogenic exotoxin B/streptococcal proteinase.

The prtT gene from Porphyromonas gingivalis ATCC 53977 was previously isolated from an Escherichia coli clone possessing trypsinlike protease activity upstream of a region encoding hemagglutinin activity (J. Otogoto and H. Kuramitsu, Infect. Immun. 61;117-123, 1993). Subsequent molecular analysis of this gene has revealed that the PrtT protein is larger than originally reported, encompassing the hemagglutination region. Results of primer extension experiments indicate that the translation start site was originally misidentified. An alternate open reading frame of nearly 2.7 kb, which encodes a protein in the size range of 96 to 99 kDa, was identified. In vitro transcription-translation experiments confirm this size, and Northern (RNA) blot experiments indicate that the protease is translated from a 3.3-kb mRNA. Searching the EMBL protein database revealed that the amino acid sequence of the revised PrtT is similar to sequences of two related proteins from Streptococcus pyogenes. PrtT is 31% identical and 73% similar over 401 amino acids to streptococcal pyrogenic exotoxin B. In addition, it is 36% identical and 74% similar over 244 amino acids with streptococcal proteinase, which is closely related to streptococcal pyrogenic exotoxin B. The similarity is particularly high at the putative active site of streptococcal proteinase, which is similar to the active sites of the family of cysteine proteases. Thus, we conclude that PrtT is a 96- to 99-kDa cysteine protease and hemagglutinin with significant similarity to streptococcal enzymes.

Amino Acid Sequence↗
PubMed1995

Mitogenicity of M5 protein extracted from Streptococcus pyogenes cells is due to streptococcal pyrogenic exotoxin C and mitogenic factor MF.

M proteins of Streptococcus pyogenes are virulence factors which impede phagocytosis, bind to many plasma proteins, and induce formation of cross-reactive autoimmune antibodies. Recently, it has been reported that some M proteins, extracted with pepsin from streptococci (pep M), are superantigens. One of these, pep M5, was investigated in detail and was shown to stimulate human T cells bearing V beta 2, V beta 4, and V beta 8. In the present study, we extracted and purified M5 protein by different biochemical methods from two M type 5 group A streptococcal strains. The crude extracts were fractionated by affinity chromatography and ion-exchange chromatography. All fractions were tested in parallel for M protein by immunoblotting and for T-cell-stimulating activity. Although several crude preparations of M5 protein were associated with mitogenicity for V beta 2 and V beta 8 T cells, the M5 proteins, irrespective of the extraction method, could be purified to the extent that they were no longer mitogenic. The mitogenic activity was not destroyed during the purification procedures but was found in fractions separated from M protein. In these fractions, streptococcal pyrogenic exotoxin C and mitogenic factor MF could be detected by protein blotting and enzyme-linked immunosorbent assay. Moreover, anti-M protein sera did not inhibit the mitogenic activity of crude extracts, but antisera which contained anti-streptococcal pyrogenic exotoxin C antibodies showed inhibition. The inability of M5 protein to stimulate T cells was confirmed with recombinant pep M5 produced in Escherichia coli. Our data strongly suggest that the mitogenic activity in M protein preparations is caused by traces of streptococcal superantigens different from M protein.

Amino Acid Sequence↗