ABSTRACT
Cladophialophora bantiana is an uncommon fungus related to the black yeasts which causes, if untreated, mostly fatal cerebral infections in immunosuppressed and competent patients. We report a case of a patient who survived a recurrent cerebral abscess caused by C. bantiana despite delayed and apparently inappropriate therapy.
Subject(s)
Brain Abscess/microbiology , Cladosporium/isolation & purification , Adult , Antifungal Agents/pharmacology , Antifungal Agents/therapeutic use , Brain Abscess/diagnosis , Brain Abscess/drug therapy , Central Nervous System Fungal Infections/diagnosis , Central Nervous System Fungal Infections/drug therapy , Cladosporium/classification , Humans , MaleABSTRACT
The lethal effects occurring in neonatal (< 24-h old) BALB/c mice after challenge with E. coli lipopolysaccharide (LPS) were significantly counteracted by pretreatment with antibacterial peptide PR-39. Neonatal mice protection was probably related to the depressive effect of PR-39 on production of TNF-alpha known to be the major mediator of the lethal effects of neonatal endotoxic shock. Indeed, TNF-alpha plasmatic levels were consistently lower in pups pretreated with PR-39 compared with controls. Administration 24 h after challenge was no longer effective. Although PR-39 and anti-TNF-alpha doses were ineffective alone, when combined at different ratios protected neonatal mice. The present experiments show the potential use of peptide PR-39 in preventing neonatal endotoxic shock.
Subject(s)
Antimicrobial Cationic Peptides/pharmacology , Antimicrobial Cationic Peptides/therapeutic use , Shock, Septic/prevention & control , Animals , Animals, Newborn , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/therapeutic use , Disease Models, Animal , Escherichia coli/chemistry , Lipopolysaccharides/isolation & purification , Lipopolysaccharides/toxicity , Mice , Mice, Inbred BALB C , Survival Analysis , Tumor Necrosis Factor-alpha/analysisABSTRACT
The present study was carried out to gain insight into the mechanisms involved in the pathogenesis of streptococcal toxic shock syndrome (TSS) and other acute invasive diseases caused by Streptococcus pyogenes (GAS). Specifically, since both whole bacteria and their soluble products are often present in the blood in these conditions, we sought to detect possible synergic activities of somatic and extracellular products in inducing mediators release. For this purpose, whole blood cultures from healthy donors were incubated with different concentrations of streptococcal pyrogenic exotoxin A (SpeA), which is considered a major molecular effector of TSS, heat-killed GAS and cell-wall components such as lipoteichoic acid (LTA) and soluble peptidoglican (sPGN). Significant levels of TNF-alpha, IL-1 alpha and IFN-gamma were found in supernatants from cultures incubated with each of the four inducers alone. Whole GAS and both cell-wall components were more effective (p < 0.05) than SpeA in inducing cytokine release. Whole GAS, at weight basis, was a more potent inducer than LTA and sPGN and LTA, at weight basis, was a more potent inducer than sPGN. In order to verify possible additive or synergic effects of exotoxic and parietal compounds in inducing cytokine release, whole blood cells were incubated with mixtures of SpeA and LTA at different molecular ratio. TNF-alpha, IL-1 alpha and IFN-gamma levels in supernatants were significantly (p < 0.05) higher in supernatants of cultures stimulated simultaneously with the two components than those of cultures stimulated with a single agent. Moreover, these levels were significantly higher than the sum of cytokine levels induced by single components. This study shows that parietal compounds can act in synergy with exotoxins in inducing the release of cytokines, which appear to be the major mediators of TSS.
Subject(s)
Bacterial Proteins , Cytokines/biosynthesis , Exotoxins/immunology , Lipopolysaccharides/immunology , Membrane Proteins , Shock, Septic/immunology , Streptococcus pyogenes/metabolism , Teichoic Acids/immunology , Blood Cells , Cells, Cultured , Humans , Interferon-gamma/biosynthesis , Interleukin-1/biosynthesis , Shock, Septic/microbiology , Streptococcal Infections/immunology , Streptococcal Infections/microbiology , Tumor Necrosis Factor-alpha/biosynthesisABSTRACT
This project focused on the effects of aflatoxin B1 (AFB1), a food-contaminating mycotoxin produced by fungi, genus Aspergillus, on the release and genetic expression of some important cytokines, i.e., (interleukin-1 alpha (IL-1 alpha), IL-6, tumor necrosis factor-alpha (TNF alpha)) by human monocytes. Monocytes, preincubated for different time periods with concentrations of AFB1 ranging from 0.01 to 1.0 pg/mL, were then activated with bacterial lipopolysaccharide. Cytokine levels were measured by immunoassay and mRNA by cDNA amplification. Pretreatment of monocytes with AFB1 resulted in a decrease in IL-1, IL-6 and TNF alpha release already at a concentration of 0.05 pg/mL. The gene expression of the cytokines considered was drastically affected by treatment with AFB1. In fact, AFB1 completely blocked the transcription of IL-1 alpha, IL-6 and TNF alpha mRNAs, while it did not affect beta-actin mRNA at the concentrations used. It therefore appears that AFB1 exerts its effect on cytokine release through selective inhibition of specific mRNA, without affecting general protein synthesis.
Subject(s)
Aflatoxin B1/toxicity , Aspergillus/metabolism , Carcinogens/toxicity , Cytokines/drug effects , Leukocytes, Mononuclear/drug effects , Cytokines/biosynthesis , Dose-Response Relationship, Drug , Humans , Leukocytes, Mononuclear/immunology , Time FactorsABSTRACT
We investigated whether immunization with recombinant anti-idiotypic antibody fragments mimicking the conformation of the capsular antigen can protect against infection by group B streptococcus, an important neonatal pathogen. Single-chain fragment-variable anti-idiotypes competed with the type III carbohydrate for binding to type-specific antibodies and elicited, in mice, the production of protective immunoglobulins reacting against the type III polysaccharide. Moreover, maternal immunization with soluble or phage-displayed fragments protected neonatal mice against streptococcal infection. These data indicate that recombinant anti-idiotypic antibodies may be useful in developing protein images of relevant carbohydrate epitopes and, ultimately, in preventing infections by encapsulated bacteria.
Subject(s)
Antibodies, Anti-Idiotypic/immunology , Immunity, Maternally-Acquired/immunology , Streptococcal Infections/immunology , Streptococcus agalactiae , Vaccines, DNA/immunology , Agglutination/drug effects , Agglutination Tests , Animals , Animals, Newborn , Antibodies, Anti-Idiotypic/administration & dosage , Antibodies, Anti-Idiotypic/genetics , Antibody Formation/drug effects , Antibody Formation/immunology , Female , Immunoglobulin Fragments/administration & dosage , Immunoglobulin Fragments/immunology , Immunoglobulin Variable Region/administration & dosage , Immunoglobulin Variable Region/immunology , Male , Mice , Mice, Inbred BALB C , Recombinant Proteins/genetics , Recombinant Proteins/immunology , Streptococcal Infections/prevention & control , Vaccination , Vaccines, DNA/geneticsABSTRACT
The bactericidal activities of macrolides (clarithromycin, roxithromycin and azithromicyn) and lansoprazole, alone and in combination, against Helicobacter pylori strains were evaluated. It was found that the association of lansoprazole and clarithromycin resulted in a marked synergism, while the combination of roxithromycin or azithromycin with lansoprazole had synergistic and additive effects.
Subject(s)
Anti-Bacterial Agents/pharmacology , Helicobacter pylori/drug effects , Omeprazole/analogs & derivatives , 2-Pyridinylmethylsulfinylbenzimidazoles , Azithromycin/pharmacology , Biopsy , Clarithromycin/pharmacology , Drug Synergism , Helicobacter pylori/isolation & purification , Humans , Kinetics , Lansoprazole , Microbial Sensitivity Tests/methods , Omeprazole/pharmacology , Roxithromycin/pharmacology , Time FactorsABSTRACT
Group B streptococcal antigens stimulated tumor necrosis factor alpha (TNF-alpha), interleukin-1 (IL-1), and IL-6 production in human blood cultures in a concentration- and time-dependent fashion. The minimal concentrations of type-specific polysaccharides, lipoteichoic acid, and group-specific polysaccharide required to produce these effects were, respectively, 0.01, 1, and 10 microg/ml. Cell separation experiments indicated that monocytes were the cell type mainly responsible for cytokine production. Time course studies indicated that TNF-alpha was released before the other cytokines. TNF-alpha, however, did not appear to directly induce IL-1beta, as shown by blockade experiments with anti-TNF-alpha antibodies. IL-6 levels were moderately but significantly decreased by anti-TNF-alpha. These data indicate that several products from group B streptococci are able to directly stimulate human monocytes to release TNF-alpha, IL-1beta, and IL-6. These findings may be clinically relevant, since proinflammatory cytokines can mediate pathophysiologic changes during sepsis.
Subject(s)
Blood/immunology , Cytokines/biosynthesis , Lipopolysaccharides/immunology , Polysaccharides, Bacterial/immunology , Streptococcus agalactiae/immunology , Teichoic Acids/immunology , Cells, Cultured , Humans , Interleukin-1/biosynthesis , Interleukin-6/biosynthesis , Leukocytes/classification , Leukocytes/immunology , Tumor Necrosis Factor-alpha/biosynthesisABSTRACT
The lethal effects occurring in neonatal (<24-h-old) BALB/c mice after challenge with 25 mg of lipopolysaccharide (LPS) per kg of body weight were significantly counteracted by pretreatment with recombinant interleukin-10 (rIL-10; 25 or 50 ng/mouse). Concordantly, blockage of endogenous IL-10 with the SXC1 monoclonal antibody increased LPS-induced mortality. Both IL-10 and SXC1 modulated the release of tumor necrosis factor alpha (TNF-alpha) so that, relative to controls, peak TNF-alpha values after LPS challenge were decreased by rIL-10 and increased by anti-IL-10.
Subject(s)
Endotoxemia/drug therapy , Interleukin-10/therapeutic use , Animals , Animals, Newborn , Antibodies, Monoclonal/pharmacology , Endotoxemia/immunology , Interleukin-10/antagonists & inhibitors , Mice , Mice, Inbred BALB C , Recombinant Proteins/therapeutic use , Tumor Necrosis Factor-alpha/metabolismABSTRACT
Cytokines are suspected to play an important role in systemic infections by group B streptococci (GBS), an important cause of neonatal sepsis. This work was undertaken to determine if interleukin 12 (IL-12) is produced in mouse pups infected with GBS and has a role in this sepsis model. IL-12 elevations were measured by both an enzyme-linked immunosorbent assay and a bioassay in plasma samples obtained from 12 to 72 h after GBS challenge. Pretreatment with neutralizing anti-IL-12 antibodies significantly increased lethality and blood CFU (P < 0.05). Conversely, either prophylactically or therapeutically administered recombinant IL-12 (rIL-12) significantly improved survival time and decreased blood CFU. Since these beneficial effects were associated with increased spleen gamma interferon (IFN-gamma) production, we examined whether the latter cytokine mediated the observed rIL-12 effects. Pretreatment with neutralizing anti-IFN-gamma monoclonal antibodies significantly counteracted the beneficial effects of rIL-12 on lethality. Our data indicate that rIL-12 is a possible candidate for treatment of GBS sepsis and that its activities in this model are at least partially mediated by IFN-gamma.
Subject(s)
Interleukin-12/physiology , Sepsis/physiopathology , Streptococcal Infections/immunology , Streptococcus agalactiae/immunology , Animals , Animals, Newborn , Interferon-gamma/metabolism , Mice , Mice, Inbred BALB C , Streptococcus agalactiae/pathogenicity , Tumor Necrosis Factor-alpha/metabolismABSTRACT
Septic shock is a major cause of mortality in neonates. The hypothesis was tested that neonatal age is associated with altered sensitivity to shock-inducing bacterial products or proinflammatory cytokines (or both). Mice of different ages were inoculated with various doses of lipopolysaccharide (LPS), superantigenic staphylococcal enterotoxin B (SEB), or recombinant tumor necrosis factor-alpha (rTNF-alpha), alone or in combination with the sensitizing agent D-galactosamine. Neonatal mice were markedly more susceptible to LPS-induced lethality but more resistant to SEB than were adults (P < .05). Mice of different ages did not differ, however, in their sensitivity to lethal activities of rTNF-alpha. Neonatal susceptibility to LPS and SEB correlated directly with plasma TNF-alpha but not IFN-gamma levels, which was confirmed by TNF-alpha and IFN-gamma blockade experiments. These data document marked age-related differences in the pathophysiology of septic shock and suggest that IFN-gamma is not an obligatory mediator of either LPS- or SEB-induced lethality in neonates.
Subject(s)
Lipopolysaccharides/toxicity , Tumor Necrosis Factor-alpha/biosynthesis , Age Factors , Animals , Animals, Newborn , Enterotoxins/toxicity , Female , Interferon-gamma/biosynthesis , Interleukin-1/biosynthesis , Male , Mice , Mice, Inbred BALB CABSTRACT
In order to ascertain if Cryptococcus neoformans components can induce interleukin-6 (IL-6) production, we stimulated human whole blood with purified capsular products. Their potencies in stimulating IL-6 release were mannoproteins > galactoxylomannan = glucuronoxylomannan > alpha(1-3)glucan. IL-6 production was tumor necrosis factor alpha independent and required the presence of monocytes and plasma. Since IL-6 can stimulate replication of the human immunodeficiency virus in monocytic cells, these findings may be clinically relevant.
Subject(s)
Cryptococcus neoformans/physiology , Interleukin-6/biosynthesis , Monocytes/metabolism , Acquired Immunodeficiency Syndrome/metabolism , Humans , Membrane Glycoproteins/pharmacology , Polysaccharides/pharmacology , Polysaccharides, Bacterial/pharmacology , Tumor Necrosis Factor-alpha/physiologyABSTRACT
Interleukin(IL)-13, a cytokine produced by T helper 2 (Th2) cells, is a powerful inhibitor of macrophage functions, including surface expression of CD14 and production of IL-1 and tumor necrosis factor (TNF)-alpha. We tested the effects of recombinant mouse(m)IL-13 in a neonatal mouse model of endotoxin shock; this is a macrophage-dependent condition, which is a model of neonatal sepsis in humans. mIL-13 (0.5 microgram/mouse) dramatically reduced the lethal effects of lipopolysaccharide (LPS) if administered either 24 or 4 h prior to or concomitantly with LPS challenge. This action might be mediated by multiple modulatory activities of IL-13 on LPS-induced cytokine secretion since, relative to control animals, the mice treated with mIL-13 had eight times lower peak blood levels of TNF. The IL-1 beta levels were also decreased, whereas increased levels of IL-6 and IL-10 were observed at several time points after LPS challenge.
Subject(s)
Animals, Newborn/immunology , Endotoxins/toxicity , Interleukin-13/therapeutic use , Shock, Septic/mortality , Shock, Septic/prevention & control , Adjuvants, Immunologic/therapeutic use , Animals , Cytokines/drug effects , Cytokines/metabolism , Female , Male , Mice , Mice, Inbred BALB C , Shock, Septic/immunologyABSTRACT
The aim of this study was to examine the ability of Pseudomonas aeruginosa components to induce release of cytokines from human leukocytes. Human whole-blood cultures were incubated with several concentrations of purified P. aeruginosa products, including porins, exomucopolysaccharide, lipopolysaccharide, and toxin A. Supernatants were assayed for tumor necrosis factor alpha (TNF-alpha) and interleukin-6 (IL-6) activities. All of the P. aeruginosa components except toxin A were able to stimulate the release of both cytokines. On a weight basis, porins were as effective as lipopolysaccharide and significantly more effective than exomucopolysaccharide in inducing IL-6 release (P < 0.05). Moreover, porins were more potent than either exomucopolysaccharide or lipopolysaccharide in inducing TNF-alpha release (P < 0.05). Further experiments using isolated leukocytes suggested that monocytes were the cell population predominantly responsible for the production of both cytokines. These data indicate that P. aeruginosa porins are able to induce significant cytokine production. These components may be responsible for the chronically overactive inflammatory response associated with persistent lung infection in cystic fibrosis patients.
Subject(s)
Bacterial Toxins/pharmacology , Glycosaminoglycans/pharmacology , Interleukin-6/metabolism , Leukocytes, Mononuclear/metabolism , Leukocytes, Mononuclear/microbiology , Lipopolysaccharides/pharmacology , Porins/pharmacology , Pseudomonas aeruginosa/chemistry , Pseudomonas aeruginosa/immunology , Tumor Necrosis Factor-alpha/metabolism , B-Lymphocytes/immunology , B-Lymphocytes/metabolism , Bacterial Toxins/isolation & purification , Cells, Cultured , Electrophoresis, Polyacrylamide Gel , Glycosaminoglycans/isolation & purification , Granulocytes/immunology , Granulocytes/metabolism , Humans , Killer Cells, Natural/immunology , Killer Cells, Natural/metabolism , Kinetics , Lipopolysaccharides/isolation & purification , Monocytes/immunology , Monocytes/metabolism , Porins/isolation & purification , T-Lymphocytes/immunology , T-Lymphocytes/metabolismABSTRACT
Compounds belonging to a new class of quinolones in which the fundamental C-6 fluorine atom was replaced were evaluated for in vitro antibacterial activity against 32 Helicobacter pylori strains. Since these substitutions resulted in higher inhibitory activities, these new desfluoroquinolones may be useful in eradicating H. pylori infections.
Subject(s)
Anti-Infective Agents/pharmacology , Helicobacter pylori/drug effects , 4-Quinolones , Microbial Sensitivity Tests , Structure-Activity RelationshipABSTRACT
Cryptococcus neoformans-induced tumor necrosis factor alpha (TNF-alpha) production may lead to increased human immunodeficiency virus replication in patients with AIDS. In order to identify cryptococcal components that are predominantly responsible for stimulating TNF production, various concentrations of glucuronoxylomannan (GXM), galactoxylomannan (GalXM), mannoproteins (MP), and alpha(1-3) [corrected] glucan were added to whole-blood cultures. All of the cryptococcal components tested, as well as whole heat-killed cryptococci, were capable of inducing TNF-alpha release in a dose-dependent manner. MP were significantly more potent than any of the other cryptococcal components tested or heat-killed cryptococci in stimulating TNF-alpha production (P < 0.05). GXM, in contrast, was significantly less potent in this activity than either GalXM or MP (P < 0.05). As little as 0.5 microg of MP per ml was sufficient to produce moderate but significant elevations of TNF-alpha release. Maximal MP-induced TNF-alpha levels were similar to those induced by Salmonella enteritidis lipopolysaccharide, our positive control. Further experiments using isolated leukocytes suggested that monocytes were the cell population mainly responsible for TNF-alpha production, although the participation of other cell types could not be excluded. The presence of complement-sufficient plasma was a necessary requirement for TNF-alpha induction by GXM, GalXM, and low doses of MP. High MP concentrations (100 microg/ml) were also capable of stimulating TNF-alpha production in the absence of plasma. These data indicate that soluble products released by C. neoformans are capable of inducing TNF-alpha secretion in human leukocytes. This may be clinically relevant, since high concentrations of such products are frequently found in the body fluids of AIDS patients infected with C. neoformans.
Subject(s)
AIDS-Related Opportunistic Infections/microbiology , Cryptococcosis , Leukocytes/microbiology , Tumor Necrosis Factor-alpha/biosynthesis , Cells, Cultured , Humans , Immunocompromised Host , Leukocytes/metabolismABSTRACT
The aim of this study was to assess the role of gamma interferon (IFN-gamma) in a neonatal mouse model of group B streptococcal (GBS) sepsis. IFN-gamma was produced by spleen cells at 24, 48, and 72 h after GBS challenge. Treatment with anti-IFN-gamma at 6 h before challenge totally abrogated the IFN-gamma response but did not affect survival. Subcutaneous administration of recombinant IFN-gamma (2,500 IU per pup) at 18 h after challenge resulted in increased survival time and reduced blood colony counts at 48 and 72 h. In vitro preincubation of neonatal whole blood with IFN-gamma before the addition of GBS resulted in significant restriction of bacterial growth. These data indicate that administration of recombinant IFN-gamma can partially restore impaired host defenses against GBS in neonatal mice. This cytokine may be useful for the treatment of neonatal infections.
Subject(s)
Interferon-gamma/pharmacology , Shock, Septic/etiology , Streptococcal Infections/etiology , Streptococcus agalactiae , Animals , Animals, Newborn , Chemotaxis, Leukocyte/drug effects , Colony Count, Microbial , Disease Models, Animal , Interferon-gamma/blood , Mice , Mice, Inbred BALB C , Neutrophils/drug effects , Shock, Septic/mortality , Streptococcal Infections/blood , Streptococcal Infections/mortality , Tumor Necrosis Factor-alpha/pharmacologyABSTRACT
Unlike the antibiotics erythromycin and penicillin G, sodium fusidate (fusidin) pretreatment (80 mg/kg of body weight) increased the survival rate of neonatal BALB/c mice challenged with Salmonella enteritidis lipopolysaccharide. Fusidin also significantly reduced the plasma tumor necrosis factor alpha levels. Hence, fusidin may prove useful in the management of bacterial sepsis in humans.
Subject(s)
Anti-Bacterial Agents/pharmacology , Fusidic Acid/pharmacology , Shock, Septic/drug therapy , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Animals , Disease Models, Animal , Female , Lipopolysaccharides , Male , Mice , Mice, Inbred BALB C , Shock, Septic/blood , Tumor Necrosis Factor-alpha/metabolismABSTRACT
We investigated the role of interleukin-10 (IL-10) in a neonatal mouse model of lethal group B streptococci (GBS) sepsis. Plasma IL-10 levels significantly increased at 24 and 48 h after GBS inoculation. Neutralization of IL-10 with specific antibodies had no effect on lethality. Administration of recombinant IL-10 at 20 or 4 h before challenge, but not at later times, resulted in decreased tumor necrosis factor alpha levels and improved survival. IL-10 could be potentially useful for the treatment of GBS sepsis.