interleukin-8 and Candidiasis

Long-term administration of azithromycin (AZM) in children with cystic fibrosis (CF) has improved outcomes. However, the doses and schedule of administration are not very well studied in children with CF.. A randomized controlled trial was conducted to compare the effect of two doses of azithromycin (5mg/kg/day and 15mg/kg/day) on FEV(1) and pulmonary exacerbations in children with cystic fibrosis. Enrolled children were randomly allocated to receive daily azithromycin (5mg/kg/day or 15mg/kg/day) for 6months. Clinical assessment and FEV(1) measurement were performed monthly.. 56 children (28 in high dose group and 28 in low dose group) were enrolled. 47 (24 and 23 children in low and high dose groups) completed 12months of follow up. There was no difference in clinical scores, FEV(1), pulmonary exacerbation rates between two groups at baseline, 6months and at 12months. Per protocol analysis revealed that pulmonary exacerbation increased after discontinuing AZM and there was significantly more increase after 12months of enrolment in children getting high dose azithromycin. There was no improvement in FEV(1) in either group at the end of treatment period. Children tolerated daily low as well as high dose AZM well for 6months. There was no significant side effect of azithromycin.. In this randomized controlled trial, we did not find differences in the effect of 2 doses (5mg/kg/day or 15mg/kg/day) of AZM on change in percentage predicted FEV(1), clinical scores, Pseudomonas colonization rates, pulmonary exacerbations and need for antibiotics. There was increase in exacerbations after stopping azithromycin in both the groups. Our results also suggest that the decrease in the incidence of LRTI persists only till 6months after discontinuing azithromycin.

Topics: Anti-Bacterial Agents; Azithromycin; Body Weight; Candidiasis; Child; Child, Preschool; Cystic Fibrosis; Female; Forced Expiratory Volume; Humans; Interleukin-8; Male; Pneumonia, Bacterial; Pseudomonas aeruginosa; Pseudomonas Infections; Spirometry; Sputum; Staphylococcal Infections; Staphylococcus aureus; Streptococcal Infections; Streptococcus pneumoniae; Treatment Outcome

Candida-associated denture stomatitis (DS) is the most frequent lesion among denture wearers, especially the elderly. DS is strongly associated with Candida albicans, as well as local and systemic factors, such as impaired immune response. Monocytes are important in the protective immune response against the fungus by the production of cytokines that recruit and activate leukocytes. There are functional changes in these cells with age, and individual alterations involving monocyte response may predispose the host to developing infections by Candida spp. In this study, our aim was to evaluate the production of TNF-α, IL-6, CXCL8, IL-1β, MCP-1 and IL-10 by monocytes from elderly denture wearers with/without DS and elderly or young non-denture wearers. We detected that monocytes from elderly denture wearers with Candida-related denture stomatitis produced lower levels of CXCL-8, IL-6 and MCP-1. This imbalance in cytokine levels was observed in spontaneous or LPS-stimulated production. Therefore, our data suggested that inherent aspects of the host, such as changes in cytokine production by monocytes, might be associated with the development and the persistence of DS irrespective of aging.

Topics: Adult; Aged; Aged, 80 and over; Candida; Candida albicans; Candida tropicalis; Candidiasis; Chemokine CCL2; Cytokines; Enzyme-Linked Immunosorbent Assay; Female; Host-Pathogen Interactions; Humans; Inflammation Mediators; Interleukin-6; Interleukin-8; Male; Middle Aged; Monocytes; Species Specificity; Stomatitis, Denture

The glucocorticoid betamethasone (BM) is frequently employed in clinical practice because of its anti-inflammatory and immunosuppressive properties. In this study, we investigated the effect of BM (1 and 2 mM) on the ability of Candida albicans to adhere to, invade and damage oral, intestinal or vaginal epithelial cells, as well as to elicit cytokine and chemokine release. BM at 2 mM concentration stimulated adherence of C. albicans to vaginal cells and facilitated the invasion of intestinal and vaginal epithelia without influencing the growth rate of invading C. albicans hyphae at any type of epithelia and BM concentrations tested. In addition, BM at 2 mM concentration also augmented C. albicans-initiated cell damage of oral and intestinal cells. Furthermore, BM exposure decreased IL-6 cytokine and IL-8 chemokine release from oral and vaginal epithelial cells and also IL-6 release from intestinal epithelium after infection with C. albicans. These observations suggest that high-dose applications of BM may predispose patients to various epithelial C. albicans infections.

Topics: Betamethasone; Candida albicans; Candidiasis; Cell Line; Epithelial Cells; Glucocorticoids; Humans; Interleukin-6; Interleukin-8

During hematogenously disseminated infection, blood-borne Candida albicans invades the endothelial cell lining of the vasculature to invade the deep tissues. Although the C. albicans Als3 invasin is critical for invasion and damage of endothelial cells in vitro, a C. albicans als3Δ/Δ mutant has normal virulence in the mouse model of disseminated infection. We hypothesized that the contribution of Als3 to virulence is obscured by the presence of additional C. albicans invasins. To elucidate the in vivo function of Als3, we heterologously expressed C. albicans ALS3 in Candida glabrata, a yeast that lacks a close ALS3 ortholog and has low virulence in mice. We found that following intravenous inoculation into mice, the ALS3-expressing strain preferentially trafficked to the brain, where it induced significantly elevated levels of myeloperoxidase, tumor necrosis factor, monocyte chemoattractant protein 1, and gamma interferon. Also, the ALS3-expressing strain had enhanced adherence to and invasion of human brain microvascular endothelial cells in vitro, demonstrating a potential mechanism for ALS3-mediated neurotropism. In addition, upon initiation of infection, the ALS3-expressing strain had increased trafficking to the cortex of the kidneys. With prolonged infection, this strain persisted in the kidneys at significantly higher levels than the control strain but did not induce an elevated inflammatory response. Finally, the ALS3-expressing strain had increased resistance to neutrophil killing in vitro. These results indicate that during disseminated infection, Als3 mediates initial trafficking to the brain and renal cortex and contributes to fungal persistence in the kidneys.

Topics: Animals; Brain; Candida albicans; Candida glabrata; Candidiasis; Cell Adhesion; Cell Line; Colony Count, Microbial; Endocytosis; Fungal Proteins; Gene Expression Regulation, Fungal; Genes, Fungal; Human Umbilical Vein Endothelial Cells; Humans; Inflammation; Interleukin-8; Kidney Cortex; Male; Mice; Mice, Inbred BALB C; Neutrophils; Peroxidase; Protein Transport

Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) has an important role not only in glycolysis but also in nonmetabolic processes, including transcription activation and apoptosis. We report the isolation of a human GAPDH (hGAPDH) (2-32) fragment peptide from human placental tissue exhibiting antimicrobial activity. The peptide was internalized by cells of the pathogenic yeast Candida albicans and initiated a rapid apoptotic mechanism, leading to killing of the fungus. Killing was dose-dependent, with 10 μg ml (3.1 μM) and 100 μg ml hGAPDH (2-32) depolarizing 45% and 90% of the fungal cells in a population, respectively. Experimental C. albicans infection induced epithelial hGAPDH (2-32) expression. Addition of the peptide significantly reduced the tissue damage as compared with untreated experimental infection. Secreted aspartic proteinase (Sap) activity of C. albicans was inhibited by the fragment at higher concentrations, with a median effective dose of 160 mg l(-1) (50 μM) for Sap1p and 200 mg l(-1) (63 μM) for Sap2p, whereas Sap3 was not inhibited at all. Interestingly, hGAPDH (2-32) induced significant epithelial IL-8 and GM-CSF secretion and stimulated Toll-like receptor 4 expression at low concentrations independently of the presence of C. albicans, without any toxic mucosal effects. In the future, the combination of different antifungal strategies, e.g., a conventional fungicidal with immunomodulatory effects and the inhibition of fungal virulence factors, might be a promising treatment option.

Topics: Antifungal Agents; Apoptosis; Aspartic Acid Proteases; Candida albicans; Candidiasis; Cell Line; Epithelium; Female; Glyceraldehyde-3-Phosphate Dehydrogenases; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Immunomodulation; Interleukin-8; Mouth Mucosa; Peptide Fragments; Placenta; Pregnancy; Toll-Like Receptor 4

Human neutrophils were found to express all known Toll-like receptors (TLRs) except TLR3 and TLR7. IRAK-4-deficient neutrophils were tested for their responsiveness to various TLR ligands. Essentially all TLR responses in neutrophils, including the induction of reactive oxygen species generation, adhesion, chemotaxis and IL-8 secretion, were found to be dependent on IRAK-4. Surprisingly, the reactivity towards certain established TLR ligands, imiquimod and ODN-CpG, was unaffected by IRAK-4 deficiency, demonstrating their activity is independent of TLR. TLR-4-dependent signaling in neutrophils was totally dependent on IRAK-4 without any major TRIF-mediated contribution. We did not observe any defects in killing capacity of IRAK-4-deficient neutrophils for Staphylococcus aureus, Escherichia coli and Candida albicans, suggesting that microbial killing is primarily TLR independent.

Topics: Adaptor Proteins, Vesicular Transport; Aminoquinolines; Bacterial Infections; Candida albicans; Candidiasis; Cell Adhesion; Cells, Cultured; Chemotaxis; Humans; Imiquimod; Interleukin-1 Receptor-Associated Kinases; Interleukin-8; Microbial Viability; Neutrophils; Oligodeoxyribonucleotides; Reactive Oxygen Species; Respiratory Burst; Signal Transduction; Staphylococcus aureus; Toll-Like Receptor 3; Toll-Like Receptor 7

Assay of cytokines and C reactive protein (CRP) in different periods of febrile neutropenia may be helpful for early defining the risk in severe infections. We determined serum interleukin-6 (IL-6), interleukin-8 (IL-8), soluble interleukin-2 receptor (sIL-2R), tumor necrosis factor alpha (TNF-alpha), interleukin-1 beta (IL-1beta), and CRP in 22 previously untreated patients with various malignancies. Samples were obtained in four different clinical periods of febrile neutropenia; prior to chemotherapy, afebrile neutropenic period after chemotherapy, febrile neutropenic period, and recovery period. When compared to sex-and age-matched group of healthy subjects, IL-6, IL-8, sIL-2R, and CRP levels were found to be elevated in all periods. The highest levels were encountered in the febrile neutropenic period. For predictivity purposes, the afebrile neutropenic period was the most important period. Serum sIL-2R, IL-6, IL-8 and CRP levels were elevated in this period. IL-8 levels showed the most stable elevation through different stages of febrile neutropenia. Serum IL-8 levels were found to have the most reliable and stable elevation in different clinical stages of febrile neutropenia. Nevertheless, IL-8 is not able to discriminate among risk groups and cannot be used as a predictive factor.

Topics: Adult; Aged; Bacteremia; Biomarkers; C-Reactive Protein; Candidiasis; Cytokines; Female; Fever; Gram-Negative Bacterial Infections; Gram-Positive Bacterial Infections; Humans; Interleukin-1beta; Interleukin-6; Interleukin-8; Male; Middle Aged; Neutropenia; Receptors, Interleukin-2; Tumor Necrosis Factor-alpha

The opportunistic fungal pathogen Candida albicans enters the bloodstream and causes hematogenously disseminated infection in hospitalized patients. During the initiation of a hematogenously disseminated infection, endothelial cells are one of the first host cells to come in contact with C. albicans. Endothelial cells can significantly influence the local host response to C. albicans by expressing leukocyte adhesion molecules and proinflammatory cytokines. Thus, it is of interest to investigate the response of endothelial cells to C. albicans in vitro. We describe the use of real-time PCR and enzyme immunoassays to measure the effects of C. albicans on the endothelial cell production of E-selectin and tumor necrosis factor alpha in vitro.

Topics: Candida albicans; Candidiasis; Cells, Cultured; Cytokines; E-Selectin; Endothelial Cells; Host-Pathogen Interactions; Humans; Immunoenzyme Techniques; In Vitro Techniques; Interleukin-8; Opportunistic Infections; Polymerase Chain Reaction; RNA, Messenger

IL-8/CXCL8 is induced during infections, but has not been reported for Candida albicans colonization of the female genital tract. Cervicovaginal lavage (CVL) samples were collected from 406 HIV-infected women. IL-8 levels were evaluated by ELISA and compared with levels of C. albicans detected by potassium hydroxide (KOH) and PCR. Levels of lactobacilli, Gardnerella vaginalis and Mycoplasma hominis were also determined by PCR. IL-8 was significantly higher in samples from women with Candida, and regression analysis showed a positive association between IL-8 and Candida. In contrast, there was an inverse relationship between lactobacilli and IL-8. G. vaginalis and M. hominis were not significantly associated with IL-8. This study has shown an association between C. albicans and levels of IL-8 in mucosal genital fluid.

Topics: Candida albicans; Candidiasis; Female; Gardnerella vaginalis; HIV Infections; Humans; Interleukin-8; Lactobacillus; Mycoplasma hominis; Vagina

The characteristic pathological feature of dermatomycosis is numerous neutrophilic infiltrates within the epidermis. However, the precise mechanism of this infiltration remains unknown. In this study, interleukins 1 beta, 6, and 8, monocyte chemotactic protein-1 (MCP-1), and tumor necrosis factor (TNF)-alpha levels in the medium where keratinocytes were co-cultured with Candida albicans, Malassezia and Trichophyton mentagrophytes, were determined by enzyme-linked immunosorbent assays (ELISAs) in order to estimate the effect of these fungi on the cytokine production from human keratinocytes. The IL-8 level in the supernatants increased with 1 to 14 hours of co-culture in response to live C. albicans, but the other cytokines were undetectable. Furthermore, the mRNA of IL- 8 in keratinocytes was also confirmed to increased. This data suggested that C. albicans directly induce interleukin 8 production from human keratinocytes without activated macrophages. The IL-6, IL-8, and TNF-alpha levels in the culture supernatants increased with 1 to 24 hours of co-culture with keratinocytes and Malassezia species but the MCP-1 level was undetectable. The IL-8 and TNF-alpha levels in the culture supernatants increased with 1 to 24 hours of co-culture with keratinocytes and Trichophyton mentagrophytes but the other cytokine levels were undetectable. The ELISA analysis of cytokine production by human keratinocytes will provide useful information in understanding the pathogenesis of dermatomycosis.

Topics: Candidiasis; Chemokine CCL2; Coculture Techniques; Cytokines; Dermatomycoses; Humans; Interleukin-1; Interleukin-6; Interleukin-8; Keratinocytes; Malassezia; Tinea Versicolor; Tumor Necrosis Factor-alpha

Topics: Candida albicans; Candidiasis; Cells, Cultured; Coculture Techniques; Gene Expression Regulation; Humans; Interleukin-8; Keratinocytes; Kinetics; RNA, Messenger; Skin Diseases; Time Factors

Systemic candidasis is a life-threatening complication of antibiotic and immunosuppressive therapies and can alter host defense mechanisms through pathways that are poorly understood. Promotion of polymorphonuclear leukocyte (PMN) chemotaxis by beta-glucan towards fMLP or IL-8 gradients demonstrates a fundamental effect on host defenses by pathogenic fungi. The aim of the present study was to determine whether recognition of beta-glucan is sufficient to alter PMN motility in the absence of agonists of G-coupled protein chemotactic receptors. Present findings demonstrate a profound increase in PMN motility by beta-glucan supplementation of a fibronectin substratum in an underagarose migration assay. Motility on beta-glucan included a 3-fold increase in distance of migration, as well as a 5-fold increase in the number of PMNs recruited into the motile phase as compared to motility on fibronectin alone. This promotion of motility is determined by the beta2 integrin complement receptor 3 (CR3) (CD11b/CD18) rather than the beta1 integrin very late antigen 3 (VLA-3), which mediates chemotaxis on beta-glucan-supplemented matrix towards fMLP. PMN motility on beta-glucan-supplemented fibronectin was selectively decreased by inhibitors of pp60 src and ras, whereas motility was promoted by inhibition of p38-MAPK. No effect of these inhibitors was seen on PMNs migrating on fibronectin alone. Migration on beta-glucan-supplemented fibronectin, but not on fibronectin alone, was negatively regulated by protein kinase C (PKC) or cAMP activation. These findings indicate that beta-glucan is sufficient to alter the migratory capacity of PMN in the absence of costimulation by fMLP. Enhanced PMN migration on beta-glucan is mediated through specific integrins and second messenger pathways that are distinct from those utilized by PMNs migrating in the absence of beta-glucan.

Topics: Candidiasis; CD18 Antigens; Cell Movement; Chemotactic Factors; Chemotaxis, Leukocyte; Enzyme Inhibitors; Fibronectins; Glucans; GTP-Binding Proteins; Humans; In Vitro Techniques; Interleukin-8; Macrophage-1 Antigen; N-Formylmethionine Leucyl-Phenylalanine; Neutrophils; Phosphatidylinositol 3-Kinases; Phosphatidylinositol Phosphates; Protein Kinase C; Protein-Tyrosine Kinases; Signal Transduction

Per protocol, adults with an Injury Severity Score of 18 or greater underwent Candida antigen titer measurements weekly. If titers were 1:4 or greater, neutrophil function against Candida albicans was determined with use of a tritiated glucose incorporation assay, and polymorphonuclear leukocytes obtained from healthy blood donors were studied concurrently for comparison. Polymorphonuclear leukocytes from healthy blood donors and injured patients with elevated titers were able to inhibit C albicans growth in a dose-dependent fashion. Polymorphonuclear leukocytes from injured patients with elevated titers had a significantly depressed ability to inhibit Calbicans growth compared with those from healthy blood donors at all effector cell-to-target cell ratios tested. Cytokine-treated polymorphonuclear leukocytes from healthy blood donors and injured patients with elevated Candida antigen titers demonstrated significantly improved anticandidal activity at all ratios of polymorphonuclear leukocytes-to-Candida. Granulocyte macrophage-colony stimulating factor was the most potent cytokine at reconstituting polymorphonuclear leukocyte function, followed by interferon gamma and interleukin 8. In conclusion, an elevated Candida antigen titer in injured adults is associated with impaired polymorphonuclear leukocyte antifungal activity. This depressed activity can be reconstituted by the addition of cytokine.

Topics: Adult; Antigens, Fungal; Biological Assay; Candidiasis; Evaluation Studies as Topic; Female; Florida; Granulocyte-Macrophage Colony-Stimulating Factor; Hospitals, General; Humans; Incidence; Injury Severity Score; Interferon-gamma; Interleukin-8; Male; Multiple Trauma; Neutrophils