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Background: Recurrent vulvovaginal candidiasis (RVVC) affects up to 8% of women. The immunopathogenesis is poorly understood but it has been suggested that RVVC might be due to dysregulated innate immune response. The aim of this study was to compare cytokine profiles in stimulated primary mononuclear cells (PBMCs) from RVVC and healthy individuals.Methods: PBMCs isolated from RVVC patients (n = 24) and healthy volunteers (n = 30) were stimulated with unspecific and pathogen-specific antigens. Cytokine production was assessed after 24 hours, 48 hours, and 7 days using ELISA.Results: No significant differences in cytokine production were found in T helper 1 (Th1), Th2, and Th17 immunity in response to both unspecific and pathogen-specific stimulations. Tumor necrosis factor-α (TNF-α) production in response to C. albicans hyphae was significantly higher in patients than controls and within the patient group, a significant positive correlation was found between interleukin-1β (IL-1β) and both TNF-α and IL-6. Both IL-1β/IL-1Ra and TNF-α/IL-10 ratios in Candida hyphae-stimulated PBMCs were significantly higher in patients than controls.Conclusions: Women affected by RVVC showed increased monocytes-derived cytokine production, which might contribute to an exaggerated vaginal immune response to Candida hyphae. RVVC patients show no defective Th-dependent adaptive immune response upon Candida stimulation. [ABSTRACT FROM AUTHOR]

Background: Candidemia, one of the most common causes of fungal bloodstream infection, leads to mortality rates up to 40% in affected patients. Understanding genetic mechanisms for differential susceptibility to candidemia may aid in designing host-directed therapies.Methods: We performed the first genome-wide association study on candidemia, and we integrated these data with variants that affect cytokines in different cellular systems stimulated with Candida albicans.Results: We observed strong association between candidemia and a variant, rs8028958, that significantly affects the expression levels of PLA2G4B in blood. We found that up to 35% of the susceptibility loci affect in vitro cytokine production in response to Candida. Furthermore, potential causal genes located within these loci are enriched for lipid and arachidonic acid metabolism. Using an independent cohort, we also showed that the numbers of risk alleles at these loci are negatively correlated with reactive oxygen species and interleukin-6 levels in response to Candida. Finally, there was a significant correlation between susceptibility and allelic scores based on 16 independent candidemia-associated single-nucleotide polymorphisms that affect monocyte-derived cytokines, but not with T cell-derived cytokines.Conclusions: Our results prioritize the disturbed lipid homeostasis and oxidative stress as potential mechanisms that affect monocyte-derived cytokines to influence susceptibility to candidemia. [ABSTRACT FROM AUTHOR]

Background. Candidemia is a severe invasive fungal infection with high mortality. Recognition of Candida species is mediated through pattern recognition receptors such as Toll-like receptors (TLRs). This study assessed whether genetic variation in TLR signaling influences susceptibility to candidemia. Methods. Thirteen mostly nonsynonymous single nucleotide polymorphisms (SNPs) in genes encoding TLRs and signaling adaptors MyD88 and Mal/TIRAP were genotyped in 338 patients (237 white, 93 African American, 8 other race) with candidemia and 351 noninfected controls (263 white, 88 African American). The SNPs significant in univariate analysis were further analyzed with multivariable logistic regression to determine association with clinical outcomes. Functional consequences of these polymorphisms were assessed via in vitro stimulation assays. Results. Analyses of TLR SNPs revealed that 3 TLR1 SNPs (R80T, S248N, I602S) were significantly associated with candidemia susceptibility in whites. This association was not found in African Americans, likely due to lower power in this smaller study population. Furthermore, these TLR1 polymorphisms displayed impaired cytokine release by primary monocytes. No associations with susceptibility to candidemia were observed for SNPs in TLR2, TLR4, TLR6, TLR9, MyD88, or TIRAP. Conclusions. Nonsynonymous SNPs in TLR1 are associated with impaired TLR1 function, decreased cytokine responses, and predisposition to candidemia in whites. [ABSTRACT FROM AUTHOR]

Background. Candidemia is an important cause of morbidity and mortality in critically ill patients or patients undergoing invasive treatments. Dectin-1 is the main β-glucan receptor, and patients with a complete deficiency of either dectin-1 or its adaptor molecule CARD9 display persistent mucosal infections with Candida albicans. The role of genetic variation of DECTIN-1 and CARD9 genes on the susceptibility to candidemia is unknown. Methods. We assessed whether genetic variation in the genes encoding dectin-1 and CARD9 influence the susceptibility to candidemia and/or the clinical course of the infection in a large cohort of American and Dutch candidemia patients (n = 331) and noninfected matched controls (n = 351). Furthermore, functional studies have been performed to assess the effect of the DECTIN-1 and CARD9 genetic variants on cytokine production in vitro and in vivo in the infected patients. Results. No significant association between the single-nucleotide polymorphisms DECTIN-1 Y238X and CARD9 S12N and the prevalence of candidemia was found, despite the association of the DECTIN-1 238X allele with impaired in vitro and in vivo cytokine production. Conclusions. Whereas the dectin-1/CARD9 signaling pathway is nonredundant in mucosal immunity to C. albicans, a partial deficiency of β-glucan recognition has a minor impact on susceptibility to candidemia. [ABSTRACT FROM AUTHOR]

Background. Dectin-1 is the major receptor for fungal β-glucans on myeloid cells. We investigated whether defective Dectin-1 receptor function, because of the early stop codon polymorphism Y238X, enhances susceptibility to invasive aspergillosis (IA) in at-risk patients.Methods. Association of Dectin-1 Y238X polymorphism with occurrence and clinical course of IA was evaluated in 71 patients who developed IA post hematopoietic stem cell transplantation (HSCT) and in another 21 non-HSCT patients with IA. The control group consisted of 108 patients who underwent HSCT. Functional studies were performed to investigate consequences of the Y238X Dectin-1 polymorphism.Results. The Y238X allele frequency was higher in non-HSCT patients with IA (19.0% vs 6.9%–7.7%; P < .05). Heterozygosity for Y238X polymorphism in HSCT recipients showed a trend toward IA susceptibility (odds ratio, 1.79; 95% CI, .77–4.19; P = .17) but did not influence clinical course of IA. Functional assays revealed that although peripheral blood mononuclear cells with defective Dectin-1 function due to Y238X responded less efficiently to Aspergillus, corresponding macrophages showed adequate response to Aspergillus.Conclusions. Dectin-1 Y238X heterozygosity has a limited influence on susceptibility to IA and may be important in susceptible non-HSCT patients. This is partly attributable to redundancy inherent in the innate immune system. Larger studies are needed to confirm these findings. [ABSTRACT FROM PUBLISHER]

Background. Our interest in immunological effects produced by vitamin D3 (1,25(OH)2D3) and its therapeutic potential prompted us to examine the role of 1,25(OH)2D3 on cytokine production by Candida albicans.Methods. Peripheral blood mononuclear cells (PBMC) with stimulated C. albicans and 1,25(OH)2D3, cytokine concentrations were measured in supernatant. Quantitative polymerase chain reaction (qPCR) was performed for T cell transcription factors, SOCS1 and 3. TLR2/4, Dectin-1, and mannose receptor expression was studied using flow cytometry and qPCR. An ex-vivo stimulation study was carried out in healthy volunteers to investigate the seasonality of immune response to C. albicans.Results. Upon in vitro C. albicans stimulation, 1,25(OH)2D3 induced a dose-dependent, down-regulation of IL-6, TNFα, IL-17, and IFNγ. It also increased IL-10 production. The shift in cytokine profile was not due to 1,25(OH)2D3 augmenting expression of either Thelper differentiation factors or SOCS1 and SOCS3 mRNA. 1,25(OH)2D3 inhibited TLR2, TLR4, Dectin-1, and MR mRNA and protein expression. In our seasonality study, both IL-17 and IFNγ levels were suppressed in summer when 25(OH)D3 levels were elevated.Conclusion. Vitamin D3 skews cytokine responses toward an antiinflammatory profile, mediated by suppression of TLR2, TLR4, Dectin-1, and MR transcription, leading to reduced surface expression. The biological relevance of these effects has been confirmed by the seasonality of cytokine responses. [ABSTRACT FROM PUBLISHER]

β(1,3)-glucans represent 40% of the cell wall of the yeast Candida albicans. The dectin-1 lectin-like receptor has shown to recognize fungal β(1,3)-glucans and induce innate immune responses. The importance of β-glucan-dectin-1 pathways for the recognition of C. albicans byhumanprimary blood cells has not been firmly established. In this study we demonstrate that cytokine production by both human peripheral blood mononuclear cells and murine macrophages is dependent on the recognition of β-glucans by dectin-1. Heat killing of C. albicans resulted in exposure of β-glucans on the surface of the cell wall and subsequent recognition by dectin-1, whereas live yeasts stimulated monocytes mainly via recognition of cell-surface mannans. Dectin-1 induced cytokine production through the following 2 pathways: Syk-dependent production of the T-helper (Th) 2-type anti-inflammatory cytokine interleukin-10 and Toll-like receptor-Myd88-dependent stimulation of monocyte-derived proinflammatory cytokines, such as tumor necrosis factor-α. In contrast, stimulation of Th1-type cytokines, such as interferon-γ, by C. albicans was independent of the recognition of β-glucans by dectin-1. In conclusion, C. albicans induces production of monocyte-derived and T cell-derived cytokines through distinct pathways dependent on or independent of dectin-1. [ABSTRACT FROM AUTHOR]

Background. Interleukin (IL)-1α and IL-1β are protective proinflammatory cytokines involved in host defense against Candida albicans. It is, however, unknown whether they provide protection through similar mechanisms. We investigated the effect of endogenous IL-1α and IL-1β on disseminated C. albicans infection. Methods. Mice deficient in the genes encoding IL-1α (IL-1α-/-), IL-1β (IL-1β-/-), or both molecules (IL-1α-/-β-/-) were used. Survival and C. albicans outgrowth in the kidneys was assessed after intravenous injection of C. albicans. Results. Both mortality and C. albicans outgrowth in the kidneys were significantly increased in IL-1α-/- and IL-1β-/- mice, compared with those in control mice, with the IL-1α-/-β-/- mice being most susceptible to disseminated candidiasis. The host defense mechanisms triggered by IL-1α and IL-1β differed from one another. IL-1β-/- mice showed decreased recruitment of granulocytes in response to an intraperitoneal C. albicans challenge, and generation of superoxide production was diminished in IL-1β-/- granulocytes. IL-1α-/- mice had a reduced capacity to damage C. albicans pseudohyphae. Protective type 1 responses were deficient in both IL-1α-/- and IL-1β-/- mice, as assessed by production of interferon-γ by splenocytes in response to heat-killed C. albicans. Conclusion. Although IL-1α and IL-1β have differential effects on the various arms of host defense, both cytokines are essential for mounting a protective host response against invasive C. albicans infection. [ABSTRACT FROM AUTHOR]

The role of endogenous tumor necrosis factor-α (TNF) and lymphotoxin-α (LT) in a model of intraabdominal Candida sepsis and abscess formation was investigated. Significantly more abscesses were observed in TNF/LT double knockout (TNF[sup -/-]LT[sup -/-]) mice, compared with that in wild-type (TNF[sup +/+]LT[sup +/+]) mice. Outgrowth of Candida in abscesses of TNF[sup -/-]LT[sup -/-] mice was 10-fold increased on day 14 and 60-fold increased on day 21 of infection. The interleukin10:interferon-γ ratio, measured in supernatants of stimulated splenocytes, shifted from 131 for TNF[sup -/-]LT[sup -/-] mice and 13.9 for TNF[sup +/+]LT[sup +/+] mice on day 8 to 0.11 for TNF[sup -/-] LT[sup -/-] mice and 11.66 for TNF[sup +/+]LT[sup +/+] mice on day 14 of infection. The diminished host resistance is explained by an impaired extracellular killing capacity of granulocytes and a delayed development of a T helper 1 response in TNF[sup -/-]LT[sup -/-] mice. In conclusion, TNF and LT are critical to the stimulation of effector cells that leads to elimination of Candida from abscesses. [ABSTRACT FROM AUTHOR]

Despite the importance of interferon (IFN)--g, tumor necrosis factor (TNF), and interleukin (IL)--18 for host defense against candidiasis, the pathways leading to their stimulation by Candi-da albicans are unclear. In a whole-blood model, IL-18 neutralization by IL-18 binding protein decreased C. albicans--induced IFN-g synthesis by 72%. Similarly, neutralization of IL-12 or IL-1b by either neutralizing antibodies or IL-1 receptor antagonist also reduced (by 65%) IFN-g production. Neutralization of TNF by TNF binding proteins resulted in only a 36% reduction of IFN-g synthesis. In contrast, production of TNF and IL-8 was largely unaffected by these cytokine inhibitors. Thus, C. albicans stimulates IFN-g production in an IL-18--, IL-12--, and IL-1b--dependent manner, whereas production of TNF and IL-8 is independent of these cyto-kines. Blocking the biologic activities of IL-18, IL-12, and IL-1b in patients (e.g., for treatment of autoimmune diseases) may result in increased susceptibility to C. albicans infection. [ABSTRACT FROM AUTHOR]

Tests the hypothesis that the increased production of interleukin 4 by CD4[sup +] and CD8[sup +] T cells from patients with tuberculosis is related to the presence of pulmonary cavities. Evaluation of the cytokine response in human tuberculosis; Decrease in the ratio of interferon-gamma and interleukin-4 production in patients with tuberculosis.

The effect of recombinant granulocyte colony-stimulating factor (rG-CSF) on acute disseminated Candida albicans infection in nonneutropenic mice was investigated. Mice treated with a single dose of rG-CSF showed a significantly reduced mortality (28% vs. 90%; P < .001). The outgrowth of C. albicans from the kidneys, spleens, and livers of rG-CSF-treated mice was significantly reduced (log cfu/g of kidney, 5.54 vs. 7.13; P < .001), as were circulating tumor necrosis factor-alpha and interleukin-1beta. After rG-CSF, the kidneys showed fewer infectious infiltrates, enhanced granulocyte influx, and almost complete absence of hyphal outgrowth. During peritoneal C. albicans infection, rG-CSF enhanced influx of granulocytes to the site of infection, and exudate granulocytes showed increased oxygen radical production. These results indicate that rG-CSF enhances host resistance to disseminated candidiasis in nonneutropenic mice through activation of granulocytes and their recruitment to the site of infection. [ABSTRACT FROM AUTHOR]

Tumor necrosis factor-a (TNF-α) and interleukin-l/3 (IL-l /3) are principal mediators of septic shock; inhibition of TNF-α production may ameliorate outcome in severe infections. Pentoxifylline, chlorpromazine, and thalidomide inhibit TNF-α production. Their effects were tested in lethal endotoxemia in sensitized mice. Only chlorpromazine significantly improved survival. Chlorpromazine and pentoxifylline significantly reduced postendotoxin circulating TNF-a, by 89% and 76%, respectively. Chlorpromazine also significantly reduced IL-lβ and soluble TNF receptor-P75. No drug improved survival in Klebsiella pneumoniae-infected mice despite significantly lower circulating TNF-α concentrations in chlorpromazine- or pentoxifylline-treated animals. The three compounds decreased circulating TNF-α in Candida albicans-infected mice, but survival was not influenced. In neutropenic mice, chlorpromazine had no influence on candidate in organs, but in normal mice, Candida counts in kidneys were higher in chlorpromazine-treated mice. Thus, inhibition of TNF-α production was of no benefit in K. pneumoniae infection and worsened outcome in C. albicans infection. [ABSTRACT FROM PUBLISHER]

The effect of recombinant rat interferonγ (rIFN-γ) on acute disseminated Candida albicans infection in mice was investigated. Outgrowth of Candida albicans in kidneys, spleen, and liver of mice treated with one intravenous (iv) dose ofrIFN-γ before iv injection of 5 X lOs cfu of Candida albicans was significantly lower than in controls over 7 days. rIFN-γ was protective when given 1 day before, simultaneously with, or 1-3 days after infection but not when given 3 days before. In mice pretreated with hydrocortisone acetate, rIFN-γ significantly reduced the outgrowth only when 103 cfu of Candida albicans was injected. Injection of rIFN-γ did not reduce the outgrowth of C. albieans in cyclophosphamide-pretreated mice and significantly increased the capacity of peripheral blood and exudate peritoneal granulocytes to kill Candida albicans in vitro. Thus, rIFN-γ enhances host resistance against acute disseminated Candida albicans infection in mice through activation of polymorphonuclear leukocytes. [ABSTRACT FROM PUBLISHER]

Comments on the article by M.V. Kalayoglu, B. Hoerneman et al, concerning the capacity of Chlamydia pneumoniae to promote oxidation of low-density lipoproteins (LDL), published in the 1999 issue of the 'Journal of Infectious Diseases.' Proinflammatory cytokines induction of the acellular components of sonicated C. pneumoniae; Non-involvement of superoxide in LDL oxidation.

A response from the author of the article "Early proinflammatory cytokines and C-reactive protein trends as predictors of outcome in invasive aspergillosis," in the 2010 issue is presented.