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Contains fulltext : 80198.pdf (Publisher’s version ) (Closed access) Differences in host immune genes may predispose to tuberculosis caused by particular Mycobacterium tuberculosis genotypes. We examined this hypothesis in Indonesia by spoligotyping M. tuberculosis isolates recovered from 336 patients with pulmonary tuberculosis and typing the patients' SLC11A1 gene (formerly known as "NRAMP1"), which is involved in susceptibility to tuberculosis. The M. tuberculosis Beijing genotype, which comprised 29.8% of all isolates, was strongly associated with 2 polymorphisms in SLC11A1: the D543N G allele (odds ratio [OR], 2.15; P=.005) and the 3' untranslated region (3'UTR) insertion/insertion genotype (OR, 2.5; P=.001). This finding supports the hypothesis of coevolution of M. tuberculosis and the human immune system.

Beta (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 beta (1,3)-glucans and induce innate immune responses. The importance of beta-glucan-dectin-1 pathways for the recognition of C. albicans by human primary 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 beta-glucans by dectin-1. Heat killing of C. albicans resulted in exposure of beta-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-alpha . In contrast, stimulation of Th1-type cytokines, such as interferon-gamma , by C. albicans was independent of the recognition of beta-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.

Contains fulltext : 208279.pdf (Publisher’s version ) (Closed access) Toll-like receptors (TLRs) represent the main class of pattern-recognition receptors involved in sensing pathogenic microorganisms. The aim of the present study was to assess the role of TLR4 in the defense against Candida albicans infection. The outgrowth of C. albicans was 10-fold higher in TLR4-defective C3H/HeJ mice, compared with that in control C3H/HeN mice (P

Item does not contain fulltext Despite the importance of interferon (IFN)-gamma, tumor necrosis factor (TNF), and interleukin (IL)-18 for host defense against candidiasis, the pathways leading to their stimulation by Candida albicans are unclear. In a whole-blood model, IL-18 neutralization by IL-18 binding protein decreased C. albicans-induced IFN-gamma synthesis by 72%. Similarly, neutralization of IL-12 or IL-1beta by either neutralizing antibodies or IL-1 receptor antagonist also reduced (by 65%) IFN-gamma production. Neutralization of TNF by TNF binding proteins resulted in only a 36% reduction of IFN-gamma synthesis. In contrast, production of TNF and IL-8 was largely unaffected by these cytokine inhibitors. Thus, C. albicans stimulates IFN-gamma production in an IL-18-, IL-12-, and IL-1beta-dependent manner, whereas production of TNF and IL-8 is independent of these cytokines. Blocking the biologic activities of IL-18, IL-12, and IL-1beta in patients (e.g., for treatment of autoimmune diseases) may result in increased susceptibility to C. albicans infection.

Contains fulltext : 19710.pdf (Publisher’s version ) (Closed access) The role of endogenous tumor necrosis factor-alpha (TNF) and lymphotoxin-alpha (LT) in a model of intraabdominal Candida sepsis and abscess formation was investigated. Significantly more abscesses were observed in TNF/LT double knockout (TNF(-/-)LT(-/-)) mice, compared with that in wild-type (TNF(+/+)LT(+/+)) mice. Outgrowth of Candida in abscesses of TNF(-/-)LT(-/-) mice was 10-fold increased on day 14 and 60-fold increased on day 21 of infection. The interleukin-10rcolon;interferon-gamma ratio, measured in supernatants of stimulated splenocytes, shifted from 131 for TNF(-/-)LT(-/-) mice and 13.9 for TNF(+/+)LT(+/+) mice on day 8 to 0.11 for TNF(-/-)LT(-/-) mice and 11.66 for TNF(+/+)LT(+/+) 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(-/-)LT(-/-) mice. In conclusion, TNF and LT are critical to the stimulation of effector cells that leads to elimination of Candida from abscesses.

Contains fulltext : 155344.pdf (Publisher’s version ) (Closed access) BACKGROUND: Q fever is an infection caused by Coxiella burnetii. Persistent infection (chronic Q fever) develops in 1%-5% of patients. We hypothesize that inefficient recognition of C. burnetii and/or activation of host-defense in individuals carrying genetic variants in pattern recognition receptors or adaptors would result in an increased likelihood to develop chronic Q fever. METHODS: Twenty-four single-nucleotide polymorphisms in genes encoding Toll-like receptors, nucleotide-binding oligomerization domain-like receptor-2, alphavbeta3 integrin, CR3, and adaptors myeloid differentiation primary response protein 88 (MyD88), and Toll interleukin 1 receptor domain-containing adaptor protein (TIRAP) were genotyped in 139 patients with chronic Q fever and in 220 controls with cardiovascular risk-factors and previous exposure to C. burnetii. Associations between these single-nucleotide polymorphisms and chronic Q fever were assessed by means of univariate logistic regression models. Cytokine production in whole-blood stimulation assays was correlated with relevant genotypes. RESULTS: Polymorphisms in TLR1 (R80T), NOD2 (1007fsX1), and MYD88 (-938C>A) were associated with chronic Q fever. No association was observed for polymorphisms in TLR2, TLR4, TLR6, TLR8, ITGAV, ITGB3, ITGAM, and TIRAP. No correction for multiple testing was performed because only genes with a known role in initial recognition of C. burnetii were included. In the whole-blood assays, individuals carrying the TLR1 80R-allele showed increased interleukin 10 production with C. burnetii exposure. CONCLUSIONS: Polymorphisms in TLR1 (R80T), NOD2 (L1007fsX1), and MYD88 (-938C>A) are associated with predisposition to development of chronic Q fever. For TLR1, increased interleukin 10 responses to C. burnetii in individuals carrying the risk allele may contribute to the increased risk of chronic Q fever.

Item does not contain fulltext Peritoneal macrophages from Toll-like receptor (TLR) 4-deficient ScCr mice produced less tumor necrosis factor, interleukin (IL)-1alpha, and IL-1beta than did macrophages of control mice, when stimulated with conidia, but not with hyphae, of Aspergillus fumigatus, a finding suggesting that TLR4-mediated signals are lost during germination. This hypothesis was confirmed by use of a TLR4-specific fibroblast reporter cell line (3E10) that responded to the conidia, but not to the hyphae, of A. fumigatus. In contrast, macrophages from TLR2-knockout mice had a decreased production of proinflammatory cytokines in response to both Aspergillus conidia and Aspergillus hyphae, and these results were confirmed in 3E10 cells transfected with human TLR2. In addition, Aspergillus hyphae, but not Aspergillus conidia, stimulated production of IL-10 through TLR2-dependent mechanisms. In conclusion, TLR4-mediated proinflammatory signals, but not TLR2-induced anti-inflammatory signals, are lost on Aspergillus germination to hyphae. Therefore, phenotypic switching during germination may be an important escape mechanism of A. fumigatus that results in counteracting the host defense.