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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. 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]