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We investigated the prevalence of azole resistance of Aspergillus fumigatus isolates in the Netherlands by screening clinical A. fumigatus isolates for azole resistance during 2013-2018. We analyzed azole-resistant isolates phenotypically by in vitro susceptibility testing and for the presence of resistance mutations in the Cyp51A gene. Over the 6-year period, 508 (11%) of 4,496 culture-positive patients harbored an azole-resistant isolate. Resistance frequency increased from 7.6% (95% CI 5.9%-9.8%) in 2013 (58/760 patients) to 14.7% (95% CI 12.3%-17.4%) in 2018 (112/764 patients) (p = 0.0001). TR34/L98H (69%) and TR46/Y121F/T289A (17%) accounted for 86% of Cyp51A mutations. However, the mean voriconazole MIC of TR34/L98H isolates decreased from 8 mg/L (2013) to 2 mg/L (2018), and the voriconazole-resistance frequency was 34% lower in 2018 than in 2013 (p = 0.0001). Our survey showed changing azole phenotypes in TR34/L98H isolates, which hampers the use of current PCR-based resistance tests. [ABSTRACT FROM AUTHOR]

Fast diagnosis of invasive pulmonary aspergillosis (IPA) is essential as early adequate therapy improves survival. However, current microbiological methods suffer from a low sensitivity or a long turnaround time, often as a result of batching. Recently, two lateral flow assays for diagnosing IPA have been CE (Conformité Européenne)-marked and commercialized. These assays can be used for fast single sample testing. However, clinical validation and comparative studies are lacking. We therefore sought to evaluate and compare these assays in adult hematology patients. We retrospectively tested 235 bronchoalveolar lavage fluid (BALf) samples of adult hematology patients from four centers using the AspLFD (OLM Diagnostics) and the sōna Aspergillus galactomannan LFA (IMMY). Both tests were read out independently by two researchers and by a digital reader. We included 11 patients with proven IPA, 64 with probable IPA, 43 with possible fungal disease, and 117 controls with no signs of IPA. In cases of proven IPA, the performance of both assays was similar. In cases of proven and probable IPA, we found an identical specificity for both assays, but a higher sensitivity (0.83 vs 0.69, P =.008) and a better negative predictive value (0.89 vs 0.82, P =.009) for the LFA. Digital readout improved the diagnostic performance of both tests. In conclusion, both assays showed a good performance for the diagnosis of IPA in BALf from adult hematology patients. Results were further improved by using a digital reader, especially for weakly positive results. [ABSTRACT FROM AUTHOR]

With the current revived interest in the use of bacteriophages for the treatment of bacterial infections, the study of mycoviruses as novel therapeutic solutions for invasive aspergillosis is the logical next step. Although ssRNA, dsRNA, and ssDNA mycoviruses have been identified, the majority of characterised mycoviruses have dsRNA genomes. Prevalence of dsRNA mycoviruses in Aspergillus spp. varies, and mycoviruses can have different effects on their fungal hosts: hypovirulence, hypervirulence, or a killer phenotype. Therapeutically, extracellular transmission of the mycovirus is essential. DsRNA mycoviruses lack an extracellular phase; however, a single ssDNA mycovirus with homologues in Aspergillus genomes has been described with an extracellular mode of transmission. Mycoviruses can induce hypovirulence or a killer phenotype, and both can be exploited therapeutically. Mycoviruses inducing hypovirulence have been used to control chestnut blight, however for aspergillosis no such mycovirus has been identified yet. Mycovirus encoded killer toxins or anti-idiotypic antibodies and killer peptides derived from these have been demonstrated to control fungal infections including aspergillosis in animals. This indicates that mycoviruses inducing both phenotypes could be exploited therapeutically as long as the right mycovirus has been identified. [ABSTRACT FROM AUTHOR]

Summary: Patients with haematological malignancies are at risk for invasive fungal diseases (IFD). A survey was conducted in all Dutch academic haematology centres on their current diagnostic, prophylactic and therapeutic approach towards IFD in the context of azole‐resistance. In all 8 centres, a haematologist and microbiologist filled in the questionnaire that focused on different subgroups of haematology patients. Fungal prophylaxis during neutropaenia was directed against Candida and consisted of fluconazole and/or amphotericin B suspension. Mould‐active prophylaxis was given to acute myeloid leukaemia patients during chemotherapy in 2 of 8 centres. All centres used azole prophylaxis in a subset of patients with graft‐versus‐host disease. A uniform approach towards the diagnosis and treatment of IFD and in particular azole‐resistant Aspergillus fumigatus was lacking. In 2017, all centres agreed to implement a uniform diagnostic and treatment algorithm regarding invasive aspergillosis with a central role for comprehensive diagnostics and PCR‐based detection of azole‐resistance. This study (DB‐MSG 002) will re‐evaluate this algorithm when 280 patients have been treated. A heterogeneous approach towards antifungal prophylaxis, diagnosis and treatment was apparent in the Netherlands. Facing triazole‐resistance, consensus was reached on the implementation of a uniform diagnostic approach in all 8 centres. [ABSTRACT FROM AUTHOR]

Caspofungin (CAS) which is used as salvage therapy in patients with invasive pulmonary aspergillosis (IPA) inhibits the 1,3-β-D-glucan synthesis in Aspergillus fumigatus. Inhibiting 1,3-β-D-glucan synthesis induces a stress response and in an invertebrate model it was demonstrated that inhibiting this response with geldamycin enhanced the therapeutic efficacy of CAS. Since geldamycin itself is toxic to mammalians, the therapeutic efficacy of combining geldamycin with CAS was not studied in rodent models. Therefore in this study we investigated if the geldamycin derivate 17-(allylamino)-17-demethoxygeldanamycin (17-AAG) was able to enhance the therapeutic efficacy of CAS in vitro and in our IPA model in transiently neutropenic rats. In vitro we confirmed the earlier demonstrated synergy between 17-AAG and CAS in ten A. fumigatus isolates. In vivo we treated A. fumigatus infected neutropenic rats with a sub-optimal dose of 0.75 mg/kg/day CAS and 1 mg/kg/day 17-AAG for ten days. Survival was monitored for 21 days after fungal inoculation. It appeared that the addition 17-AAG delayed death but did not improve overall survival of rats with IPA. Increasing the doses of 17-AAG was not possible due to hepatic toxicity. This study underlines the need to develop less toxic and more fungal specific geldamycin derivatives and the need to test such drugs not only in invertebrate models but also in mammalian models. [ABSTRACT FROM AUTHOR]

Invasive Candida spp. infections are increasingly diagnosed in critically ill patients. For initial treatment, an echinocandin is recommended with a possible step-down to fluconazole when the patients' condition is improving and the isolate appears susceptible, but there are no data to support such policy. We studied the safety and efficacy of step-down therapy in critically ill patients with culture proven deep seated or bloodstream infections by C. albicans susceptible to fluconazole. All patients admitted into the intensive care unit from January 2010 to December 2014, who had a culture proven invasive C. albicans infection and received initial treatment with an echinocandin for at least 4 days were included. Data on patient characteristics, treatment and vital outcomes were assessed. Of the 56 patients, 32 received step-down fluconazole therapy, at median day 5, whereas the echinocandin was continued in the other 24. No differences where seen in baseline characteristics or risk factors for invasive C. albicans infection between the two groups. Response rates were similar and no difference where seen in 28-day or 90-day mortality between the groups. Step-down therapy to fluconazole may be safe and effective in critically ill patients with invasive infections by C. albicans, susceptible to fluconazole, who have clinically improved as early as 4 days after start of treatment with an echinocandin. [ABSTRACT FROM AUTHOR]

An improved number of anti-fungal drugs are currently available for the treatment of invasive aspergillosis (IA). While serial galactomannan index (GMI) measurement can be used to monitor response to treatment, the extent to which different anti-fungal regimens can affect galactomannan levels is unknown. In 147 IA patients receiving either voriconazole (VCZ) or conventional amphotericin B (CAB) in a multicentre clinical trial, we performed post-hoc analyses of GMI trends in relation to outcomes. The generalized estimation equations approach was used to estimate changes in the effect size for GMI over time within patients. Patients who received VCZ primary therapy and had good treatment response 12 weeks later showed earlier decreases in GMI values at Week 1 and Week 2 (p = 0.001 and 0.046 respectively) as compared to patients who only received CAB. At end-of-randomized therapy (EORT), which was a pre-set secondary assessment point for all patients who switched from randomized primary (CAB or VCZ) to an alternative anti-fungal drug, treatment failure was associated with increasing GMI at Weeks 1 and 2 in CAB-primary treated patients (p = 0.022 and 0.046 respectively). These distinct trends highlight the variations in GMI kinetics with the use of different anti-fungal drugs and their implications in relation to IA treatment response. [ABSTRACT FROM AUTHOR]

Aspergillus fumigatus is a fungus that causes opportunistic infections in immunocompromised patients, with high morbidity and mortality. In its turn, A. fumigatus can become infected with mycoviruses. Most mycoviruses have a dsRNA genome and can cause fungal hypovirulence. For that reason, mycoviruses could theoretically be used as therapeutic tools to combat fungal infections. We determined if a certain genetic make-up of A. fumigatus was associated with the presence of mycoviruses in 86 clinical A. fumigatus isolates. Mycovirus screening was performed by isolating dsRNA from mycelial cultures using a Trizol/Chloroform method. The genetic relatedness of dsRNA infected A. fumigatus was determined by cell surface protein (CSP) typing and determination of the mating type. Sixteen (18.6%) of the 86 clinical A. fumigatus isolates contained dsRNA. The A. fumigatus collection could be divided into 11 different CSP types. DsRNA infected A. fumigatus isolates had similar CSP types as non-infected isolates. In both cases, the CSP types t01, t02, t03 and t04 were the most prevalent and the distribution comparable to the CSP types observed in other Dutch collections. Mating types MAT1-1 and MAT1-2 were evenly distributed among all A. fumigatus strains, regardless of CSP type. No difference was observed in mycovirus infections between MAT1-1 and MAT1-2 isolates. DsRNA mycovirus infections in A. fumigatus are not related to either CSP or mating type and therefore represent an interesting future therapeutic tool to combat fungal infections. [ABSTRACT FROM AUTHOR]

Objectives The underlying mechanism for amphotericin B-induced acute kidney injury (AKI) remains poorly understood and may be immunologically mediated. We assessed whether the development of nephrotoxicity is linked to a distinct cytokine profile in patients receiving amphotericin B deoxycholate (AmBD). Patients and methods In 58 patients who received AmBD, circulating serum interleukin (IL)-6, IL-8 and IL-10 were measured at baseline, week 1 and week 2 of antifungal treatment and correlated to the development of renal impairment. The Cox proportional hazards model approach was adopted for analysis. Results The P value was 0.026 for the overall effect of IL-6 on time to development of AKI. An increasing or non-receding IL-6 trend by week 1 of AmBD treatment (followed by a decreasing or non-receding IL-6 trend from week 1 to week 2) correlated with an increased likelihood of nephrotoxicity [hazard ratio (HR) 6.93, P value 0.005 and HR 3.46, P value 0.035, respectively]. Similarly, persistently increasing IL-8 levels were linked to a 3.84-fold increased likelihood of AKI. Conclusions In patients receiving AmBD, persistence of an elevated pro-inflammatory cytokine milieu is associated with a predisposition to drug-related kidney injury. [ABSTRACT FROM PUBLISHER]

Eumycetoma is a morbid chronic granulomatous subcutaneous fungal disease. Despite high environmental exposure to this fungus in certain regions of the world, only few develop eumycetoma for yet unknown reasons. Animal studies suggest that co-infections skewing the immune system to a Th2-type response enhance eumycetoma susceptibility. Since chronic schistosomiasis results in a strong Th2-type response and since endemic areas for eumycetoma and schistosomiasis do regionally overlap, we performed a serological case-control study to identify an association between eumycetoma and schistosomiasis. Compared to endemic controls, eumycetoma patients were significantly more often sero-positive for schistosomiasis (p = 0.03; odds ratio 3.2, 95% CI 1.18–8.46), but not for toxoplasmosis, an infection inducing a Th1-type response (p = 0.6; odds ratio 1.5, 95% CI 0.58–3.83). Here, we show that schistosomiasis is correlated to susceptibility for a fungal disease for the first time. Author Summary: Eumycetoma is a mutilating fungal disease of mainly the foot and is found in (sub)tropical regions such as Sudan. At the moment it is not understood why some people develop eumycetoma and others not. In the regions were eumycetoma is prevalent many other infections are also found. These infections could alter the immune system which makes people more or less susceptible in obtaining another infection. One of the infections with such an effect is Schistosomiasis. In Africa, eumycetoma is found in regions were schistosomiasis is prevalent. In this study we show that eumycetoma patients more often have antibodies against Schistosoma species, than healthy controls from the same region. In contrast, eumycetoma patients did not have more often antibodies against Toxoplasma species. This might implicate that schistosomiasis predisposes eumycetoma development. If schistosomiasis indeed predisposes eumycetoma development, eradicating Schistosoma in a population could also lower the number of eumycetoma cases in that area, which in the end could lead to intervention strategies not only for schistosomiasis but also for eumycetoma. [ABSTRACT FROM AUTHOR]

Eumycetoma is a morbid chronic granulomatous subcutaneous fungal disease. Despite high environmental exposure to this fungus in certain regions of the world, only few develop eumycetoma for yet unknown reasons. Animal studies suggest that co-infections skewing the immune system to a Th2-type response enhance eumycetoma susceptibility. Since chronic schistosomiasis results in a strong Th2-type response and since endemic areas for eumycetoma and schistosomiasis do regionally overlap, we performed a serological case-control study to identify an association between eumycetoma and schistosomiasis. Compared to endemic controls, eumycetoma patients were significantly more often sero-positive for schistosomiasis (p = 0.03; odds ratio 3.2, 95% CI 1.18–8.46), but not for toxoplasmosis, an infection inducing a Th1-type response (p = 0.6; odds ratio 1.5, 95% CI 0.58–3.83). Here, we show that schistosomiasis is correlated to susceptibility for a fungal disease for the first time. [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. 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]

Joosten LAB, van de Veerdonk F, Vonk AG, Boerman OC, Keuter M, Fantuzzi G, Verschueren I, van der Poll T, Dinarello CA, Kullberg BJ, Van der Meer JWM, Netea MG. Differential susceptibility to lethal endotoxaemia in mice deficient in IL-1α, IL-1β or IL-1 receptor type I. APMIS 2010; 118: 1000-7. The role of intereukin-1 (IL-1) in mortality caused by endotoxaemia remains controversial. While IL-1 receptor antagonist (IL-1Ra) protects mice from lethal endotoxaemia, mice deficient in IL-1β (IL-1β) display normal susceptibility to lipopolysaccharide (LPS). The aim of this study was to identify the source of these discrepancies. Mice deficient in IL-1α, IL-1β or IL-1R type I were injected intraperitoneally with Escherichia coli or Salmonella typhimurium LPS. Survival of the mice was examined and compared with C57/Bl6 wild-type mice. In addition, serum cytokine concentrations were determined after LPS challenge and in vitro cytokine production by peritoneal macrophages was analysed. Clearance of radioactive IL-1α was examined in IL-1α and wild-type mice. IL-1β mice were normally susceptible to endotoxaemia and cytokine production did not differ from that in control mice. Surprisingly, LPS mortality in IL-1α mice was significantly greater than that in control mice, accompanied by higher interferon-γ release. These effects were mediated by a distorted homeostasis of IL-1RI receptors, as shown by a strongly delayed clearance of IL-1α. In contrast to the IL-1α and IL-1β mice, IL-1RI mice were completely resistant to high doses of LPS. In conclusion, IL-1RI-mediated signals are crucial in mediating mortality occurring as a result of lethal endotoxaemia. Investigation of IL-1-mediated pathways in IL-1 knock-out mice is complicated by a distorted homeostasis of IL-1Rs. [ABSTRACT FROM AUTHOR]

Background. Monitoring treatment response in invasive aspergillosis is challenging, because an immunocompromised host may not exhibit reliable symptoms and clinical signs. Cytokines play a pivotal role in mediating host immune response to infection; therefore, the profiling of biomarkers may be an appropriate surrogate for disease status. Methods. We studied, in a cohort of 119 patients with invasive aspergillosis who were recruited in a multicenter clinical trial, serum interleukin (IL)-6, IL-8, IL-10, interferon-g, and C-reactive protein (CRP) trends over the first 4 weeks of therapy and correlated these trends to clinical outcome parameters. Results. Circulating IL-6 and CRP levels were high at initiation of therapy and generally showed a downward trend with antifungal treatment. However, subjects with adverse outcomes exhibited a distinct lack of decline in IL-6 and CRP levels at week 1, compared with responders (Pp.02, for both IL-6 and CRP). Nonresponders also had significantly elevated IL-8 levels (P=.001). Conclusions. High initial IL-8 and persistently elevated IL-6, IL-8, and CRP levels after initiation of treatment may be early predictors of adverse outcome in invasive aspergillosis. Cytokine and CRP profiles could be used for early identification of patients with a poor response to antifungal treatment who may benefit from more-aggressive antimicrobial regimens. [ABSTRACT FROM AUTHOR]

Both interferon-γ-producing type 1 T helper (Th1)- and interleukin-17 (IL-17)-producing Th17 cells have been proposed to be involved in anti-fungal host defence. Although invasive aspergillosis is one of the most severe human fungal infections, little is known regarding the relative importance of the Th1 versus Th17 cellular immune pathways for the human anti- Aspergillus host defence. Using human peripheral blood mononuclear cells and a system consisting of monocyte-derived macrophages with lymphocytes, we found that Aspergillus fumigatus is a weak inducer of human IL-17 but induces a strong Th1 response. These data were validated by the very low IL-17 levels in bronchoalveolar lavage fluid and serum of patients with invasive aspergillosis. Surprisingly, live A. fumigatus reduced IL-17 production induced by mitogenic stimuli. This effect was mediated through the propensity of A. fumigatus to metabolize tryptophan and release kynurenine, which modulates the inflammatory response through inhibition of IL-17 production. In conclusion, A. fumigatus does not stimulate production of IL-17 and human host defence against aspergillosis may not rely on potent Th17 responses. [ABSTRACT FROM AUTHOR]

A successful pathogen is one that is able to effectively survive and evade detection by the host innate immune defense. Fungal pathogens have adopted strategies which evade host defense and eventually cause disease in at-risk patients. Shielding of stimulatory surface recognition molecules, shedding of decoy components, induction of anti-inflammatory signals, complement evasion and resilient survival capacity are successful evasion mechanisms employed by fungal pathogens. Understanding these complex pathways of immune evasion can potentially contribute to development of novel therapeutic strategies against fungal infections. [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]

For quantitative assessment of polymorphonuclear granulocyte (PMN)-mediated pseudohyphal damage, an improved tetrazolium (2,3-bis-(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide; XTT) dye assay was developed. The modified assay proved to be a reliable indicator of viable pseudohyphal inoculum sizes. In addition, the influence of various endogenous pro-inflammatory cytokines on the capacity of PMN to damage Candida albicans pseudohyphae was investigated. PMN obtained from mice in which the genes encoding for tumor necrosis factor-α /lymphotoxin-α (TNF/LT), interferon-γ (IFNγ), interleukin (IL)-1α, or IL-1β were disrupted, showed a significantly reduced pseudohyphal damage capacity in comparison with control PMN. The reduction amounted 25% for TNF -/ - LT -/ - , 11% for IFNγ -/ - , 21% for IL-1α -/ - , and 34% for IL-1α -/ - β -/ - PMN. In contrast, deficiency of IL-12 or IL-18 did not result in a diminished capacity to damage pseudohyphae and the capacity of PMN to damage Candida pseudohyphae was even slightly increased by 10% in IL-18 -/ - mice. These data suggest that endogenous pro-inflammatory cytokines are able to modulate antihyphal activity of PMN, the main effector cells against disseminated candidiasis by virtue of their capacity to kill both Candida blastoconidia and pseudohyphae. [ABSTRACT FROM AUTHOR]

The effect of hyperlipoproteinemia on systemic candidiasis was investigated by assessing the susceptibility of hyperlipoproteinemic, apolipoprotein E (ApoE)-deficient (ApoE-/-) mice to a systemic Candida albicans infection. The absence of ApoE in these mice resulted in an eightfold increase in plasma lipoprotein concentrations in the very low-density lipoprotein (VLDL) fraction, as compared with levels seen in ApoE+/+ mice. Mortality due to candidemia was significantly higher (86%) in ApoE-/- mice than in ApoE+/+ mice (52%), and in platings of homogenized kidney material on fungal culture medium, ApoE-/- mice yielded significantly higher levels of C. albicans outgrowth than did ApoE+/+ mice. C. albicans grew twofold better in ApoE-/- plasma in 4 h than in ApoE+/+ plasma, and depletion of lipoproteins from plasma resulted in a significant seven- to tenfold increase in C. albicans growth. Recombinant ApoE did not directly inhibit C. albicans growth. Our data indicate that the increased susceptibility of ApoE-/- mice to C. albicans is due both to increased growth of blastoconidia in ApoE-/- mice in response to the availability of lipids as nutrients, and to the neutralization of candidacidal factors by lipoproteins. This study suggests that lipoproteins play a significant role in host defense against candidiasis. [ABSTRACT FROM AUTHOR]

IFN-γ plays a crucial role in the defense against infection with Candida albicans. Since IL-18 and IL-12 are strong stimuli of IFN-γ production, we investigated whether endogenous IL-18 and IL-12 are involved in the host defense during disseminated candidiasis. IL-18 knockout (IL-18-/-) mice, but not IL-12-/- mice, displayed an increased mortality due to C. albicans infection, accompanied by a decreased clearance of the yeasts from the kidneys late during the course of infection. Histopathology of the organs, combined with phagocyte recruitment experiments, showed a decreased influx of monocytes at the sites of Candida infection, mainly in the IL-18-/- mice. Whereas production of the chemokine KC was decreased in both IL-18-/- and IL-12-/- mice, MIP-2 production was deficient only in IL-18-/- animals, which may explain the differences in phagocyte recruitment. In addition, although IFN-γ production capacity, as a parameter of the Th1-protective immunity, was reduced by 65 to 80% in the IL-12-/- mice, this defect was even more pronounced in the IL-18-/- mice (85 to 95% downmodulation). In conclusion, the anticandidal effects of endogenous IL-18 are mediated late during the infection by assuring a proper IFN-γ response and promoting the infiltration of the site of infection by monocytes. [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]

Examines the role of toll-like receptors in the host defense against disseminated candidiasis. Involvement of sensing pathogenic microorganisms; Production of tumor necrosis factor and interleukin; Importance of Candida albicans in human disease.