epiglucan and Histoplasmosis

In this retrospective study, (1->3)-β-d-glucan (B-glucan) was an unreliable marker for AIDS-related Pneumocystis jirovecii pneumonia (PCP) because a high percentage of participants with progressive disseminated histoplasmosis and respiratory symptoms had a positive B-glucan result. Where histoplasmosis is common, attributing B-glucan positivity to PCP without further testing risks misdiagnosis.

Topics: Acquired Immunodeficiency Syndrome; beta-Glucans; Glucans; Histoplasmosis; Humans; Pneumocystis carinii; Pneumonia, Pneumocystis; Retrospective Studies

Fungal cell walls contain β-glucan polysaccharides that stimulate immune responses when recognized by host immune cells. The fungal pathogen

Topics: beta-Glucans; Glucan 1,3-beta-Glucosidase; Glucan Endo-1,3-beta-D-Glucosidase; Histoplasma; Histoplasmosis; Humans; Substrate Specificity

The fungal pathogen Histoplasma capsulatum parasitizes host phagocytes. To avoid antimicrobial immune responses, Histoplasma yeasts must minimize their detection by host receptors while simultaneously interacting with the phagocyte. Pathogenic Histoplasma yeast cells, but not avirulent mycelial cells, secrete the Eng1 protein, which is a member of the glycosylhydrolase 81 (GH81) family. We show that Histoplasma Eng1 is a glucanase that hydrolyzes β-(1,3)-glycosyl linkages but is not required for Histoplasma growth in vitro or for cell separation. However, Histoplasma yeasts lacking Eng1 function have attenuated virulence in vivo, particularly during the cell-mediated immunity stage. Histoplasma yeasts deficient for Eng1 show increased exposure of cell wall β-glucans, which results in enhanced binding to the Dectin-1 β-glucan receptor. Consistent with this, Eng1-deficient yeasts trigger increased tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6) cytokine production from macrophages and dendritic cells. While not responsible for large-scale cell wall structure and function, the secreted Eng1 reduces levels of exposed β-glucans at the yeast cell wall, thereby diminishing potential recognition by Dectin-1 and proinflammatory cytokine production by phagocytes. In α-glucan-producing Histoplasma strains, Eng1 acts in concert with α-glucan to minimize β-glucan exposure: α-glucan provides a masking function by covering the β-glucan-rich cell wall, while Eng1 removes any remaining exposed β-glucans. Thus, Histoplasma Eng1 has evolved a specialized pathogenesis function to remove exposed β-glucans, thereby enhancing the ability of yeasts to escape detection by host phagocytes.. The success of Histoplasma capsulatum as an intracellular pathogen results, in part, from an ability to minimize its detection by receptors on phagocytic cells of the immune system. In this study, we showed that Histoplasma pathogenic yeast cells, but not avirulent mycelia, secrete a β-glucanase, Eng1, which reduces recognition of fungal cell wall β-glucans. We demonstrated that the Eng1 β-glucanase promotes Histoplasma virulence by reducing levels of surface-exposed β-glucans on yeast cells, thereby enabling Histoplasma yeasts to escape detection by the host β-glucan receptor, Dectin-1. As a consequence, phagocyte recognition of Histoplasma yeasts is reduced, leading to less proinflammatory cytokine production by phagocytes and less control of Histoplasma infection in vivo Thus, Histoplasma yeasts express two mechanisms to avoid phagocyte detection: masking of cell wall β-glucans by α-glucan and enzymatic removal of exposed β-glucans by the Eng1 β-glucanase.

Topics: beta-Glucans; Fungal Proteins; Glycoside Hydrolases; Histoplasma; Histoplasmosis; Humans; Lectins, C-Type; Receptors, Immunologic; Virulence

A 59-year-old patient with multiple myeloma on maintenance chemotherapy presented with fever, weight loss, and night sweats. An F-18 fluorodeoxyglucose (FDG) positron emission tomography (PET) computed tomography (CT) showed intra-abdominal lymphadenopathy with a mesenteric mass that led to further workup and diagnosis of histoplamosis. The patient was treated with amphotericin B and subsequently switched to itraconazole. This exemplifies the usefulness of FDG PET CT in diagnosis of infectious complications.

Topics: Amphotericin B; Antifungal Agents; Antineoplastic Agents; beta-Glucans; Colonoscopy; Fever; Fluorodeoxyglucose F18; Gastrointestinal Diseases; Hematopoietic Stem Cell Transplantation; Histoplasma; Histoplasmosis; Humans; Ileum; Intestinal Obstruction; Itraconazole; Lymphadenopathy; Male; Middle Aged; Multiple Myeloma; Positron-Emission Tomography; Radiopharmaceuticals; Tomography, X-Ray Computed; Weight Loss

Histoplasma capsulatum (Hc) is a facultative, intracellular parasite of worldwide significance. Infection with Hc produces a broad spectrum of diseases and may progress to a life-threatening systemic disease, particularly in individuals with HIV infection. Resolution of histoplasmosis is associated with the activation of cell-mediated immunity, and leukotriene B(4) plays an important role in this event. Lipid bodies (LBs) are increasingly being recognized as multifunctional organelles with roles in inflammation and infection. In this study, we investigated LB formation in histoplasmosis and its putative function in innate immunity. LB formation in leukocytes harvested from Hc-infected C57BL/6 mice peaks on day 2 postinfection and correlates with enhanced generation of lipid mediators, including leukotriene B(4) and PGE(2). Pretreatment of leukocytes with platelet-activating factor and BLT1 receptor antagonists showed that both lipid mediators are involved in cell signaling for LB formation. Alveolar leukocytes cultured with live or dead Hc also presented an increase in LB numbers. The yeast alkali-insoluble fraction 1, which contains mainly beta-glucan isolated from the Hc cell wall, induced a dose- and time-dependent increase in LB numbers, indicating that beta-glucan plays a signaling role in LB formation. In agreement with this hypothesis, beta-glucan-elicited LB formation was inhibited in leukocytes from 5-LO(-/-), CD18(low) and TLR2(-/-) mice, as well as in leukocytes pretreated with anti-Dectin-1 Ab. Interestingly, human monocytes from HIV-1-infected patients failed to produce LBs after beta-glucan stimulation. These results demonstrate that Hc induces LB formation, an event correlated with eicosanoid production, and suggest a role for these lipid-enriched organelles in host defense during fungal infection.

Topics: Adult; Animals; beta-Glucans; CD18 Antigens; Cell Wall; Enzyme-Linked Immunosorbent Assay; Female; Histoplasma; Histoplasmosis; HIV Infections; HIV-1; Humans; Lectins, C-Type; Leukocytes, Mononuclear; Leukotriene B4; Lipids; Male; Membrane Proteins; Mice; Mice, Inbred C57BL; Mice, Knockout; Middle Aged; Nerve Tissue Proteins; Organelles; Toll-Like Receptor 2

We evaluated the Fungitell beta-glucan (BG) test with specimens from patients with presumed histoplasmosis. The sensitivity of the test was 87% in histoplasmosis cases and had a specificity of 68% with controls. Histoplasmosis should be considered as a possible cause for a positive BG test, but such results may be found with many other conditions that are clinically similar to this fungal disease. Therefore, there is a need to conduct confirmatory tests for histoplasmosis in the appropriate clinical setting.

Topics: Antigens, Fungal; beta-Glucans; Fungemia; Histoplasma; Histoplasmosis; Humans; Lung Diseases, Fungal; Proteoglycans; Sensitivity and Specificity; Serologic Tests

Topics: beta-Glucans; Blastomyces; Blastomycosis; Endemic Diseases; Histoplasma; Histoplasmosis; Humans; Proteoglycans; Reagent Kits, Diagnostic

The Fungitell assay (Associates of Cape Cod, Inc.) is a commercial test that detects (1-3)-beta-D-glucan (BG) and is intended for diagnosis of invasive fungal infections. To evaluate the Fungitell assay, we tested serum and plasma samples from healthy blood donors and from patients with blood cultures positive for yeast or bacteria. All 36 blood donors were BG negative, and 13 of 15 candidemic patients were BG positive. Of 25 bacteremic patients, 14 (10 with gram-positive bacteremia) were BG positive. One of the latter patients with Staphylococcus aureus bacteremia also had invasive candidiasis, based on histological findings in a tissue biopsy; therefore, the BG result was a true positive. The sensitivity, specificity, and positive and negative predictive values of the Fungitell assay, by patient, for these three groups were 93.3%, 77.2%, 51.9%, and 97.8%, respectively. We also performed the Fungitell assay on sera that had been tested for Aspergillus galactomannan or Histoplasma antigen. All six Histoplasma antigen-positive patients and 31 of 32 Aspergillus galactomannan-positive patients were also BG positive. BG results for the 10 Histoplasma antigen-negative and the 32 Aspergillus galactomannan-negative patients varied, but we were unable to confirm many of the results. Between-run coefficients of variance (CVs) for the assay ranged from 3.2% to 16.8%; within-run CVs were < or =4.8%. The correlation coefficient for an interlaboratory reproducibility study was 0.9892. Concentrations of hemoglobulin, bilirubin, and triglycerides that caused 20% interference were 588, 72, and 466 mg/dl, respectively. Our results suggest that the Fungitel assay may be most useful for excluding invasive fungal infection.

Topics: Aspergillosis; Aspergillus; beta-Glucans; Candidiasis; Fungemia; Histoplasma; Histoplasmosis; Humans; Reagent Kits, Diagnostic; Reproducibility of Results

In the present study, we evaluated the levels of MIP-1alpha and eotaxin and in vivo migration in the peritoneal cavity model, in mice inoculated with live yeast forms of Histoplasma capsulatum or the beta-glucan cell wall component of this fungus, and the influence of a leukotriene biosynthesis inhibitor, MK886, on the release of these chemokines in relation to cell recruitment.. Female outbred Swiss mice (N = 4-5 per group, 3-4 wk, were used. Mice were injected i.p. with 1 ml of the 6 x 10(5) live yeast form of the fungus or with 10 microg of beta-glucan from the cell wall fraction, and treated daily with MK886 (1 mg kg(-1), p.o.) or vehicle.. The fungus induced rapid generation of high levels of MIP-1alpha, which remained elevated from 4-48 h whereas very little eotaxin was detected at any time point (Fig. 1A and B). In contrast, the beta-glucan induced a little MIP-1alpha but considerably higher concentrations of eotaxin within the first four hours; however, the level of neither chemokine was sustained (Fig. 2A and B). Treatment of animals with MK886 was effective in reducing the numbers of neutrophils, eosinophils and, to a lesser degree, mononuclear cells accumulating in the peritoneal cavity in response to both the live fungus (Fig. 1C-E) and the cell wall beta-glucan (Fig. 2C-E).. The results suggest that chemokines and leukotrienes may play key roles in the inflammatory cell influx to H. capsulatum infection or to the inoculation of the beta-glucan cell wall component of this fungus

Topics: Animals; beta-Glucans; Cell Wall; Chemokine CCL11; Chemokine CCL3; Chemokine CCL4; Chemokines; Chemokines, CC; Female; Histoplasma; Histoplasmosis; Inflammation; Leukocytes; Leukotrienes; Macrophage Inflammatory Proteins; Mice; Time Factors