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PubMed2000

Regulation of infection with Histoplasma capsulatum by TNFR1 and -2.

The concerted action of several cytokines is necessary for resolution of both primary and secondary infection with Histoplasma capsulatum. Among the soluble factors that contribute to tissue sterilization, TNF-alpha stands as a central mediator of protective immunity to this fungus. In this study, we explored the regulation of protective immunity by TNFR1 and -2. In primary pulmonary infection, both TNFR1-/- and -2-/- mice manifested a high mortality after infection with H. capsulatum, although TNFR1-/- mice were more susceptible than TNFR2 -/- mice. Overwhelming infection in the former was associated with a pronounced decrement in the number of inflammatory cells in the lungs and elevated IFN-gamma and TNF-alpha levels in the lungs. In contrast, IFN-gamma levels were markedly decreased in TNFR2-/- mice, and treatment with this cytokine restored protective immunity. Lung macrophages from both groups of knockout mice released substantial amounts of NO. Upon secondary infection, TNFR2-/- mice survived rechallenge and cleared infection as efficiently as C57BL/6 animals. In contrast, mice given mAb to TNFR1 succumbed to reexposure, and the high mortality was accompanied by a significant increase in fungal burden in the lungs. Both IL-4 and IL-10 were elevated in the lungs of these mice. The results demonstrate the pivotal influence of TNFR1 and -2 in controlling primary infection and highlight the differences between these receptors for regulation reexposure histoplasmosis.

Animals↗
PubMed2001

Histoplasma capsulatum yeasts are phagocytosed via very late antigen-5, killed, and processed for antigen presentation by human dendritic cells.

Histoplasma capsulatum (Hc) is a facultative, intracellular parasite of world-wide importance. As the induction of cell-mediated immunity to Hc is of critical importance in host defense, we sought to determine whether dendritic cells (DC) could function as a primary APC for this pathogenic fungus. DC obtained by culture of human monocytes in the presence of GM-CSF and IL-4 phagocytosed Hc yeasts in a time-dependent manner. Upon ingestion, the intracellular growth of yeasts within DC was completely inhibited compared with rapid growth within human macrophages. Electron microscopy of DC with ingested Hc revealed that many of the yeasts were degraded as early as 2 h postingestion. In contrast to macrophages, human DC recognized Hc yeasts via the fibronectin receptor, very late Ag-5, and not via CD18 receptors. DC stimulated Hc-specific lymphocyte proliferation in a concentration-dependent manner after phagocytosis of viable and heat-killed Hc yeasts, but greater proliferation was achieved after ingestion of viable yeasts. These data demonstrate that human DC can phagocytose and degrade a fungal pathogen and subsequently process the appropriate Ags for stimulation of lymphocyte proliferation. In vivo, such interactions between DC and Hc may facilitate the induction of cell-mediated immunity.

Adult↗
PubMed2001

Perforin is required for primary immunity to Histoplasma capsulatum.

Protective immunity against primary and secondary infection by the fungus Histoplasma capsulatum (HC) is multifactorial, requiring cells of the innate and adaptive immune response. Effector mechanisms that could mediate intracellular killing of HC include cytokines such as IFN-gamma and TNF-alpha and/or direct cytolytic activity by T and NK cells. In this regard, although previous work has clearly demonstrated a critical role for IFN-gamma and TNF-alpha in limiting fungal growth in primary HC infection, less is known regarding the role of cytolytic mechanisms. The studies reported here first address the role of perforin in mediating immunity to HC. Remarkably, perforin-deficient knockout (PfKO) mice were shown to have accelerated mortality and increased fungal burden following a lethal or sublethal primary challenge. These data established an essential role for perforin in primary immunity systemic HC infection. Interestingly, depletion of CD8(+) T cells in PfKO mice caused a further increase in fungal burden and accelerated mortality, suggesting a perforin-independent role for CD8(+) T cells. Moreover, adoptive transfer of CD8(+) T cells from PfKO mice into IFN-gamma(-/-) mice caused a reduction in fungal burden following infectious challenge compared with control IFN-gamma(-/-) mice. Together, these data suggest that CD8(+) T cells can mediate immunity to HC through both perforin-dependent and -independent mechanisms.

Animals↗
PubMed2001

V beta 6+ T cells are obligatory for vaccine-induced immunity to Histoplasma capsulatum.

We examined TCR usage to a protective fragment of heat shock protein 60 from the fungus, Histoplasma capsulatum. Nearly 90% of T cell clones from C57BL/6 mice vaccinated with this protein were Vbeta6+; the remainder were Vbeta14+. Amino acid motifs of the CDR3 region from Vbeta6+ cells were predominantly IxGGG, IGG, or SxxGG, whereas it was uniformly SFSGG for Vbeta14+ clones. Short term T cell lines from Vbeta6+-depleted mice failed to recognize Ag, and no T cell clones could be generated. To determine whether Vbeta6+ cells were functionally important, we eliminated them during vaccination. Depletion of Vbeta6+ cells abrogated protection in vivo and upon adoptive transfer of cells into TCR alphabeta(-/-) mice. Transfer of a Vbeta6+, but not a Vbeta14+, clone into TCR alphabeta(-/-) mice prolonged survival. Cytokine generation by Ag-stimulated splenocytes from immunized mice depleted of Vbeta6+ cells was similar to that of controls. The efficacy of the Vbeta6+ clone was associated with elevated production of IFN-gamma, TNF-alpha, and GM-CSF compared with that of the Vbeta14+ clone. More Vbeta6+ cells were present in lungs and spleens of TCR alphabeta(-/-) on day 3 postinfection compared with Vbeta14+ cells. Thus, a single Vbeta family was essential for vaccine-induced immunity. Moreover, the mechanism by which Vbeta6+ contributed to protective immunity differed between unfractionated splenocytes and T cell clones.

Adoptive Transfer↗
PubMed2002

The protective immune response to heat shock protein 60 of Histoplasma capsulatum is mediated by a subset of V beta 8.1/8.2+ T cells.

Immunization with recombinant heat shock protein 60 (rHsp60) from Histoplasma capsulatum or a region of the protein designated fragment 3 (F3) confers protection from a subsequent challenge in mice. To determine the T cell repertoire involved in the response to Hsp60, T cell clones from C57BL/6 mice immunized with rHsp60 were generated and examined for Vbeta usage by flow cytometry and RT-PCR. Vbeta8.1/8.2(+) T cells were preferentially expanded; other clones bore Vbeta4, -6, or -11. When Vbeta8.1/8.2(+) cells were depleted in mice, Vbeta4(+) T cell clones were almost exclusively isolated. Measurement of cytokine production demonstrated that nine of 16 Vbeta8.1/8.2(+) clones were Th1, while only three of 13 non-Vbeta8.1/8.2(+) clones were Th1. In mice immunized with rHsp60, depletion of Vbeta8.1/8.2(+), but not Vbeta6(+) plus Vbeta7(+), T cells completely abolished the protective efficacy of Hsp60 to lethal and sublethal challenges. Examination of the TCR revealed that a subset of Vbeta8.1/2(+) clones that produced IFN-gamma and were reactive to F3 shared a common CDR3 sequence, DGGQG. Transfer of these T cell clones into TCR alpha/beta(-/-) or IFN-gamma(-/-) mice significantly improved survival, while transfer of other Vbeta8.1/8.2(+) clones that were F3 reactive but were Th2 or clones that were not reactive to F3 but were Th1 did not confer protection. These data indicate that a distinct subset of Vbeta8.1/8.2(+) T cells is crucial for the generation of a protective response to rHsp60.

Animals↗
PubMed2003

Identification of heat shock protein 60 as the ligand on Histoplasma capsulatum that mediates binding to CD18 receptors on human macrophages.

Histoplasma capsulatum (Hc), is a facultative intracellular fungus that binds to CD11/CD18 receptors on macrophages (Mphi). To identify the ligand(s) on Hc yeasts that is recognized by Mphi, purified human complement receptor type 3 (CR3, CD11b/CD18) was used to probe a Far Western blot of a detergent extract of Hc cell wall and cell membrane. CR3 recognized a single 60-kDa protein, which was identified as heat shock protein 60 (hsp60). Biotinylation of viable yeasts, followed by precipitation with streptavidin-coated beads, and Western blotting with anti-hsp60 demonstrated that hsp60 was on the surface of Hc yeasts. Electron and confocal microscopy revealed that hsp60 resided on the yeast cell wall in discrete clusters. Recombinant hsp60 (rhsp60) inhibited attachment of Hc yeasts to Mphi. Recombinant hsp60 and Abs to CD11b and CD18 inhibited binding of yeasts to Chinese hamster ovary cells transfected with CR3 (CHO3). Polystyrene beads coated with rhsp60 bound to Mphi, and attachment was inhibited by Abs to CD11 and CD18. Freeze/thaw extract (F/TE), a preparation of Hc yeast surface proteins that contained hsp60, inhibited the attachment of Hc yeasts to Mphi. Depletion of hsp60 from F/TE removed the capacity of F/TE to block binding of Hc to Mphi. Interestingly, rhsp60 did not inhibit binding of Hc yeasts to dendritic cells (DC), which recognize Hc via very late Ag 5. Moreover, F/TE inhibited attachment of Hc to DC even when depleted of hsp60. Thus, Hc hsp60 appears to be a major ligand that mediates attachment of Hc to Mphi CD11/CD18, whereas DC recognize Hc via a different ligand(s).

Animals↗
PubMed2003

Protective and memory immunity to Histoplasma capsulatum in the absence of IL-10.

We determined whether the absence of IL-10 in mice influenced protective and memory immunity to Histoplasma capsulatum. IL-10(-/-) mice cleared primary and secondary infection more rapidly than wild-type controls. Administration of mAb to TNF-alpha or IFN-gamma, but not GM-CSF, abrogated protection in naive IL-10(-/-) mice; mAb to TNF-alpha, but not IFN-gamma or GM-CSF, subverted protective immunity in secondary histoplasmosis. The inflammatory cell composition in IL-10(-/-) mice was altered in those given mAb to IFN-gamma or TNF-alpha. More Gr-1(+) and Mac-3(+) cells were present in lungs of IL-10(-/-) mice given mAb to IFN-gamma, and treatment with mAb to TNF-alpha sharply reduced the number of CD8(+) cells in lungs of IL-10(-/-) mice. We ascertained whether the lack of IL-10 modulated memory T cell generation or the protective function of cells. The percentage of CD3(+), CD44(high), CD62(low), and IFN-gamma(+) cells in IL-10(-/-) mice was higher than that of wild-type at day 7 but not day 21 or 49 after immunization. Fewer splenocytes from immunized IL-10(-/-) mice were required to mediate protection upon adoptive transfer into infected TCR alphabeta(-/-) mice. Hence, deficiency of IL-10 confers a salutary effect on the course of histoplasmosis, and the beneficial effects of IL-10 deficiency require endogenous TNF-alpha and/or IFN-gamma. Memory cell generation was transiently increased in IL-10(-/-) mice, but the protective function conferred by cells from these mice following immunization is strikingly more vigorous than that of wild-type.

Adoptive Transfer↗
PubMed2006

Human macrophages do not require phagosome acidification to mediate fungistatic/fungicidal activity against Histoplasma capsulatum.

Histoplasma capsulatum (Hc) is a facultative intracellular fungus that modulates the intraphagosomal environment to survive within macrophages (Mphi). In the present study, we sought to quantify the intraphagosomal pH under conditions in which Hc yeasts replicated or were killed. Human Mphi that had ingested both viable and heat-killed or fixed yeasts maintained an intraphagosomal pH of approximately 6.4-6.5 over a period of several hours. These results were obtained using a fluorescent ratio technique and by electron microscopy using the 3-(2,4-dinitroanilo)-3'-amino-N-methyldipropylamine reagent. Mphi that had ingested Saccharomyces cerevisae, a nonpathogenic yeast that is rapidly killed and degraded by Mphi, also maintained an intraphagosomal pH of approximately 6.5 over a period of several hours. Stimulation of human Mphi fungicidal activity by coculture with chloroquine or by adherence to type 1 collagen matrices was not reversed by bafilomycin, an inhibitor of the vacuolar ATPase. Human Mphi cultured in the presence of bafilomycin also completely degraded heat-killed Hc yeasts, whereas mouse peritoneal Mphi digestion of yeasts was completely reversed in the presence of bafilomycin. However, bafilomycin did not inhibit mouse Mphi fungistatic activity induced by IFN-gamma. Thus, human Mphi do not require phagosomal acidification to kill and degrade Hc yeasts, whereas mouse Mphi do require acidification for fungicidal but not fungistatic activity.

Animals↗
PubMed1977

Occurrence of Histoplasma capsulatum Darling, 1906 in Israel, with a review of the current status of histoplasmosis in the Middle East.

The isolation of Histoplasma capsulatum from a bat cave in the Galilee region of Israel is reported along with the discovery of a bat (Myotis myotis) infected by H. capsulatum. Soils collected in avian and chiropteran habitats throughout Israel also yielded the following fungi of medical interest: Arthroderma quadrifidum, A. tuberculatum, Candida parapsilosis, Chrysosporium indicum, C. keratinophilum, C. tropicum, Cryptococcus neoformans, Ctenomyces serratus, Microsporum gypseum, and Petriellidium boydii. All available reports concerning the occurrence of H. capsulatum and histoplasmosis in the Middle East are critically reviewed.

Animals↗
PubMed1978

Humoral and cell-mediated immunity to Histoplasma capsulatum during experimental infection in neotropical bats (Artibeus lituratus).

The humoral and cell-mediated immune responses of the large, frugivorus bat, Artibeus lituratus, were studied following intraperitoneal injection of 10 or 10(4) viable mycelial particles of Histoplasma capsulatum. Most bats had both cultural and histologic evidence of disease at autopsy. Utilizing a technique designed to measure the volume of footpad swelling in hypersensitive bats a significant degree of delayed hypersensitivity to histoplasmin was evident in both groups 4 to 6 wk after infection. Precipitating antibodies first appeared in the serum 3 wk after infection, but only in the animals infected with 10(4) viable organisms. Both the double diffusion and counterimmunoelectrophoresis techniques for antibody gave identical results. These findings suggest that A. lituratus is very susceptible to infection with H. capsulatum, and that a mild infection will stimulate delayed hypersensitivity to the organism but only low levels of antibody. The footpad test utilized in this study may be a sensitive and practical method for detecting natural infection in bats.

Animals↗
PubMed1979

Immune responses in bats following intranasal infection with Histoplasma capsulatum.

Groups of bats (Artibeus lituratus) were infected by the intranasal instillation of a suspension of mycelia and spore particles of Histoplasma capsulatum containing either 10(4) or 10(6) viable units. Bats infected with the high dose had viable H. capsulatum in the lungs, liver, spleen and gut as early as 2 weeks post-infection. Complement-fixing antibodies to the organism were detectable 3 weeks after infection, whereas precipitating antibodies were not persent until 5 weeks. Significantly delayed hypersensitivity to histoplasmin was noted at 2 and 4 weeks after infection. By 9 weeks, delayed hypersensitivity had waned, while antibodies could still be demonstrated. The observation that bats are susceptible to respiratory infection with H. capsulatum suggests a mechanism by which the disease may be maintained within a colony. Delayed hypersensitivity appears to be a sensitive, but transient, indicator of active histoplasmosis in bats.

Animals↗
PubMed1982

Contribution of bats to the maintenance of Histoplasma capsulatum in a cave microfocus.

Bracken Cave, a large natural cavern located 25 miles northeast of San Antonio, Texas, serves as nursery roost for millions of Mexican free-tailed bats (Tadarida brasiliensis). Ten days after spending several hours in the cave in early May 1979, three graduate students presented with signs and symptoms compatible with acute pulmonary histoplasmosis. A study was initiated to determine the presence and location of Histoplasma capsulatum in the cave and its inhabitants. The fungus was cultured directly from guano at five of nine sites sampled. Sentinel mice left for several hours at one of three positive sites developed histoplasmosis within 30 days after exposure. Autopsy was done on a total of 28 bats and their lungs, liver and spleen were cultured for viable H. capsulatum. In addition, sera from 58 bats were tested for antibodies to H. capsulatum, using a double diffusion test employing commercial reagents. All bat cultures and sera were negative. We conclude that the students were infected by massive exposure to viable H. capsulatum in aerosols created by disturbing guano deposits near the mouth of the cave. Tadarida brasiliensis contributes to a suitable environment for fungal proliferation, but does not appear to play an active role in the maintenance or dissemination of the fungus in Bracken Cave.

Animals↗
PubMed1991

Histoplasmosis relapse in patients with AIDS: detection using Histoplasma capsulatum variety capsulatum antigen levels.

OBJECTIVE: To assess the accuracy of Histoplasma capsulatum variety capsulatum polysaccharide antigen testing for the identification of histoplasmosis relapse in patients with the acquired immunodeficiency syndrome (AIDS). DESIGN: A retrospective study using stored specimens. SETTING: A referral center and several private hospitals. PATIENTS: Twenty episodes of histoplasmosis relapse were evaluated in 17 patients with AIDS from November 1987 to August 1990. Controls included 30 patients with AIDS and histoplasmosis who did not have a relapse during maintenance therapy and who were initially tested during the same week as the patients with relapse. A second control group included seven patients with AIDS and histoplasmosis who were evaluated for relapse on 23 occasions; relapse, however, was excluded on each occasion. MEASUREMENTS: To avoid interassay variability, specimens were tested for H.c. var. capsulatum polysaccharide antigen with the same radioimmunoassay. MAIN OUTCOME MEASURE: The change in the H.c. var. capsulatum polysaccharide antigen level during successful as opposed to unsuccessful maintenance therapy for the prevention of histoplasmosis relapse. MAIN RESULTS: For the 20 episodes of relapse (17 patients), H.c. var. capsulatum antigen levels increased by at least 2 radioimmunoassay units in 12 of 14 serum specimens tested (85.7%; 95% Cl, 57.2% to 98.2%) and in 17 of 18 urine specimens tested (94.4%; Cl, 72.7% to 99.9%). Antigen levels increased in the urine or serum in 1 of 83 specimens (1.2%; CI, 0.03% to 6.6%) obtained on 56 occasions (1.8%; CI, 0.04% to 9.6%) from controls (specificity, 98.2%; CI, 90.4% to 99.96%). In three cases of relapse, antigen levels increased before clinical relapse, antigen levels increased before clinical relapse was suspected. Complement fixation titers increased by at least 2 dilutions in 4 of 11 cases (36.4%; CI, 10.9% to 69.2%) but in 0 of 9 control patients (CI, 0% to 28.3%). CONCLUSION: An increase in H.c. var. capsulatum polysaccharide antigen levels of 2 units or more strongly suggests histoplasmosis relapse. The presence of increasing titers of anti-H.c. var. capsulatum antibodies by complement fixation is less accurate for the diagnosis of relapse.

Acquired Immunodeficiency Syndrome↗
PubMed1998

[American pulmonary histoplasmosis caused by Histoplasma capsulatum].

American pulmonary histoplasmosis is a deep mycosis imported from North America caused by the inhalation of Histoplasma capsulatum. It is endemic in several countries throughout the world and occasional cases have been reported in France, mainly imported from out lying French territories. The most frequent clinical forms observed in immunocompetent subjects are generally benign or silent and usually limited to a fortuitously discovered pulmonary nodule. Massive exposure may lead to an acute primary invasion producing a miliary aspect. Chronic forms simulating tuberculosis are exceptional. Inversely, opportunistic histoplasmosis in AIDS patients can produce an severe multiple organ disease. Ideally, mycelium should be isolated for diagnosis, a task which is easier in disseminated or operated nodular forms. More often, the epidemiological context, clinical and radiological features, the elimination of differential diagnoses and, retrospectively, serology are sufficient for diagnosis. The clinical course is usually favorable. Itraconazole is the treatment of choice for symptomatic or complicated forms.

AIDS-Related Opportunistic Infections↗
PubMed1999

Regulation of the macrophage vacuolar ATPase and phagosome-lysosome fusion by Histoplasma capsulatum.

Histoplasma capsulatum (Hc) maintains a phagosomal pH of about 6.5. This strategy allows Hc to obtain iron from transferrin, and minimize the activity of macrophage (Mo) lysosomal hydrolases. To determine the mechanism of pH regulation, we evaluated the function of the vacuolar ATPase (V-ATPase) in RAW264.7 Mo infected with Hc yeast or the nonpathogenic yeast Saccharomyces cerevisae (Sc). Incubation of Hc-infected Mo with bafilomycin, an inhibitor of the V-ATPase, did not affect the intracellular growth of Hc, nor did it affect the intraphagosomal pH. In contrast, upon addition of bafilomycin, phagosomes containing Sc rapidly changed their pH from 5 to 7. Hc-containing phagosomes had 5-fold less V-ATPase than Sc-containing phagosomes as quantified by immunoelectron microscopy. Furthermore, Hc-containing phagosomes inhibited phagolysosomal fusion as quantified by the presence of acid phosphatase, accumulation of LAMP2, and fusion with rhodamine B-isothiocyanate-labeled dextran-loaded lysosomes. Finally, in Hc-containing phagosomes, uptake of ferritin was equivalent to phagosomes containing Sc, indicating that Hc-containing phagosomes have full access to the early "bulk flow" endocytic pathway. Thus, Hc yeasts inhibit phagolysosomal fusion, inhibit accumulation of the V-ATPase in the phagosome, and actively acidify the phagosomal pH to 6.5 as part of their strategy to survive in Mo phagosomes.

Animals↗
PubMed2001

[Tibial abscess caused by histoplasma capsulatum].

Disseminated histoplasmosis is the most serious form of the disease produced by the fungus Histoplasma capsulatum. Histoplasmosis was first described by Darling in 1906, and it is endemic in certain areas of Central and Southeastern regions of USA, and most Latin America countries, including the Pampa húmeda and Mesopotamia regions in Argentina, but in other continents it has a limited regional distribution. Lung involvement predominates in 90% of cases, but H. capsulatum may involve bone and soft tissues. Bone lesions without other signs of infection are very rare, and are often misdiagnosed as cancer. We report a case of disseminated histoplasmosis in a man with a myelodysplasia who presented a left tibial abscess, without any clinical evidence of pulmonary involvement. The patient was successfully treated with itraconazole.

Abscess↗
PubMed1975

Synergism of amphotericin B and 2-deoxyglucose against Histoplasma capsulatum yeasts in vitro.

The glucose analogue, 2-deoxyglucose (2DG), enhances both the fungistatic and the fungicidal action of amphotericin B in Fungizone (Squibb) against Histoplasma capsulatum yeasts in vitro. This synergistic effect is more pronounced when the test substances are incorporated in double-diffusion agar plates than in liquid medium. Minimum inhibitory concentrations for 2DG and amphotericin B in Fungizone have been established. The effects of components of Fungizone other than amphotericin B as clinically administered were also studied. Neither sodium desoxycholate nor phosphate buffer had any effect on the test organisms when used in recommended clinical concentrations. The 5% glucose infusion solution greatly enhanced the growth of the pathogen and markedly decreased the effectiveness of amphotericin B. H. capsulatum yeasts quickly became resistant to stepwise increases of Fungizone but not of 2DG. Susceptibility to amphotericin B and to 2DG increased with time within certain limits of exposure. The A (albino) phenotype of H. capsulatum is considerably more resistant to amphotericin B than the B (brown) phenotype, but there are no differences in susceptibilities to 2DG. The potential clinical applications of these studies are discussed, since experimental animals and man are reported to tolerate large amounts of 2DG. The incorporation of 2DG in the polyene antibiotic preparation would render it more effective at lower doses and would decrease clinical toxicity.

Amphotericin B↗
PubMed1975

Retention of albino and brown phenotypes of Histoplasma capsulatum by liquid nitrogren refrigeration.

Pathogenic differences between albino (A) and brown (B) phenotypes of Histoplasma capsulatum for experimental animals, and serological differences between A- and B- derived histoplasmins or yeast-phase antigens, necessitate the retention of these phenotypes in culture for diagnoses and epidemiologic studies. Selected strains of A and B types were frozen in liquid nitrogen (LN) and stored for 6-9 months in the vapor phase of a LN refrigerator (-165 degrees C). The strains were tested by using Berliner's method for differentiation of these two phenotypes. The results have proved that the LN refrigeration can be used for long-term conservation to prevent the conversion of B type into the A type in vitro.

Color↗