Dimorphic Fungus Histoplasma Capsulatum Research Articles

Disseminated histoplasmosis in a renal transplant recipient – a fatal case report

Histoplasmosis is an infectious disease caused by the dimorphic fungus Histoplasma capsulatum.. The disseminated form is usually found in immunocompromised patients. A 53 year-old man, renal transplant recipient, was admitted with fever, dyspnea, productive cough, adynamia and weight loss. He was septic, but hemodynamically stable. The tracheal aspirate found intracellular fungi and the peripheral blood exam was compatible with histoplasmosis. The patient presented a progressive worsening of respiratory pattern and needed mechanical ventilation, vasoactive drugs and hemodialysis. A large spectrum antimicrobial therapy was started, including amphotericin B, but the patient died. Keyword: Disseminated histoplasmosis. Kidney transplantation. Immunosuppression DOI: http://dx.doi.org/10.3329/jom.v12i2.7125 JOM 2011; 12(2): 163-165

Acute systemic histoplasmosis associated with chorioretinitis in an immunocompetent adolescent

Histoplasmosis is an endemic, systemic mycosis caused by the dimorphic fungus Histoplasma capsulatum. A minority of patients develop asymptomatic chorioretinitis known as presumed ocular histoplasmosis syndrome (POHS), which is typically associated with chorioretinal scarring and peripapillary atrophy and occasionally with choroidal neovascularization secondary to maculopathy. We report a case of acute severe bilateral chorioretinitis associated with disseminated H. capsulatum in an immunocompetent adolescent boy living in an endemic area. The chorioretinitis did not respond to systemic antifungal therapy, but both his systemic illness and ocular lesions resolved with the addition of systemic steroids.

Disseminated Histoplasmosis in a Patient with Advanced HIV Disease - Lessons Learnt from Bangladesh

Histoplasmosis is a systemic fungal disease, also known as Darling's disease, caused by the dimorphic fungus Histoplasma capsulatum. It is usually self-limiting or localized in immunecompetent individuals whereas in patients with acquired immune deficiency syndrome (AIDS), it occurs in the disseminated form in 95% of cases. Although histoplasmosis predominates in the Americas (United States and Latin America, including Brazil) as an important infection among AIDS patients, it is not common in Bangladesh. In contrast, tuberculosis is extremely common in Bangladesh, with an estimated prevalence of 387 per 100,000 people. Here, a confirmed case of disseminated histoplasmosis is reported in Bangladesh in a known HIV-positive patient, which was initially suspected to be extrapulmonary tuberculosis.

Histoplasmose pulmonar cavitária crônica

Histoplasmosis is a systemic mycosis caused by the thermally dimorphic fungus Histoplasma capsulatum, which can be isolated from soil contaminated with droppings from birds or bats. Chronic cavitary pulmonary histoplasmosis is one of the rarest clinical presentations of this disease. The differential diagnosis with tuberculosis should be made in patients presenting with cavitated lesions in upper lung segments. We report the case of a female patient with chronic cavitary pulmonary histoplasmosis who had presented with progressive dyspnea and worsening of the radiological pattern over a four-year period.

The CCL7-CCL2-CCR2 Axis Regulates IL-4 Production in Lungs and Fungal Immunity

Expression of the chemokine receptor CCR2 can be detrimental or beneficial for infection resolution. Herein, we examined whether CCR2 was requisite for control of infection by the dimorphic fungus Histoplasma capsulatum. H. capsulatum-infected CCR2(-/-) mice manifested defects in inflammatory cell recruitment, increased IL-4, and progressive infection. Increased IL-4 in CCR2(-/-) mice primarily contributed to decreased host resistance as demonstrated by the ability of IL-4-neutralized CCR2(-/-) mice to resolve infection without altering inflammatory cell recruitment. Surprisingly, numerous alveolar macrophages and dendritic cells contributed to IL-4 production in CCR2(-/-) mice. IL-4-mediated impairment of immunity in CCR2(-/-) mice was associated with increased arginase-1 and YM1 transcription and increased transferrin receptor expression by phagocytic cells. Immunity in mice lacking the CCR2 ligand CCL2 was not impaired despite decreased inflammatory cell recruitment. Neutralization of the CCR2 ligand CCL7 in CCL2(-/-) mice, but not wild type, resulted in increased IL-4 and fungal burden. Thus, CCL7 in combination with CCL2 limits IL-4 generation and exerts control of host resistance. Furthermore, increased phagocyte-derived IL-4 in CCR2(-/-) mice is associated with the presence of alternatively activated phagocytic cells.

Histoplasmose

Histoplasmosis is a fungal infection caused by the dimorphic fungus Histoplasma capsulatum. It is classically considered an endemic mycosis, even though the fungus has an opportunistic behavior in immunocompromised patients. People acquired the infection through the inhalation of conidial forms present in the environmental, such as caves dwelling bats and soils inhabited by chickens. The clinical features may vary from asymptomatic infections to disseminated severe forms that affect patients with acquired immunodeficiency syndrome or hematological malignancies and allograft recipients. The diagnosis is based on the detection of the fungus in organic fluids (sputum, blood, liquor) or tissues (histopathological assays), in the culture of biological samples and serological assays. The treatment of severe chronic respiratory acute or localized forms can be performed with oral azolic (itraconazol) and in the disseminated forms, the amphotericin B (preferentially the lipidic formulations) consists in the elected drug to initiate the therapy. Nowadays, histoplasmosis represents one of the most important systemic mycosis in the Americas, with broad distribution in all regions of Brazil.

Neutral Storage Lipids of Histoplasma capsulatum: Effect of Culture Age

Lipids contribute significantly to the pathogenesis of fungal infectious diseases and an understanding of lipid metabolism occurring in fungal pathogens can help the development of more efficient antifungal therapeutic strategies. In this study, the effect of culture age on the distribution of fatty acids among different neutral lipid (NL) classes in the dimorphic fungus Histoplasma capsulatum was investigated. Yeast cells of the G217B strain grown in two different media were collected after 4 and 7 days of growth, which roughly correspond to log and stationary culture growth phases, respectively. Neither culture age nor medium type had any influence on qualitative fatty acid (FA) profiles; however, the FA percentage composition varied with culture growth. A culture age-related decrease in the content of unsaturated FAs could be observed in all four of the NL classes examined, but the most intensive changes were detected in diacylglycerol and free FA fractions. Conversely, an increase in saturated FAs was observed. The transcriptional analysis of two major delta 9- and delta 12-FA desaturase genes, ode1 and sde1, showed no differences in their expression levels under experimental conditions. These results showing the dynamics of changes in FA composition in the NL fraction were concomitant with nutrient exhaustion in aging H. capsulatum cultures. Overall, the results presented in this work not only have implications for our knowledge of basic lipid biochemistry of H. capsulatum, but also will contribute to better understanding of biology and pathogenesis of this fungus and, consequently, can help in the discovery of more effective antifungal drugs.

Clinical and laboratory features of disseminated histoplasmosis in HIV patients from Brazil

To identify the main clinical and laboratory features of disseminated histoplasmosis (DH) in human immunodeficiency virus (HIV) patients and compare them with those of HIV patients with other opportunistic diseases. Retrospective study of HIV patients comparing the clinical and laboratory data of patients with and without DH. Univariate and multivariate analyses were performed to verify the risk factors related to DH. In total, 378 HIV patients were included, 164 with DH and 214 with other opportunistic diseases. Acute renal failure, respiratory insufficiency and septic shock were more frequent in DH patients, who also had a higher mortality (32%vs. 14%, P < 0.001). Independent risk factors for DH were: acute renal failure [odds ratio (OR) 5.2; 95% confidence interval (CI) 3.2-8.5; P < 0.001], splenomegaly (OR 3.4; 95% CI 1.19-9.9; P < 0.001), respiratory insufficiency (OR 2.7 95% CI 1.5-5.0; P < 0.001), proteinuria (OR 2.7; 95% CI 1.3-5.2; P = 0.03), hypotension (OR 2.5; 95% CI 1.2-5.0; P = 0.008), hepatomegaly (OR 2.4; 95% CI 1.2-4.8; P = 0.01), cutaneous lesions (OR, 1.9; 95% CI 1.0-3.3; P = 0.02) and weight loss (OR 1.8; 95% CI 1.0-3.1; P = 0.03). Our results suggest that DH is a severe opportunistic disease with high mortality rate, which should be promptly recognized in order to provide early specific treatment.

Imported Acute Histoplasmosis With Rheumatologic Manifestations in Spanish Travelers: Table 1

Histoplasmosis is an infection that occurs when conidia of the dimorphic fungus Histoplasma capsulatum var capsulatum are inhaled into the lungs. It is the most common systemic mycosis diagnosed among European travelers returning from endemic areas of Central and South America, 1–3 and in recent years, a growing number of cases, both isolated and in clusters, have been detected in nonendemic areas such as Europe. 4–7 This rise in apparent cases of histoplasmosis is thought to be a result of increased international travel, especially tourism, cooperation, and trade. However, heightened awareness of the clinical manifestations and epidemiology of histoplasmosis by health care practitioners in these countries may have also played a part in increasing diagnosis. Published data have undoubtedly underestimated the true magnitude of this travel‐related mycosis (as well as other geographically restricted endemic mycoses such as coccidiomycosis, paracoccidioidomycosis, and penicilliosis), and many cases, especially those asymptomatic or presenting as a mild nondescript febrile illness, often go undiagnosed. Most cases of imported histoplasmosis are known to occur in small clusters with a common source of infection. Usually, the individuals affected in these outbreaks have a history of participation in leisure and work activities, which involve heavy exposure to bat or bird droppings (mostly cavers and volunteers with recent involvement in cleaning tasks or rehabilitation of old buildings). 8–12 More than 95% of immunocompetent people remain asymptomatic following low‐inoculum infection with H capsulatum . 2 In the few symptomatic cases which occur, clinical presentation includes a self‐limited benign pulmonary illness with fever, malaise, dry cough, and chest pain. Disseminated severe disease is only observed in those individuals with a high degree of prior exposure to guano or impaired cellular immunity. 6,13,14 Here, we describe an outbreak of acute histoplasmosis with unusual clinical manifestations among four previously healthy Spanish travelers who had …

Penoscrotal histoplasmosis following bladder carcinoma

Histoplasmosis is caused by a dimorphic fungus Histoplasma capsulatum. Transmission is via inhalation and lungs are the most commonly affected site. Other sites are involved uncommonly and genitals are rarely involved. The case is reported herein of a man with penoscrotal histoplasmosis following bladder carcinoma that had been treated with intravesical bacille Calmette-Guerin. He presented with multiple ulcers on the penis and scrotum that coalesced, followed by the appearance of cutaneous lesions. The condition responded well to itraconazole. To the best of our knowledge, this is the first case of penoscrotal histoplasmosis following bladder carcinoma.

Role of the Synthase Domain of Ags1p in Cell Wall α-Glucan Biosynthesis in Fission Yeast

The cell wall is important for maintenance of the structural integrity and morphology of fungal cells. Besides beta-glucan and chitin, alpha-glucan is a major polysaccharide in the cell wall of many fungi. In the fission yeast Schizosaccharomyces pombe, cell wall alpha-glucan is an essential component, consisting mainly of (1,3)-alpha-glucan with approximately 10% (1,4)-linked alpha-glucose residues. The multidomain protein Ags1p is required for alpha-glucan biosynthesis and is conserved among cell wall alpha-glucan-containing fungi. One of its domains shares amino acid sequence motifs with (1,4)-alpha-glucan synthases such as bacterial glycogen synthases and plant starch synthases. Whether Ags1p is involved in the synthesis of the (1,4)-alpha-glucan constituent of cell wall alpha-glucan had remained unclear. Here, we show that overexpression of Ags1p in S. pombe cells results in accumulation of (1,4)-alpha-glucan. To determine whether the synthase domain of Ags1p is responsible for this activity, we overexpressed Ags1p-E1526A, which carries a mutation in a putative catalytic residue of the synthase domain, but observed no accumulation of (1,4)-alpha-glucan. Compared with wild-type Ags1p, this mutant Ags1p showed a markedly reduced ability to complement the cell lysis phenotype of the temperature-sensitive ags1-1 mutant. Therefore, we conclude that, in S. pombe, the production of (1,4)-alpha-glucan by the synthase domain of Ags1p is important for the biosynthesis of cell wall alpha-glucan.

Histoplasmosis: presentaciones clínicas y pruebas de laboratorio en un centro brasileño

Histoplasmosis, caused by the dimorphic fungus Histoplasma capsulatum, is endemic in many regions of the Americas, Asia and Africa. It has a wide spectrum of clinical manifestations, from asymptomatic infection to severe disseminated disease. A retrospective study was carried out to describe the clinical forms and assess the clinical significance of the laboratory diagnostic tests of patients with histoplasmosis during the period of July 1987 to December 2003 at Instituto de Pesquisa Clínica Evandro Chagas/ FIOCRUZ, RJ, Brazil. Seventy-four patients were included. Forty-nine percent of the cases (n = 36) occurred in HIV positive patients who presented with disseminated disease. The remaining 38 cases were classified in different clinical forms. Histoplasma capsulatum was isolated from 69.5% of the clinical specimens sent to culture. Immunodiffusion and immunoblot were positive in 72.6% and 100% of the performed tests, respectively. Histopathologic findings suggestive of H. capsulatum were found in 63.2% of the performed exams. Serology had a lower proportion of positivity amongst AIDS patients, when compared with HIV negative patients (X2 = 6.65; p lower than 0.008). Statistical differences between AIDS and non-AIDS patients were not observed with culture and histopathology. The specific role of each test varies according to the clinical form. Physicians need to know the value and limitations of the available diagnostic tests, but before that, they have to think about histoplasmosis and consider this clinical entity in their differential diagnosis.

CAMP Is Involved in Transcriptional Regulation of Δ9-Desaturase during Histoplasma capsulatum Morphogenesis

We have characterized the promoter region of the Δ9-desaturase gene from two different strains of the dimorphic fungus Histoplasma capsulatum. Desaturase transcription is regulated in the two phases of growth: it is transcribed in the yeast phase at 37°C, while it is inactive in the mycelial phase at 25°C. Phase transition can be induced by shifting the temperature from 25 to 37°C or by adding cAMP to the growth medium. We have identified a stress-responsive cis element (STRE) responsive to cyclic AMP (cAMP)-signaling pathway and demonstrated that this element acts in H. capsulatum. We have also identified an element, hereafter called DRE (Desaturase Regulatory Element), present in the promoters of the H. capsulatum and S. cerevisiae Δ9-desaturase gene. We show that this element is necessary but not sufficient to regulate transcription of the H. capsulatum Δ9-desaturase gene.

Transcript splicing is essential for functional Histoplasma capsulatum URA5 expression.

The isolation of auxotrophic markers is important for molecular genetic studies of the dimorphic fungus Histoplasma capsulatum. We have isolated a UV-induced mutant of H. capsulatum, resulting in nonreverting uracil auxotrophy due to a mutation in the URA5 gene. In this study, we show that this mutation is a GG to TA conversion bordering the 5' donor splice site of intron 2. The mutation results in the lack of splicing of intron 2 from the URA5 transcript, and subsequently premature termination of the peptide. This study is the first showing that consensus Group II intron sequences are both utilized and essential for functional expression of a gene in H. capsulatum.

Isolation and characterization of α‐tubulin genes from Septoria tritici and Rhynchosporium secalis, and comparative analysis of fungal α‐tubulin sequences

The α-tubulin genes from Septoria tritici and Rhynchosporium secalis have been cloned and sequenced. The predicted amino acid sequence and intron structure showed strong homology with other known filamentous fungal α-tubulins. Comparison of sixteen fungal α-tubulin sequences based on amino acid sequence homology and intron structure identified five groups of proteins. Group 1 consists of filamentous fungi, including S. tritici and R. secalis, the dimorphic fungus Histoplasma capsulatum, and Pneumocystis carinii. Group 2 includes two divergent isoforms from Neurospora crassa and Aspergillus nidulans. Group 3 includes the yeast Saccharomyces cerevisiae and the dimorphic fungus Candida albicans. Group 4 contains the single yeast Schizosaccharomyces pombe. Group 5 includes the only Basidiomycete, Schizophyllum commune. This analysis supports the classification of P. carinii as a primitive Ascomycete. The presence of an additional glycine residue between the second and third amino acid found only in Group 2 proteins may indicate a functionally distinct fungal isotype. Implications in terms of structure-function relationships for α-tubulin molecules are discussed. Cell Motil. Cytoskeleton 41:247–253, 1998. © 1998 Wiley-Liss, Inc.

Isolation and characterization of a calmodulin-encoding cDNA from the pathogenic fungus Histoplasma capsulatum.

We describe in this paper the isolation and complete sequence of a calmodulin (CaM) encoding cDNA from the dimorphic pathogenic fungus Histoplasma capsulatum (GenBank accession U12505). The deduced amino acid sequence was identical to the CaM of Aspergillus nidulans and had only one amino acid difference from the CaM of Neurospora crassa. Saccharomyces cerevisiae CaM, however, has only about 60% amino acid identity compared with H. capsulatum. These data further support the close relationship of Histoplasma to the filamentous ascomycetes. Histoplasma CaM was expressed as a single major transcript of approximately 1200 nt. in both the yeast and mould growth forms. CaM mRNA levels were approximately two-fold greater in the yeast than in the mould form of the organism. Southern blot analysis indicated that the H. capsulatum CaM gene is present in a single copy.

Histoplasmosis—Kentucky, 1995

Histoplasmosis is an infection resulting from inhalation of spores from the dimorphic fungus Histoplasma capsulatum; the condition primarily affects the lungs. During August 1995, the Department for Health Services, Kentucky Cabinet for Human Resources (KDHS), and local public health officials investigated two unrelated outbreaks of acute histoplasmosis in eastern Kentucky. This report summarizes preliminary findings of the investigations of these outbreaks.

Cloning and analysis of cDNA encoding an elongation factor 1 α from the dimorphic fungus histoplasma capsulatum

The cDNA encoding translation elongation factor 1 α (EF-lα) was isolated from the dimorphic fungus, Histoplasma capsulatum (Hc), an important pathogen of man. A cDNA library was probed with the tefl gene from the fungus Mucor racemosus. Ten independent clones were isolated, all with similar restriction patterns. The longest clone (1.96 kb) was sequenced. Southern blot analysis revealed that the Hc tefl gene was present as a single copy. A single transcript of approx. 2300 nucleotides was found in total RNA from both the yeast and mold forms of the organism. Comparison of the deduced 460-amino-acid Hc EF-1α protein to EF-1 α proteins from other species of fungi revealed the greatest degree of similarity to proteins from the filamentous ascomycetes Podospora anserina and Trichoderma reesei. Phylogenetic tree analysis of fungal tef genes indicated that Hc is most closely related to filamentous ascomycetes and most distantly related to the budding yeast Saccharomyces cerevisiae.

Histoplasmosis in a Miniature Sicilian Burro

Large animals appear less susceptible to clinical disease caused by the dimorphic fungus Histoplasma capsulatum than are dogs and cats. Review of the literature revealed only 16 documented cases of naturally occurring histoplasmosis in equids. A case of the pulmonic form in a 7-month-old Tennessee Walking Horse colt with intestinal parasitism was reported in 1948. 16 The organism was cultured from the spleen and fetal membranes of a “normal mare” in 1951, and abortion in clinically normal mares was also documented. Histopathologic identification of the organisms in sections of bone marrow from a Thoroughbred gelding with primary lesions of equine infectious anemia was reported in 1969. More recent reports include granulomatous colitis in a Quarterhorse gelding in 1973 and ulcerative colitis with proteinlosing enteropathy associated with intestinal salmonellosis and histoplasmosis in a Quarterhorse stallion. Diagnosis and treatment of the pulmonic form of the disease was described in 1990. Nine diagnosed cases between 1986 and 1990 were documented, 4 of which were abortions and 4 which involved the pulmonic form in neonates. A case of naturally occurring histoplasmosis has not been described in a burro. evaluation for equine infectious anemia was negative prior to transport in this animal. The referring veterinarian related a history of chronic weight loss. Two weeks prior to case submission, the burro was noted to have lost approximately one third of her body weight. Complete blood counts and serum chemical profiles were within normal limits. Fecal flotation was negative for parasite ova. The jenny was afebrile. Despite intravenous fluid therapy with lactated Ringer’s solution and 5% dextrose in conjunction with administration of oral electrolytes and chloramphenicol therapy, the jenny remained anorexic and listless. Euthanasia was elected, and gross necropsy was performed. Gross lesions were confined to the colon and mesentery. Mesenteric lymph nodes were enlarged. There was thickening of the colonic wall, which contained multiple firm, white nodules of various sizes beneath the serosa and along the mesenteric attachment.

Autonomous replication of foreign DNA in Histoplasma capsulatum: role of native telomeric sequences.

Genetic transformation of the dimorphic pathogenic fungus Histoplasma capsulatum can result in chromosomal integration of the transforming DNA or the generation of multicopy linear plasmids carrying the transforming DNA. We showed previously that Escherichia coli plasmids do not replicate autonomously in H. capsulatum without significant modifications, one of which is the in vivo addition of Histoplasma telomeres at the termini of linear DNA. To address the requirements for autonomous replication in H. capsulatum, we constructed a circular E. coli plasmid containing adjacent inverted stretches of Histoplasma telomeric repeats separated by a unique restriction site. The linearized plasmid bearing telomeric termini was maintained in H. capsulatum without modification other than the addition of more telomeric sequence. We recovered the original plasmid in E. coli after removal of the telomeric termini by using engineered restriction sites. Thus, no special Histoplasma modification or sequence other than the telomeres was needed for autonomous replication in H. capsulatum. Additionally, this plasmid provides a shuttle vector that replicates autonomously in E. coli (as a circular plasmid) and in H. capsulatum (as a linear plasmid).