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Microbes and Infection Jul 2008Histoplasma capsulatum is the most common cause of invasive fungal pulmonary disease worldwide. The interaction of H. capsulatum with a host is a complex, dynamic... (Review)
Review
Histoplasma capsulatum is the most common cause of invasive fungal pulmonary disease worldwide. The interaction of H. capsulatum with a host is a complex, dynamic process. Severe disease most commonly occurs in individuals with compromised immunity, and the increasing utilization of immunomodulators in medicine has revealed significant risks for reactivation disease in patients with latent histoplasmosis. Fortunately, there are well developed molecular tools and excellent animal models for studying H. capsulatum virulence and numerous recent advances have been made regarding the pathogenesis of this fungus that will improve our capacity to combat disease.
Topics: Antibodies, Monoclonal; Databases, Genetic; Fungal Vaccines; Histoplasma; Histoplasmosis; Host-Pathogen Interactions; Humans
PubMed: 18672088
DOI: 10.1016/j.micinf.2008.07.011 -
American Journal of Hematology Nov 2002
Topics: Blood; Histoplasma; Histoplasmosis; Humans; Male; Middle Aged
PubMed: 12410581
DOI: 10.1002/ajh.10197 -
MBio Dec 2021Lipids play a fundamental role in fungal cell biology, being essential cell membrane components and major targets of antifungal drugs. A deeper knowledge of lipid...
Lipids play a fundamental role in fungal cell biology, being essential cell membrane components and major targets of antifungal drugs. A deeper knowledge of lipid metabolism is key for developing new drugs and a better understanding of fungal pathogenesis. Here, we built a comprehensive map of the Histoplasma capsulatum lipid metabolic pathway by incorporating proteomic and lipidomic analyses. We performed genetic complementation and overexpression of H. capsulatum genes in Saccharomyces cerevisiae to validate reactions identified in the map and to determine enzymes responsible for catalyzing orphan reactions. The map led to the identification of both the fatty acid desaturation and the sphingolipid biosynthesis pathways as targets for drug development. We found that the sphingolipid biosynthesis inhibitor myriocin, the fatty acid desaturase inhibitor thiocarlide, and the fatty acid analog 10-thiastearic acid inhibit H. capsulatum growth in nanomolar to low-micromolar concentrations. These compounds also reduced the intracellular infection in an alveolar macrophage cell line. Overall, this lipid metabolic map revealed pathways that can be targeted for drug development. It is estimated that 150 people die per hour due to the insufficient therapeutic treatments to combat fungal infections. A major hurdle to developing antifungal therapies is the scarce knowledge on the fungal metabolic pathways and mechanisms of virulence. In this context, fungal lipid metabolism is an excellent candidate for developing drugs due to its essential roles in cellular scaffolds, energy storage, and signaling transductors. Here, we provide a detailed map of Histoplasma capsulatum lipid metabolism. The map revealed points of this fungus lipid metabolism that can be targeted for developing antifungal drugs.
Topics: Fatty Acids; Fungal Proteins; Histoplasma; Histoplasmosis; Humans; Lipid Metabolism; Lipidomics; Proteomics; Sphingolipids
PubMed: 34809453
DOI: 10.1128/mBio.02972-21 -
Frontiers in Cellular and Infection... 2020is a thermodimorphic fungus that causes histoplasmosis, a mycosis of global incidence. The disease is prevalent in temperate and tropical regions such as North America,...
is a thermodimorphic fungus that causes histoplasmosis, a mycosis of global incidence. The disease is prevalent in temperate and tropical regions such as North America, South America, Europe, and Asia. It is known that during infection macrophages restrict Zn availability to as a microbicidal mechanism. In this way the present work aimed to study the response of to zinc deprivation. analyses showed that has eight genes related to zinc homeostasis ranging from transcription factors to CDF and ZIP family transporters. The transcriptional levels of , , and were induced under zinc-limiting conditions. The decrease in Zn availability increases fungicidal macrophage activity. Proteomics analysis during zinc deprivation at 24 and 48 h showed 265 proteins differentially expressed at 24 h and 68 at 48 h. Proteins related to energy production pathways, oxidative stress, and cell wall remodeling were regulated. The data also suggested that low metal availability increases the chitin and glycan content in fungal cell wall that results in smoother cell surface. Metal restriction also induces oxidative stress triggered, at least in part, by reduction in pyridoxin synthesis.
Topics: Asia; Europe; Histoplasma; North America; Zinc
PubMed: 33330123
DOI: 10.3389/fcimb.2020.573097 -
Proceedings of the National Academy of... Aug 2000The success of Histoplasma capsulatum as an intracellular pathogen depends completely on successful conversion of the saprophytic mycelial (mold) form of this fungus to... (Review)
Review
The success of Histoplasma capsulatum as an intracellular pathogen depends completely on successful conversion of the saprophytic mycelial (mold) form of this fungus to a parasitic yeast form. It is therefore not surprising that yeast phase-specific genes and gene products are proving to be important for survival and proliferation of H. capsulatum within macrophages. In this study, we have focused on the role and regulation of two yeast-specific characteristics: alpha-(1,3)-glucan, a cell wall polysaccharide modulated by cell-density (quorum) sensing, and a secreted calcium-binding protein (CBP) that is essential for pathogenicity.
Topics: Calcium-Binding Proteins; Cell Wall; Gene Expression Regulation; Glucans; Histoplasma; Phenotype; Virulence
PubMed: 10922037
DOI: 10.1073/pnas.97.16.8794 -
MBio Apr 2022Intracellular pathogens residing within macrophage phagosomes are challenged with recognizing the phagosomal environment and appropriately responding to changing host...
Intracellular pathogens residing within macrophage phagosomes are challenged with recognizing the phagosomal environment and appropriately responding to changing host defense strategies imposed in this organelle. One such phagocyte defense is the restriction of available copper as a form of nutritional immunity during the adaptive immune response to fungal pathogens. The intracellular fungal pathogen Histoplasma capsulatum adapts to this decreased copper through upregulation of the Ctr3 copper transporter. In this study, we show that recognizes the characteristic low-copper phagosomal environment of activated macrophages through the copper-dependent transcriptional regulator Mac1. Multiple -acting regulatory sequences in the promoter control upregulation of transcription under low-copper conditions, and the loss of Mac1 function prevents induction of Ctr3 under low-copper conditions. During adaptive immunity, this loss of copper sensing by Mac1 attenuates virulence more severely than loss of Ctr3 alone, indicating that Mac1 controls the expression of additional mechanisms important for pathogenesis. Transcriptional profiling of yeasts identified a small regulon of Mac1-dependent genes, with the most strongly regulated genes encoding proteins linked to copper, iron, and zinc homeostasis and defenses against reactive oxygen (iron-requiring catalase [CatB] and superoxide dismutase [Sod4]). Accordingly, the loss of Mac1 function increased sensitivity to copper and iron restriction and blocked low-copper-induced expression of extracellular catalase activity. Thus, Mac1-mediated sensing of low-copper signals to yeasts their residence within the activated macrophage phagosome, and in response, yeasts produce factors, including non-copper-dependent factors, to combat the enhanced defenses of activated macrophages. Histoplasma capsulatum is a fungal pathogen that survives and grows within host macrophages. For successful infection, must sense and adapt to a dynamic intracellular environment over the course of an infection. We demonstrate that the copper-dependent transcription factor, Mac1, enables sensing of low copper that characterizes the phagosome environment of activated macrophages. Histoplasma recognition of this state leads not only to upregulation of copper acquisition mechanisms but also to other non-copper-related pathogenesis strategies, including scavenging of other metals and detoxification of reactive oxygen produced by host cells. The limited set of genes regulated by Mac1 compared to those of other fungal pathogens suggests a response that has been tailored specifically for 's life inside the phagosome. Thus, low levels of phagosomal copper serve as a signal to , enabling responses to the enhanced antimicrobial defenses resulting from immune activation of macrophages.
Topics: Adaptive Immunity; Catalase; Copper; Histoplasma; Iron; Oxygen; Phagosomes
PubMed: 35404120
DOI: 10.1128/mbio.03773-21 -
The Lancet. Microbe May 2021The classic geographical range of histoplasmosis in North America primarily includes the states and provinces adjacent to the Ohio, Mississippi, and St Lawrence...
BACKGROUND
The classic geographical range of histoplasmosis in North America primarily includes the states and provinces adjacent to the Ohio, Mississippi, and St Lawrence riverways. Although Alberta, Canada is not typically considered a region of risk for histoplasmosis, cases with suspected local acquisition have been reported. We aimed to investigate the epidemiology and geographical distribution of cases of histoplasmosis in Alberta to assess evidence for local acquisition of infections, using genomic analysis for corroboration.
METHODS
We did an epidemiological and genomic investigation, in which laboratory-confirmed cases of histoplasmosis were reviewed in Alberta from 2011, when the disease became reportable, until 2018. We used data attained from Alberta Health. Travel and exposure histories and clinical features were reviewed. Definite local acquisition was defined as a case without previous travel outside Alberta or associated with a common-source outbreak within the province, whereas probable local acquisition was a sporadic case with travel outside Alberta but compelling local exposures. Genomes of selected case isolates were analysed, including those from cases suspected to have been locally acquired and imported.
FINDINGS
Between Jan 1, 2011, and June 30, 2018, 45 cases of histoplasmosis were identified. Participants had a median age of 53 years (range 17-77) and 32 [71%] were male. Among 34 patients with documented travel histories, ten (29%) had never left the province. 11 cases were of definite local acquisition, including eight cases from three common-source outbreaks and three sporadic cases in patients who had never travelled outside Alberta. The common-source outbreaks all involved exposure to bats or their droppings in chimneys or attics of private dwellings or churches. Four patients had travelled outside Alberta but compelling evidence was seen for local exposure to bat guano. Genome sequencing showed that isolates from cases of definite and probable local acquisition clustered together and were genetically distinct from isolates from suspected imported cases and other published isolates.
INTERPRETATION
Using epidemiological and genomic analyses, we established that cases of histoplasmosis have been acquired in Alberta, thus expanding the geographical range of Histoplasma spp much further northwest than was previously appreciated. Histoplasmosis should be considered in patients with compatible symptoms outside areas of classic geographical risk.
FUNDING
None.
Topics: Adolescent; Adult; Aged; Alberta; Animals; Chiroptera; Female; Genomics; Histoplasma; Histoplasmosis; Humans; Male; Middle Aged; Travel; Young Adult
PubMed: 35544208
DOI: 10.1016/S2666-5247(20)30229-9 -
FEMS Microbiology Letters Nov 2011Histoplasma capsulatum is the leading cause of endemic mycosis in the world. Analyses of clinical isolates from different endemic regions show important diversity within... (Review)
Review
Histoplasma capsulatum is the leading cause of endemic mycosis in the world. Analyses of clinical isolates from different endemic regions show important diversity within the species. Recent molecular studies of two isolates, the Chemotype I NAm2 strain G217B and the Chemotype II Panamanian strain G186A, reveal significant genetic, structural, and molecular differences between these representative Histoplasma strains. Some of these variations have functional consequences, representing distinct molecular mechanisms that facilitate Histoplasma pathogenesis. The realization of Histoplasma strain diversity highlights the importance of characterizing Histoplasma virulence factors in the context of specific clinical strain isolates.
Topics: Endemic Diseases; Genetic Variation; Histoplasma; Histoplasmosis; Humans; Virulence Factors
PubMed: 22092757
DOI: 10.1111/j.1574-6968.2011.02363.x -
Microbiological Reviews Jun 1989Several fungi can assume either a filamentous or a unicellular morphology in response to changes in environmental conditions. This process, known as dimorphism, is a... (Review)
Review
Several fungi can assume either a filamentous or a unicellular morphology in response to changes in environmental conditions. This process, known as dimorphism, is a characteristic of several pathogenic fungi, e.g., Histoplasma capsulatum, Blastomyces dermatitidis, and Paracoccidioides brasiliensis, and appears to be directly related to adaptation from a saprobic to a parasitic existence. H. capsulatum is the most extensively studied of the dimorphic fungi, with a parasitic phase consisting of yeast cells and a saprobic mycelial phase. In culture, the transition of H. capsulatum from one phase to the other can be triggered reversibly by shifting the temperature of incubation between 25 degrees C (mycelia) and 37 degrees C (yeast phase). Mycelia are found in soil and never in infected tissue, in contrast to the yeast phase, which is the only form present in patients. The temperature-induced phase transition and the events in establishment of the disease state are very likely to be intimately related. Furthermore, the temperature-induced phase transition implies that each growth phase is an adaptation to two critically different environments. A fundamental question concerning dimorphism is the nature of the signal(s) that responds to temperature shifts. So far, both the responding cell component(s) and the mechanism(s) remain unclear. This review describes the work done in the last several years at the biochemical and molecular levels on the mechanisms involved in the mycelium to yeast phase transition and speculates on possible models of regulation of morphogenesis in dimorphic pathogenic fungi.
Topics: Cell Wall; Histoplasma; Histoplasmosis; Humans; Virulence
PubMed: 2666842
DOI: 10.1128/mr.53.2.186-209.1989 -
Journal of Clinical Microbiology Jul 2022