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Stephanie M Lawry, Brad Tebbets, Iain Kean, Douglas Stewart, Joel Hetelle, Bruce S Klein
Novel anti-fungal drugs and targets are urgently needed. Group III hybrid histidine kinases (HHKs) represent an appealing new therapeutic drug target because they are widely expressed in fungi but absent in humans. We investigated the mode of action of the widely utilized, effective fungicide fludioxonil. The drug acts in an HHK-dependent manner by constitutive activation of the HOG (high osmolarity glycerol) pathway, but its mechanism of action is poorly understood. Herein, we report a new mode of drug action that entails conversion of the HHK from a kinase into a phosphatase...
November 21, 2016: Antimicrobial Agents and Chemotherapy
Andrej Spec, Christopher R Barrios, Usama Ahmad, Laurie A Proia
Severe pulmonary or disseminated histoplasmosis often necessitates presumptive antifungal treatment while awaiting definitive diagnosis. Histoplasma antigen assays have improved sensitivity but results may lag up to 7 days. In order to increase diagnostic certainty, "soft clues" may be looked for in laboratory and radiologic data, such as elevated alkaline phosphatase or ferritin levels and findings of mediastinal adenopathy or hepatosplenomegaly. To determine if elevated aspartate aminotransferase (AST) to alanine aminotransferase (ALT) ratio is specific to histoplasmosis or a non-specific marker for disseminated fungal infection or sepsis in general, we retrospectively examined records of all patients diagnosed with an endemic fungal infection (EFI) at Rush University Medical Center from January of 1997 to October of 2012, and a cohort of septic patients with elevated liver enzymes...
October 14, 2016: Medical Mycology: Official Publication of the International Society for Human and Animal Mycology
Jennifer L Anderson, Jennifer K Meece, Matthew C Hall, Holly M Frost
Relapse or recurrence of blastomycosis in patients is rare. Re-infection of a patient with blastomycosis has not been previously reported. In this report, we describe relapse or reinfection with Blastomyces in 2 immunocompetent patients. This is the first study in which genetic typing was performed on paired Blastomyces isolates from the same patient obtained months apart.
September 2016: Medical Mycology Case Reports
Michael F Rosser, Dana M Lindemann, Anne M Barger, Matthew C Allender, Shih-Hsuan Hsiao, Mark E Howes
A 5-yr-old, intact male red ruffed lemur ( Varecia rubra ) presented for evaluation as the result of a 1-wk history of lethargy and hyporexia. Physical examination findings included thin body condition, muffled heart sounds, harsh lung sounds, and liquid brown diarrhea. Complete blood count and serum biochemistry showed an inflammatory leukogram, mild hyponatremia, and mild hypochloremia. Orthogonal trunk radiographs revealed a severe alveolar pattern in the right cranial lung lobes with cardiac silhouette effacement...
September 2016: Journal of Zoo and Wildlife Medicine: Official Publication of the American Association of Zoo Veterinarians
Holly M Frost, Jennifer L Anderson, Lynn Ivacic, Brian L Sloss, John Embil, Jennifer K Meece
BACKGROUND: Single nucleotide polymorphism (SNP) genotyping is increasingly being utilized for molecular typing of pathogens and is cost-effective, especially for large numbers of isolates. The goals of this study were 1) to develop and validate a SNP assay panel for genetic analysis of Blastomyces spp., 2) ascertain whether microsatellite genotyping and the SNP genotyping with the developed panel resolve identical genetic groups, and 3) explore the utility of SNPs for examining phylogenetic and virulence questions in humans...
2016: BMC Infectious Diseases
Kristie D Goughenour, Chad A Rappleye
Dimorphic fungi cause several endemic mycoses which range from subclinical respiratory infections to life-threatening systemic disease. Pathogenic-phase cells of Histoplasma, Blastomyces, Paracoccidioides and Coccidioides escape elimination by the innate immune response with control ultimately requiring activation of cell-mediated immunity. Clinical management of disease relies primarily on antifungal compounds; however, dimorphic fungal pathogens create a number of challenges for antifungal drug therapy. In addition to the drug toxicity issues known for current antifungals, barriers to efficient drug treatment of dimorphic fungal infections include natural resistance to the echinocandins, residence of fungal cells within immune cells, the requirement for systemic delivery of drugs, prolonged treatment times, potential for latent infections, and lack of optimized standardized methodology for in vitro testing of drug susceptibilities...
September 19, 2016: Virulence
Kristy Koselny, Julianne Green, Louis DiDone, Justin P Halterman, Annette W Fothergill, Nathan P Wiederhold, Thomas F Patterson, Melanie T Cushion, Chad Rappelye, Melanie Wellington, Damian J Krysan
Only one new class of antifungal drugs has been introduced into clinical practice in the last 30 years, and thus the identification of small molecules with novel mechanisms of action is an important goal of current anti-infective research. Here, we describe the characterization of the spectrum of in vitro activity and in vivo activity of AR-12, a celecoxib derivative which has been tested in a phase I clinical trial as an anticancer agent. AR-12 inhibits fungal acetyl coenzyme A (acetyl-CoA) synthetase in vitro and is fungicidal at concentrations similar to those achieved in human plasma...
December 2016: Antimicrobial Agents and Chemotherapy
Thomas M Jetmore, Jennifer Phan, Abideen O Yekinni
Blastomyces dermatitidis is a thermally dimorphic fungus endemic to the North American soil near the Mississippi, Ohio, and St. Lawrence river valleys, as well as the Great Lakes Basin. It is responsible for blastomycosis, a systemic pyogranulomatous disease. Blastomycosis of the head and neck is decidedly uncommon and often mistaken for cancer. There are only 3 previous case reports of blastomycosis presenting as an intranasal lesion. We report the unusual case of a 24-year-old man with blastomycosis presenting with a 4-week history of a progressively enlarging intranasal mass who had complete resolution of symptoms after treatment with itraconazole and surgical excision of the lesion...
August 2016: Ear, Nose, & Throat Journal
P C Wang, B T Mo, Y Chen, Q F Zeng, L B Wang
Karst mountainous ecosystems are associated with karst rocky desertification (KRD), which can greatly impact soil structure and function. Despite the importance of soil microbes as a major factor maintaining ecosystem stability, we know little about the effect on soil fungal communities of KRD in karst regions. We investigated this relationship across a gradient of KRD soils from Guizhou, China by polymerase chain reaction and denaturing gradient gel electrophoresis (PCR-DGGE). Fungal diversity indices (Shannon-Wiener, richness, and evenness) significantly differed (P < 0...
2016: Genetics and Molecular Research: GMR
John Berger, Felix Zamora, Eitan Podgaetz, Rafael Andrade, H Erhan Dincer
BACKGROUND AND OBJECTIVES: Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is the procedure of choice for the evaluation of mediastinal/hilar lymph node enlargements. Granulomatous inflammation of the mediastinal/hilar lymph nodes is often identified on routine histology. In addition, mediastinal lymphadenopathy may be present with undiagnosed infection. We sought to determine the usefulness of routine cultures and histology for infectious etiologies in a fungal endemic area when granulomatous inflammation is identified...
July 2016: Endoscopic Ultrasound
Lisa R McTaggart, Elizabeth M Brown, Susan E Richardson
Blastomyces dermatitidis and Blastomyces gilchristii are dimorphic fungal pathogens that cause serious pulmonary and systemic infections in humans. Although their natural habitat is in the environment, little is known about their specific ecologic niche(s). Here, we analyzed 25 microsatellite loci from 169 strains collected from various regions throughout their known endemic range in North America, representing the largest and most geographically diverse collection of isolates studied to date. Genetic analysis of multilocus microsatellite data divided the strains into four populations of B...
2016: PloS One
Nicole M Nemeth, G Douglas Campbell, Paul T Oesterle, Lenny Shirose, Beverly McEwen, Claire M Jardine
Blastomyces dermatitidis, a fungus that can cause fatal infection in humans and other mammals, is not readily recoverable from soil, its environmental reservoir. Because of the red fox's widespread distribution, susceptibility to B. dermatitidis, close association with soil, and well-defined home ranges, this animal has potential utility as a sentinel for this fungus.
July 2016: Emerging Infectious Diseases
Alison F A Chaves, Marina V Navarro, Daniele G Castilho, Juliana C P Calado, Palloma M Conceição, Wagner L Batista
Paracoccidioides brasiliensis and P. lutzii, thermally dimorphic fungi, are the causative agents of paracoccidioidomycosis (PCM). Paracoccidioides infection occurs when conidia or mycelium fragments are inhaled by the host, which causes the Paracoccidioides cells to transition to the yeast form. The development of disease requires conidia inside the host alveoli to differentiate into yeast cells in a temperature-dependent manner. We describe the presence of a two-component signal transduction system in P. brasiliensis, which we investigated by expression analysis of a hypothetical protein gene (PADG_07579) that showed high similarity with the dimorphism-regulating histidine kinase (DRK1) gene of Blastomyces dermatitidis and Histoplasma capsulatum This gene was sensitive to environmental redox changes, which was demonstrated by a dose-dependent decrease in transcript levels after peroxide stimulation and a subtler decrease in transcript levels after NO stimulation...
August 2016: FEMS Yeast Research
George R Thompson, Adrian Rendon, Rodrigo Ribeiro Dos Santos, Flavio Queiroz-Telles, Luis Ostrosky-Zeichner, Nkechi Azie, Rochelle Maher, Misun Lee, Laura Kovanda, Marc Engelhardt, Jose A Vazquez, Oliver A Cornely, John R Perfect
BACKGROUND: Invasive fungal diseases (IFD) caused by Cryptococcus and dimorphic fungi are associated with significant morbidity and mortality. Isavuconazole (ISAV) is a novel, broad-spectrum, triazole antifungal agent (IV and by mouth [PO]) developed for the treatment of IFD. It displays potent activity in vitro against these pathogens and in this report we examine outcomes of patients with cryptococcosis or dimorphic fungal infections treated with ISAV. METHODS: The VITAL study was an open-label nonrandomized phase 3 trial conducted to evaluate the efficacy and safety of ISAV treatment in management of rare IFD...
August 1, 2016: Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America
Theo N Kirkland
The small number of fungi that commonly cause disease in normal people share the capacity to grow as mycelia in the soil at 25°C and as yeast (or spherules) in mammals at 37°C. This remarkable conversion has long been a topic of interest in medical mycology. The conidia to yeast conversion has been studied by transcription profiling in several fungal species, including Histoplasma capsulatum, Paracoccidioides brasiliensis, Coccidioides spp., Blastomyces dermatitidis, and Talaromyces marneffei One limitation of transcriptional profiling is determining which genes are involved in the process of conversion to yeast as opposed to a result of conversion to yeast...
August 1, 2016: Medical Mycology: Official Publication of the International Society for Human and Animal Mycology
S He, A Cuguilliere
We report a case of pulmonary blastomycosis in a young man recently returned from a journey in Canada. He had acute pneumonia resistant to various antibiotics. Blastomycosis is an endemic mycosis in Canada and the United States, most frequently affecting the lungs, although extrapulmonary dissemination occurs in approximately one third of cases. Diagnosis is made by identification of Blastomyces dermatidis at direct examination or in culture. The lack of precise knowledge concerning the natural habitat of this microorganism is an obstacle to effective prevention...
January 2016: Médecine et Santé Tropicales
Pamela Talley, Stacy Holzbauer, Kirk Smith, William Pomputius
On April 20, 2015, a female aged 15 years sought care at her pediatrician's office after 5 days of fever, myalgia, left parietal headache, and photophobia. A rapid influenza assay was negative, and erythrocyte sedimentation rate and total white blood cell count were normal. She improved with symptomatic care at home, but returned to her pediatrician's office on April 28, reporting recurrence of her headache and photophobia and new onset of a stiff neck. She was admitted to the hospital, where she was febrile to 102...
March 11, 2016: MMWR. Morbidity and Mortality Weekly Report
Huafeng Wang, Vanessa LeBert, Mengyi Li, Tassanee Lerksuthirat, Kevin Galles, Bruce Klein, Marcel Wüthrich
We investigated how innate sensing by the mannose receptor (MR) influences the development of antifungal immunity. We demonstrate that MR senses mannan on the surface of attenuated Blastomyces dermatitidis vaccine yeast and that MR(-/-) mice demonstrate impaired vaccine immunity against lethal experimental blastomycosis, compared with wild-type control mice. Using naive Blastomyces-specific transgenic CD4(+) T cells, we found that MR regulates differentiation of naive T cells into T-helper type 17 (Th17) effector cells, which are essential in vaccine immunity against systemic dimorphic fungi...
June 1, 2016: Journal of Infectious Diseases
Alana K Sterkel, Jenna L Lorenzini, J Scott Fites, Kavitha Subramanian Vignesh, Thomas D Sullivan, Marcel Wuthrich, Tristan Brandhorst, Nydiaris Hernandez-Santos, George S Deepe, Bruce S Klein
Systemic fungal infections trigger marked immune-regulatory disturbances, but the mechanisms are poorly understood. We report that the pathogenic yeast of Blastomyces dermatitidis elaborates dipeptidyl-peptidase IVA (DppIVA), a close mimic of the mammalian ectopeptidase CD26, which modulates critical aspects of hematopoiesis. We show that, like the mammalian enzyme, fungal DppIVA cleaved C-C chemokines and GM-CSF. Yeast producing DppIVA crippled the recruitment and differentiation of monocytes and prevented phagocyte activation and ROS production...
March 9, 2016: Cell Host & Microbe
Daniel Dalcin, Aaron Rothstein, Joanna Spinato, Nicholas Escott, Julianne V Kus
Since the 2013 description of Blastomyces gilchristii, research describing the virulence or clinical outcome of B. gilchristii infection has been lacking. We report molecular evidence of B. gilchristii as an etiologic agent of fatal acute respiratory distress syndrome. B. gilchristii infection was confirmed by PCR and sequence analysis.
February 2016: Emerging Infectious Diseases
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