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Gregory C Kujoth, Thomas D Sullivan, Richard Merkhofer, Taek-Jin Lee, Huafeng Wang, Tristan Brandhorst, Marcel Wüthrich, Bruce S Klein
Blastomyces dermatitidis is a human fungal pathogen of the lung that can lead to disseminated disease in healthy and immunocompromised individuals. Genetic analysis of this fungus is hampered by the relative inefficiency of traditional recombination-based gene-targeting approaches. Here, we demonstrate the feasibility of applying CRISPR/Cas9-mediated gene editing to Blastomyces , including to simultaneously target multiple genes. We created targeting plasmid vectors expressing Cas9 and either one or two single guide RNAs and introduced these plasmids into Blastomyces via Agrobacterium gene transfer...
April 3, 2018: MBio
Gopal P Dahal, Ronald E Viola
Pathogenic fungi represent a growing threat to human health, with an increase in the frequency of drug-resistant fungal infections. Identifying targets from among the selected metabolic pathways that are unique to microbial species presents an opportunity to develop new antifungal agents against new and untested targets to combat this growth threat. Aspartate semialdehyde dehydrogenase (ASADH) catalyzes a key step in a uniquely microbial amino acid biosynthetic pathway and is essential for microbial viability...
March 1, 2018: SLAS Discovery
Jennie M Jankovsky, Robert L Donnell
A 20-y-old female llama ( Lama glama) was euthanized after a history of chronic dyspnea and osteoarthritis. At autopsy, the lungs were covered by clear gelatinous material and expanded by firm, variably discrete, tan-white nodules up to 8 cm diameter containing tan-white, viscous material. The tracheobronchial lymph nodes were firm and enlarged up to 6 × 4 × 3 cm; the thoracic aorta and carotid arteries were lined by hard, tan-white, mineralized intimal plaques. Histologic examination of lung revealed numerous 10-20 μm diameter yeasts with clear 1-2 μm thick double-contoured walls, central basophilic nuclei, and frequent broad-based budding, consistent with Blastomyces dermatitidis...
January 1, 2018: Journal of Veterinary Diagnostic Investigation
Nydiaris Hernández-Santos, Darin L Wiesner, J Scott Fites, Andrew J McDermott, Thomas Warner, Marcel Wüthrich, Bruce S Klein
Lung epithelial cells (LECs) are strategically positioned in the airway mucosa to provide barrier defense. LECs also express pattern recognition receptors and a myriad of immune genes, but their role in immunity is often concealed by the activities of "professional" immune cells, particularly in the context of fungal infection. Here, we demonstrate that NF-κB signaling in LECs is essential for immunity against the pulmonary fungal pathogen Blastomyces dermatitidis. LECs orchestrate innate antifungal immunity by augmenting the numbers of interleukin-17A (IL-17A)- and granulocyte-macrophage colony-stimulating factor (GM-CSF)-producing innate lymphocytes, specifically "natural" Th17 (nTh17) cells...
March 20, 2018: Cell Host & Microbe
Shifteh Vahidi, Amy Beckman, Kellen Albrecht, Sophie Arbefeville, Patricia Ferrieri, Khalid Amin
Urinary tract blastomycosis is an uncommon manifestation of disseminated Blastomyces infection. Here, we report a 50-year-old male with common variable immunodeficiency who presented with urinary symptoms and a renal mass concerning for a kidney neoplasm. Urine cytology revealed typical broad-based budding yeasts with thick-walled refractile capsules, leading to diagnosis of urinary tract blastomycosis. In this case, urine cultures were negative, and urine cytology was the main method of diagnosis of blastomycosis...
March 23, 2018: Diagnostic Cytopathology
Aaron R Kuzel, Muhammad Uzair Lodhi, Intekhab Askari Syed, Tehmina Zafar, Umar Rahim, Mehenaz Hanbazazh, Nadia Naumova, Mustafa Rahim
Blastomycosis is a dimorphic fungus caused by the species of Blastomyces dermatitidisand Blastomyces gilchristii, which are endemic to the Ohio River and Mississippi River Valleys. It is commonly found in soil or decomposing wood. It is capable of infecting both immunocompromised and immunocompetent patients via the respiratory tract by inhaling conidia, where it may remain asymptomatic for a prolonged period of time. Extrapulmonary complications can occur in disseminated disease due to haematogenous spread from the lungs to other organ systems...
January 21, 2018: Curēus
Matthew T Koroscil, Andrew Skabelund
Introduction: Blastomyces dermatitidis is a dimorphic fungus endemic to the Mississippi River valley. We describe a rare case of chronic pulmonary blastomycosis complicated by large pulmonary cavitation in a young service member who was misdiagnosed with active pulmonary tuberculosis. Case Presentation: A 25-year-old active duty male presented to his primary care provider with complaints of hemoptysis, fatigue, weight loss, and fever. Computed tomography chest with contrast identified a large cavitary lesion in the right upper lobe (RUL)...
March 14, 2018: Military Medicine
Joseph A McBride, Gregory M Gauthier, Bruce S Klein
This review article focuses on the mechanisms underlying temperature adaptation and virulence of the etiologic agents of blastomycosis, Blastomyces dermatitidis, Blastomyces gilchristii, and Blastomyces percursus. In response to temperature, Blastomyces undergoes a reversible morphologic switch between hyphae and yeast known as the phase transition. The conversion to yeast for Blastomyces and related thermally dimorphic fungi is essential for virulence. In the yeast phase, Blastomyces upregulates the essential virulence factor, BAD1, which promotes attachment to host cells, impairs activation of immune cells, and blunts cytokine release...
March 13, 2018: Virulence
Jessica Mak, Ayman Al Habeeb, Mona Al Kalabi, Afsaneh Alavi
Blastomyces dermatitidis is typically contracted through inhalation of the dimorphic conidia, resulting in pulmonary infection as well as extrapulmonary disease through hematogenous spread. Blastomycosis is considered one of the great mimickers in medicine, with verrucous cutaneous blastomycosis resembling skin malignancy and B dermatitidis pulmonary infections often confused with lung cancer. Cutaneous blastomycosis can also often mimic pyoderma gangrenosum and should be considered in the differential diagnosis in any suspected case...
February 1, 2018: Journal of Cutaneous Medicine and Surgery
Nam K Ku, Sheeja T Pullarkat, Young S Kim, Liang Cheng, Dennis O'Malley
In pathologic specimen, Histoplasma capsulatum can frequently be identified by morphology and special stains such as GMS and PAS. Incidentally, we noted unusual staining of the platelet associated marker CD42b/GP1b expressed on the surface of fungal organisms. Evaluation of additional cases demonstrated that a majority of histoplasmosis cases (15/18 cases; 83%) showed positive staining with CD42b/GP1b, comparable to GMS stain results. Other platelet associated markers such as Factor VIII and CD61 showed no or rare expression (1/18 cases with Factor VIII)...
February 2018: Annals of Diagnostic Pathology
Andrew Walkty, Yoav Keynan, James Karlowsky, Perry Dhaliwal, John Embil
Blastomyces dermatitidis is a thermally dimorphic fungus that is capable of causing pulmonary and extra-pulmonary disease, including infections of the central nervous system (CNS). Diagnosis of CNS blastomycosis with non-invasive testing can be difficult, and a surgical biopsy may ultimately be required for microbiological and/or histopathological confirmation. A case of B. dermatitidis meningitis is presented where the diagnosis was made by testing cerebrospinal fluid (CSF) using the MVista® Blastomyces Quantitative Antigen Enzyme Immunoassay test...
February 2018: Diagnostic Microbiology and Infectious Disease
Nathan P Wiederhold, Hoja P Patterson, Bich Hue Tran, Christopher M Yates, Robert J Schotzinger, Edward P Garvey
Background: Invasive fungal infections, including those caused by yeasts, moulds and endemic organisms, can be significant causes of morbidity and mortality in immunocompromised hosts, those with multiple comorbidities and occasionally immunocompetent hosts. Current antifungal agents are often limited by drug toxicities, drug interactions or the development of resistance. VT-1598 is a novel tetrazole that has greater specificity for fungal Cyp51 than currently available triazoles and thus the potential for clinically significant drug interactions is reduced...
February 1, 2018: Journal of Antimicrobial Chemotherapy
Pratibha Singhi, Arushi Gahlot Saini
Central nervous system fungal infections can be broadly divided into those that infect a healthy host such as Cryptococcus, Coccidioides, Histoplasma, Blastomyces, Sporothrix spp., and those that cause opportunistic infections in an immunocompromised host such as Candida, Aspergillus, Zygomycetes, Trichosporon spp. The clinical manifestations of central nervous system fungal infections commonly seen in children in clinical practice include a chronic meningitis or meningoencephalitis syndrome, brain abscess, rhino-cerebral syndrome and rarely, a fungal ventriculitis...
November 11, 2017: Indian Journal of Pediatrics
Zhenying Zhang, Binbin Hou, Yong Zhuo Wu, Ying Wang, Xiaoming Liu, Shixin Han
Sporothrix schenckii is a pathogenic dimorphic fungus with a global distribution. It grows in a multicellular hyphal form at 25˚C and a unicellular yeast form at 37˚C. The morphological switch from mold to yeast form is obligatory for establishing pathogenicity in S. schenckii. Two‑component signaling systems are utilized by eukaryotes to sense and respond to external environmental changes. DRK1is a hybrid histidine kinase, which functions as a global regulator of dimorphism and virulence in Blastomyces dermatitidis and Histoplasma capsulatum...
January 2018: Molecular Medicine Reports
M Ben Salem, M Hamouda, M Mohamed, S Aloui, A Letaief, A Moussa, H Skhiri, A Zakahama, N Ben Dhia
Fungal infections have an important role in organ transplant recipients, and in some cases can be lethal. Blastomycosis is rare in kidney transplantation. We present a case of cutaneous blastomycosis in a kidney transplant recipient in Tunisia, a country outside the known endemic countries. This case, with the very uncommon and unexpected diagnosis of blastomycosis, demonstrates the diversity of infections in transplant recipients and reflects the importance of histologic and serologic tests in the immunocompromised patient...
September 2017: Transplantation Proceedings
Jennifer L Hsu, B Joel Tjarks, Aaron Berg, Tony Oliver
Blastomycosis is an endemic fungal infection commonly found within the Mississippi and Ohio River basins and Great Lakes region. While patients typically present with acute pneumonia, Blastomyces dermatitidis has the potential to spread hematogenously, resulting in disseminated infection of multiple organs. In this report, we describe a 57-year-old male with disseminated blastomycosis acquired in South Dakota. The diagnostic evaluation was confounded by concern for malignancy given the involvement of multiple locations, including brain, lungs, adrenal glands, and testes...
April 2017: South Dakota Medicine: the Journal of the South Dakota State Medical Association
Aiham H Jbeli, John Yu
Malignant glioblastoma multiform (GBM) is the most common primary malignancy of the brain in the U.S. Temozolomide (TMZ) is the cornerstone of management along with surgical resection and radiotherapy. Because of the reduction in the CD4+ lymphocyte count as a side effect of TMZ use, this patient population is under risk for opportunistic infections like Pneumocystis jiroveci. A male patient with newly diagnosed glioblastoma multiform presented with non-productive cough and chest pain. Before presentation, the patient received the standard therapy including surgical resection, radiation and TMZ...
October 2016: South Dakota Medicine: the Journal of the South Dakota State Medical Association
Richard J Wang, Robert F Miller, Laurence Huang
Many fungi cause pulmonary disease in patients with human immunodeficiency virus (HIV) infection. Pathogens include Pneumocystis jirovecii, Cryptococcus neoformans, Aspergillus spp, Histoplasma capsulatum, Coccidioides spp, Blastomyces dermatitidis, Paracoccidioides brasiliensis, Talaromyces marneffei, and Emmonsia spp. Because symptoms are frequently nonspecific, a high index of suspicion for fungal infection is required for diagnosis. Clinical manifestations of fungal infection in HIV-infected patients frequently depend on the degree of immunosuppression and the CD4+ helper T cell count...
September 2017: Clinics in Chest Medicine
Joseph A McBride, Gregory M Gauthier, Bruce S Klein
The causal agents of blastomycosis, Blastomyces dermatitidis and Blastomyces gilchristii, belong to a group of thermally dimorphic fungi that can infect healthy and immunocompromised individuals. Following inhalation of mycelial fragments and spores into the lungs, Blastomyces spp convert into pathogenic yeast and evade host immune defenses to cause pneumonia and disseminated disease. The clinical spectrum of pulmonary blastomycosis is diverse. The diagnosis of blastomycosis requires a high degree of clinical suspicion and involves culture-based and non-culture-based fungal diagnostic tests...
September 2017: Clinics in Chest Medicine
Huafeng Wang, Taek-Jin Lee, Scott J Fites, Richard Merkhofer, Robert Zarnowski, Tristan Brandhorst, Kevin Galles, Bruce Klein, Marcel Wüthrich
The development of vaccines against fungi and other intracellular microbes is impeded in part by a lack of suitable adjuvants. While most current vaccines against infectious diseases preferentially induce production of antibodies, cellular immunity is essential for the resolution of fungal infections. Microbes such as fungi and Mycobacterium tuberculosis require Th17 and Th1 cells for resistance, and engage the C-type lectin receptors including Dectin-2. Herein, we discovered a novel Dectin-2 ligand, the glycoprotein Blastomyces Eng2 (Bl-Eng2)...
August 2017: PLoS Pathogens
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