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Veterinary Clinical Pathology Jun 2024A 9-month-old female intact toy poodle and a 1-year-old female intact Labrador retriever mix presented to separate teaching hospitals for chronic histories of malaise...
A 9-month-old female intact toy poodle and a 1-year-old female intact Labrador retriever mix presented to separate teaching hospitals for chronic histories of malaise and clinicopathologic evidence of hepatic dysfunction. The signalment and clinical histories of these dogs prompted consideration of a congenital portosystemic shunt as a primary differential. However, microscopic evaluation of peritoneal effusion, pleural effusion, and peripheral blood samples from the dogs revealed round to ovoid yeast organisms morphologically most compatible with Histoplasma capsulatum. Additional testing confirmed histoplasmosis in each case. The poodle underwent a computed tomography (CT) study, which showed hepatomegaly with a spleno-gonadal shunt, pancreatic and gastric wall edema, and marked peritoneal effusion, findings compatible with portal hypertension and secondary acquired shunt formation. The dog was later humanely euthanized due to clinical deterioration, and on necropsy hepatic histoplasmosis was verified, with additional affected tissues comprising lungs and spleen. The Labrador Retriever mix responded clinically and clinicopathologically to antifungal therapy, though no abdominal imaging was performed to definitively exclude the possibility of a congenital portosystemic shunt. In retrospect, several features were more compatible with histoplasmosis than portosystemic shunt in these cases, including hyperbilirubinemia, effusion, and hepatomegaly. These findings serve as a reminder of the need to interpret serum biochemical findings in the context of the totality of the clinicopathologic data and imaging findings, as well as the diagnostic value of microscopy in the evaluation of hematologic and body cavity fluid samples.
Topics: Animals; Dogs; Histoplasmosis; Dog Diseases; Female; Antifungal Agents; Histoplasma; Tomography, X-Ray Computed
PubMed: 38684471
DOI: 10.1111/vcp.13354 -
Emerging Microbes & Infections Dec 2024Histoplasmosis is an endemic mycosis in North America frequently reported along the Ohio and Mississippi River Valleys, although autochthonous cases occur in non-endemic...
Histoplasmosis is an endemic mycosis in North America frequently reported along the Ohio and Mississippi River Valleys, although autochthonous cases occur in non-endemic areas. In the United States, the disease is provoked by two genetically distinct clades of , (Nam1) and (Nam2). To bridge the molecular epidemiological gap, we genotyped 93 isolates (62 novel genomes) including clinical, environmental, and veterinarian samples from a broader geographical range by whole-genome sequencing, followed by evolutionary and species niche modelling analyses. We show that histoplasmosis is caused by two major lineages, and ; with sporadic cases caused by in California and Texas. While is prevalent in eastern states, was found to be prevalent in the central and western portions of the United States, but also geographically overlapping in some areas suggesting that these species might co-occur. Species Niche Modelling revealed that thrives in places with warmer and drier conditions, while is endemic to areas with cooler temperatures and more precipitation. In addition, we predicted multiple areas of secondary contact zones where the two species co-occur, potentially facilitating gene exchange and hybridization. This study provides the most comprehensive understanding of the genomic epidemiology of histoplasmosis in the USA and lays a blueprint for the study of invasive fungal diseases.
Topics: Histoplasmosis; Histoplasma; Genotype; Genomics; Texas
PubMed: 38465644
DOI: 10.1080/22221751.2024.2315960 -
American Journal of Ophthalmology Case... Dec 2023Presumed ocular histoplasmosis syndrome (POHS) is a posterior segment disorder that is usually subclinical unless choroidal neovascular membrane (CNVM) develops. It is...
PURPOSE
Presumed ocular histoplasmosis syndrome (POHS) is a posterior segment disorder that is usually subclinical unless choroidal neovascular membrane (CNVM) develops. It is thought to be the sequela of a prior systemic infection with , and evidence supporting this association is based on epidemiologic, animal, and few enucleation studies. Acute presentation of chorioretinal involvement during an initial histoplasmosis systemic infection in immunocompetent patients is rarely reported, presumably due to the usual lack of or minimal symptoms of both the systemic and ocular disease. We report on an immunocompetent male with choroidal lesions detected during disseminated histoplasmosis infection and characterize the lesions using multimodal imaging.
OBSERVATIONS
A 17-year-old male presented when routine optometry screening detected two deep, yellowish-white lesions in the left fundus. Optical coherence tomography (OCT) imaging confirmed a choroidal mass with extension through Bruch's membrane into the subretinal space and a small amount of subretinal fluid. Fluorescein angiography was suggestive of CNVM. There were no clinical findings of intraocular inflammation, and the patient was initially lost to follow-up. Eight weeks after last follow-up, the patient presented to the emergency department with fatigue, mild respiratory symptoms, and abdominal pain for the last month. Imaging revealed a mediastinal mass with hilar extension and innumerable nodules throughout the lung and spleen. Serum IgM/IgG were positive, and biopsy of the mediastinal mass revealed organisms. The patient was treated with antifungals and discharged. The patient underwent an extensive immunologic evaluation while admitted, which did not reveal an underlying immunodeficiency. On last follow-up, the choroidal lesions were smaller and more consolidated, and the subretinal fluid had resolved.
CONCLUSIONS AND IMPORTANCE
We present a patient with choroidal lesions in the setting of disseminated systemic histoplasmosis infection and characterize a lesion using multimodal imaging. The presentation of acute chorioretinal lesions in the setting of biopsy proven systemic infection supports as the etiology of POHS.
PubMed: 37546375
DOI: 10.1016/j.ajoc.2023.101896 -
Journal of Fungi (Basel, Switzerland) May 2024causes a fungal respiratory disease. Some studies suggest that the fungus requires zinc to consolidate the infection. This study aimed to investigate the influence of...
causes a fungal respiratory disease. Some studies suggest that the fungus requires zinc to consolidate the infection. This study aimed to investigate the influence of zinc and the metal chelator TPEN on the growth of in planktonic and biofilm forms. The results showed that zinc increased the metabolic activity, cell density, and cell viability of planktonic growth. Similarly, there was an increase in biofilm metabolic activity but no increase in biomass or extracellular matrix production. N'-N,N,N,N-tetrakis-2-pyridylmethylethane-1,2 diamine (TPEN) dramatically reduced the same parameters in the planktonic form and resulted in a decrease in metabolic activity, biomass, and extracellular matrix production for the biofilm form. Therefore, the unprecedented observations in this study highlight the importance of zinc ions for the growth, development, and proliferation of cells and provide new insights into the role of metal ions for biofilm formation in the dimorphic fungus , which could be a potential therapeutic strategy.
PubMed: 38786716
DOI: 10.3390/jof10050361 -
Journal of Infection in Developing... Feb 2024Pulmonary histoplasmosis is a fungal disease that is endemic in North and Central America. It is relatively rare in China and commonly misdiagnosed as tuberculosis or... (Review)
Review
INTRODUCTION
Pulmonary histoplasmosis is a fungal disease that is endemic in North and Central America. It is relatively rare in China and commonly misdiagnosed as tuberculosis or cancer due to nonspecific clinical and radiographic manifestations. Rapid and accurate pathogen tests are critical for the diagnosis of pulmonary histoplasmosis.
METHODOLOGY
We report two cases of pulmonary histoplasmosis. We collected all the relevant case reports on the Chinese mainland (from 1990 to 2022) to analyze features of this disease among Chinese patients.
RESULTS
A total of 42 articles reporting 101 cases were identified, and the two cases reported in this article were also included for analysis. Sixty-three (61.2%) patients had respiratory symptoms and 35 (34.0%) patients were asymptomatic. The most common radiographic findings were pulmonary nodules or masses (81.6%). Twenty-two (21.4%) patients were misdiagnosed as tuberculosis, and 37 (35.9%) were misdiagnosed as lung tumors before pathological findings. Metagenomic next‑generation sequencing (mNGS) testing provided a rapid diagnostic and therapeutic basis for three patients.
CONCLUSIONS
Clinical features and imaging findings of pulmonary histoplasmosis are not specific. Relevant epidemiological history and timely pathogen detection are important for diagnosis. mNGS can shorten the time required for diagnosis and allow earlier initiation of targeted antibiotic therapy.
Topics: Humans; Histoplasmosis; Histoplasma; Pneumonia; Tuberculosis; Lung Diseases, Fungal
PubMed: 38484351
DOI: 10.3855/jidc.17934 -
American Journal of Transplantation :... Jul 2023
Topics: Humans; Kidney Transplantation; Skin; Skin Diseases; Transplant Recipients; Diarrhea; Histoplasmosis
PubMed: 37394268
DOI: 10.1016/j.ajt.2023.03.006 -
Annals of Diagnostic Pathology Apr 2024Intraoperative consultation of donor liver is an important part of transplant evaluation and determination of liver eligibility. In this study, we describe incidental...
Intraoperative consultation of donor liver is an important part of transplant evaluation and determination of liver eligibility. In this study, we describe incidental pathologic findings discovered during the pretransplant evaluation of liver donors in our Institution from 1/2010 to 12/2022. During this 13-year period 369 intraoperative consultations from 262 liver donors were performed. Of those cases, incidental findings were identified in 22 cases (5.9 %) from 19 donors (7.3 %); two donors had more than one lesion. The median age of this subset of patients was 53 years (range: 18-70) and females predominated (63 %). Sixteen of the donors had abnormal findings in the liver: 6 bile duct hamartoma (BDH), 5 hyalinized nodule with Histoplasma capsulatum, 5 focal nodular hyperplasia (FNH), 2 bile duct adenomas (BDA), 1 biliary cyst and 1 hemangioma. One donor had both FNH and a BDH. One BDH and 1 BDA case was misdiagnosed as malignancy during the frozen section evaluation. Three donors had extrahepatic pathologies: a pancreatic tail schwannoma, a low-grade appendiceal mucinous neoplasm, and a lymph node with metastatic endometrial endometrioid adenocarcinoma. Of the 19 livers, the final organ disposition was available for 9: 6 were transplanted (67 %) and 3 were discarded (33 %). Two of the 3 discarded organs were misdiagnosed BDH and BDA cases, and one was incorrectly reported as having 90 % microvesicular steatosis during the frozen assessment. We present the clinicopathologic characteristics of liver donors with incidental findings during the pre-transplant evaluation which could lead to unwarranted graft dismissal if misdiagnosed. Additionally, incidental fungal infections can have implications for immunosuppressive therapy and the decision to use or reject the graft.
Topics: Female; Humans; Adolescent; Young Adult; Adult; Middle Aged; Aged; Liver Transplantation; Incidental Findings; Living Donors; Liver; Fatty Liver
PubMed: 38266545
DOI: 10.1016/j.anndiagpath.2024.152266 -
MSphere Aug 2023The rapid development of CRISPR/CRISPR-associated (Cas) systems has revolutionized the ability to produce genetic mutations in a desired locus, particularly in organisms...
The rapid development of CRISPR/CRISPR-associated (Cas) systems has revolutionized the ability to produce genetic mutations in a desired locus, particularly in organisms with low rates of homologous recombination. is an important respiratory and systemic fungal pathogen that has few reverse genetic options. We describe an optimized CRISPR/Cas system for the efficient generation of mutations in desired genes. The limited requirements for CRISPR/Cas, namely a gene-targeting guide RNA (gRNA) and expression of a Cas endonuclease, enabled both the gRNA and the Cas9 gene to be expressed from a single episomal vector. The gRNAs are expressed from a strong Pol(II) promoter, a critical parameter for increasing the recovery of mutated genes, and processed into the mature gRNA by ribozymes in the mRNA. Expression of dual-tandem gRNAs facilitates the generation of gene deletions at a good frequency which can be detected by PCR-based screening of pooled isolates resulting in the isolation of marker-less deletion mutants. The CRISPR/Cas system is encoded on an episomal telomeric vector facilitating curing strains of the CRISPR/Cas vector upon generation of the mutant. We demonstrate the successful application of this CRISPR/Cas system in diverse species and applicable for multiple genes. The optimized system shows promise for accelerating reverse genetic studies in spp. IMPORTANCE The ability to eliminate gene product functions is central to understanding molecular mechanisms. In the fungal pathogen , methods to inactivate or deplete gene products are inefficient, which hampers progress in defining 's virulence mechanisms. We describe an efficient CRISPR/Cas-based system for generating gene deletions in and show its validation on multiple genes with selectable and non-selectable phenotypes.
Topics: CRISPR-Cas Systems; Gene Editing; Histoplasma; Gene Deletion; Plasmids
PubMed: 37389430
DOI: 10.1128/msphere.00178-23 -
Journal of Fungi (Basel, Switzerland) Jan 2024Histoplasmosis is a widespread systemic disease caused by , prevalent in the Americas. Despite its significant morbidity and mortality rates, no vaccines are currently...
Histoplasmosis is a widespread systemic disease caused by , prevalent in the Americas. Despite its significant morbidity and mortality rates, no vaccines are currently available. Previously, five vaccine targets and specific epitopes for were identified. Immunoinformatics has emerged as a novel approach for determining the main immunogenic components of antigens through in silico methods. Therefore, we predicted the main helper and cytotoxic T lymphocytes and B-cell epitopes for these targets to create a potential multi-epitope vaccine known as HistoVAC-TSFM. A total of 38 epitopes were found: 23 common to CTL and B-cell responses, 11 linked to HTL and B cells, and 4 previously validated epitopes associated with the B subunit of cholera toxin, a potent adjuvant. In silico evaluations confirmed the stability, non-toxicity, non-allergenicity, and non-homology of these vaccines with the host. Notably, the vaccine exhibited the potential to trigger both innate and adaptive immune responses, likely involving the TLR4 pathway, as supported by 3D modeling and molecular docking. The designed HistoVAC-TSFM appears promising against , with the ability to induce important cytokines, such as IFN-γ, TNF-α, IL17, and IL6. Future studies could be carried out to test the vaccine's efficacy in in vivo models.
PubMed: 38248954
DOI: 10.3390/jof10010043 -
BioRxiv : the Preprint Server For... Nov 2023is a dimorphic fungal pathogen acquired via inhalation of soil-resident spores. Upon exposure to mammalian body temperatures, these fungal elements transform into...
UNLABELLED
is a dimorphic fungal pathogen acquired via inhalation of soil-resident spores. Upon exposure to mammalian body temperatures, these fungal elements transform into yeasts that reside primarily within phagocytes. Macrophages (MΦ) provide a permissive environment for fungal replication until T cell-dependent immunity is engaged. MΦ activated by granulocyte-MΦ colony stimulating factor (GM-CSF) induce metallothioneins (MTs) that bind zinc (Zn) and deprive yeast cells of labile Zn, thereby disabling fungal growth. Prior work demonstrated that the high affinity zinc importer, ZRT2, was important for fungal survival in vivo. Hence, we constructed a yeast cell reporter strain that expresses green fluorescent protein (GFP) under the control of this importer. This reporter accurately responds to medium devoid of Zn. ZRT2 expression increased (∼5-fold) in GM-CSF, but not interferon-γ, stimulated MΦ. To examine the in vivo response, we infected mice with reporter yeasts and assessed ZRT2 expression at 0-, 3-, 7-, and 14-days post-infection (dpi). ZRT2 expression minimally increased at 3-dpi and peaked on 7-dpi, corresponding with onset of adaptive immunity. We discovered that the major phagocyte populations that restrict Zn to the fungus are interstitial MΦ and exudate MΦ. Neutralizing GM-CSF blunted control of infection but unexpectedly increased ZRT2 expression. This increase was dependent on another cytokine that activates MΦ to control replication, M-CSF. These findings illustrate the reporter's ability to sense Zn and and correlate ZRT2 activity with GM-CSF and M-CSF activation of MΦ.
IMPORTANCE
Phagocytes use an arsenal of defenses to control replication of yeasts, one of which is limitation of trace metals. On the other hand, combats metal restriction by upregulating metal importers such as the Zn importer ZRT2. This transporter contributes to pathogenesis upon activation of adaptive immunity. We constructed a fluorescent ZRT2 reporter to probe Zn sensing during infection and exposed a role for M-CSF activation of macrophages when GM-CSF is absent. These data highlight the ways in which fungal pathogens sense metal deprivation in vivo and reveal the potential of metal-sensing reporters. The work adds a new dimension to studying how intracellular pathogens sense and respond to the changing environments of the host.
PubMed: 38014056
DOI: 10.1101/2023.11.14.567133