scholarly journals Dissemination of Cryptococcus neoformans via localised proliferation and blockage of blood vessels

2017 ◽  
Author(s):  
Josie F Gibson ◽  
Robert J Evans ◽  
Aleksandra Bojarczuk ◽  
Richard Hotham ◽  
Anne K Lagendijk ◽  
...  
Keyword(s):  
Blood Vessel ◽  
Cryptococcus Neoformans ◽  
Blood Vessels ◽  
Cryptococcal Meningitis ◽  
Fungal Pathogen ◽  
Vascular Damage ◽  
Cryptococcal Infection ◽  
Vessel Damage ◽  
Junction Protein ◽  
Life Threatening

AbstractCryptococcus neoformans is an opportunistic fungal pathogen that can cause life-threatening cryptoccocal meningitis, predominantly within immunocompromised individuals. Cortical infarcts are observed in as many as 30% of cryptococcal meningitis cases, being particularly common in severe infection. Limited clinical case studies suggest infarcts are secondary to vasculitis and blood vessel damage caused by cryptococcal infection. However, the cause of infarcts in cryptococcal infection has not been determined. To examine potential causes of vascular damage and cryptococcal dissemination in cryptococcal infection, the zebrafish C. neoformans infection model was used. We demonstrate that spread of cryptococci from the vasculature occurs at sites where cryptococci grow within the blood vessels, originating from a single or small number of cryptococci. We find that cryptococcal cells become trapped within the vasculature and can proliferate there resulting in vasodilation. Localised cryptococcal growth in the vasculature is also associated with sites of dissemination – in some cases simultaneously with a loss of blood vessel integrity. Using a cell-cell junction protein reporter (VE-cadherin) we identified sites dissemination associated with both intact blood vessels and where vessel rupture occurred. Thus, we have identified a mechanism for blood vessel damage during cryptococcal infection that may represent a cause of the vascular damage and cortical infarction observed in cryptococcal meningitis.Author summaryHuman infection by the fungal pathogen, Cryptococcus neoformans, can lead to life-threatening cryptococcal meningitis. In severe cases of cryptococcal meningitis, a lack of blood supply can cause tissue death and a resulting area of dead tissue (infarct) in the brain. Although vasculature inflammation in known to occur in cryptococcal meningitis, the cause of infarcts in unknown. Using a zebrafish model of cryptococcal infection, the growth and dissemination of fungal cells was observed over time. We show that cryptococcal cells become trapped and proliferate in the vasculature, resulting in cryptococcoma that damage the blood vessels. We propose that vessel damage results from increased blood pressure caused by cryptococci blocking blood vessels suggesting that the vascular damage that ensues on cryptococcoma formation may in turn be a cause of infarct formation seen in cryptococcal meningitis.

scholarly journals Central Nervous System Vasculitis for Cryptococcosis in an Immunocompetent Patient

Diseases ◽  
2018 ◽  
Vol 6 (3) ◽  
pp. 75 ◽  
Author(s):  
Dan Zimelewicz Oberman ◽  
Liliana Patrucco ◽  
Carolina Cuello Oderiz
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Cryptococcus Neoformans ◽  
Cryptococcal Meningitis ◽  
Fungal Pathogen ◽  
Immunocompetent Patient ◽  
Central Nervous System Vasculitis ◽  
Diagnostic Challenge ◽  
Threatening Condition ◽  
Life Threatening

Cryptococcal meningitis is a life-threatening condition caused by a fungal pathogen, Cryptococcus neoformans, that can infect both immunosuppressed and immunocompetent hosts. It is an important cause of morbidity and mortality in severely immunodeficient patients. However, in an immunocompetent patient it represents a diagnostic challenge, mainly because it is extremely rare, but also because of its nonspecific clinical manifestation. Neurovascular involvement in cryptococcal meningitis is rare and not well known and only few reports have described this association. We describe a cryptococcal meningitis in an immunocompetent patient associated with central nervous system vasculitis.

Vasculitis

2018 ◽  
Author(s):  
Raashid Luqmani
Keyword(s):  
Connective Tissue ◽  
Blood Vessel ◽  
Blood Vessels ◽  
Vessel Wall ◽  
Connective Tissue Diseases ◽  
Blood Vessel Wall ◽  
Target Organs ◽  
Laboratory Features ◽  
Life Threatening ◽  
Pulmonary Capillaritis

The vasculitides are a heterogeneous group of disorders that can range from mild inflammation of blood vessels in the skin, to organ- and life-threatening diseases. The term ‘vasculitis’ is a pathological description of blood vessel wall inflammation which leads to ischaemia and infarction of the target organs. Definitions and classifications of the primary vasculitides are mainly based on the predominant calibre of the blood vessels involved but incorporate clinical, pathological, and laboratory features. The secondary vasculitides usually occur in the context of other connective tissue diseases and are not discussed further in this section. Goodpasture’s disease is not usually included in the primary vasculitides, but has compatible clinical features of pulmonary capillaritis and glomerulonephritis.

scholarly journals Transcription factor Liv4 is required for growth and pathogenesis of Cryptococcus neoformans

2020 ◽  
Vol 20 (3) ◽  
Author(s):  
Jiu Yi ◽  
Junjun Sang ◽  
Jingyu Zhao ◽  
Lei Gao ◽  
Yali Yang ◽  
...  
Keyword(s):  
Cell Wall ◽  
Cryptococcus Neoformans ◽  
Fungal Pathogen ◽  
Regulatory Mechanisms ◽  
Regulatory Function ◽  
Growth Defect ◽  
Detailed Characterization ◽  
Phenotypic Changes ◽  
Life Threatening

ABSTRACT Cryptococcus neoformans is an important invasive fungal pathogen that causes life-threatening meningoencephalitis in humans. Its biological and pathogenic regulatory mechanisms remain largely unknown, particularly due to the presence of those core transcription factors (TFs). Here, we conducted a detailed characterization of the TF Liv4 in the biology and virulence of C. neoformans. Deletion of TF Liv4 protein resulted in growth defect under both normal and stress conditions (such as high temperature and cell wall/membrane damaging agents), drastic morphological damage and also attenuated virulence in C. neoformans. These phenotypic changes might be contributed to transcriptional abnormality in the liv4Δ mutant, in which several cryptococcal genes involved in energy metabolism and cell wall integrity were downregulated. Furthermore, ChIP-seq and ChIP-qPCR assays suggested TF Liv4 might exert its regulatory function in transcription by its activation of RBP1 in C. neoformans. Taken together, our work highlights the importance of TF Liv4 in the growth and virulence of C. neoformans, and it facilitates a better understanding of cryptococcal pathogenesis mechanisms.

scholarly journals Immunoglobulin G3 blocking antibodies to the fungal pathogen Cryptococcus neoformans.

1996 ◽  
Vol 183 (4) ◽  
pp. 1905-1909 ◽  
Author(s):  
G Nussbaum ◽  
R Yuan ◽  
A Casadevall ◽  
M D Scharff
Keyword(s):  
Cryptococcus Neoformans ◽  
Host Defense ◽  
Fungal Pathogen ◽  
Capsular Polysaccharide ◽  
Protective Efficacy ◽  
Antibody Therapy ◽  
Antibody Isotype ◽  
Cryptococcal Infection ◽  
Epitope Specificity ◽  
Blocking Antibodies

Vaccination and infection can elicit protective and nonprotective antibodies to the fungus Cryptococcus neoformans in mice. The effect of nonprotective antibodies on host defense is unknown. In this study we used mixtures of protective and nonprotective monoclonal antibodies (mAbs) to determine if nonprotective mAbs blocked the activity of the protective mAbs. Antibody isotype and epitope specificity are important in determining the ability to prolong survival in mice given a lethal C. neoformans infection. Three different nonprotective immunoglobulin (Ig) G23 mAbs to cryptococcal capsular polysaccharide were used to study the interaction between the IgG3 isotype and protective IgG1 and IgG2a mAbs in murine cryptococcal infection. One IgG3 mAb reduced the protective efficacy of an IgG1 with identical epitope specificity. A second IgG3 mAb with different epitope specificity also reduced the protection provided by the IgG1 mAb. The protective efficacy of an IgG2a mAb was also dramatically decreased by still another IgG3 mAb. To our knowledge this is the first report of blocking antibodies to a fungal pathogen. The results have important implications for the development of vaccines and passive antibody therapy against C. neoformans.

scholarly journals Blood vessel occlusion by Cryptococcus neoformans is a mechanism for haemorrhagic dissemination of infection

2020 ◽  
Author(s):  
Josie F Gibson ◽  
Aleksandra Bojarczuk ◽  
Robert J Evans ◽  
Alfred Kamuyango ◽  
Richard Hotham ◽  
...  
Keyword(s):  
Blood Vessel ◽  
Cryptococcus Neoformans ◽  
Severe Infection ◽  
Cell Junctions ◽  
Cell Junction ◽  
Vascular Events ◽  
Zebrafish Model ◽  
Vessel Occlusion ◽  
Vessel Damage

AbstractMeningitis caused by infectious pathogens are associated with vessel damage and infarct formation, however the physiological cause is unknown. Cryptococcus neoformans, is a human fungal pathogen and causative agent of cryptococcal meningitis, where vascular events are observed in up to 30% of cases, predominantly in severe infection. Therefore, we aimed to investigate how infection may lead to vessel damage and associated pathogen dissemination using a zebrafish model for in vivo live imaging. We find that cryptococcal cells become trapped within the vasculature (dependent on there size) and proliferate there resulting in vasodilation. Localised cryptococcal growth, originating from a single or small number of cryptococcal cells in the vasculature was associated with sites of dissemination and simultaneously with loss of blood vessel integrity. Using a cell-cell junction tension reporter we identified dissemination from intact blood vessels and where vessel rupture occurred. Finally, we manipulated blood vessel stifness via cell junctions and found increased stiffness resulted in increased dissemination. Therefore, global vascular vasodilation occurs following infection, resulting in increased vessel tension which subsequently increases dissemination events, representing a positive feedback loop. Thus, we identify a mechanism for blood vessel damage during cryptococcal infection that may represent a cause of vascular damage and cortical infarction more generally in infective meningitis.

scholarly journals The Pathogenic Fungus Cryptococcus neoformans Expresses Two Functional GDP-Mannose Transporters with Distinct Expression Patterns and Roles in Capsule Synthesis

2007 ◽  
Vol 6 (5) ◽  
pp. 776-785 ◽  
Author(s):  
Tricia R. Cottrell ◽  
Cara L. Griffith ◽  
Hong Liu ◽  
Ashley A. Nenninger ◽  
Tamara L. Doering
Keyword(s):  
Cryptococcus Neoformans ◽  
Fungal Pathogen ◽  
Pathogenic Fungus ◽  
Expression Patterns ◽  
Growth Conditions ◽  
Phosphomannose Isomerase ◽  
Microarray Experiments ◽  
Life Threatening ◽  
Nucleotide Sugars ◽  
Intracellular Organelles

ABSTRACT Cryptococcus neoformans is a fungal pathogen that is responsible for life-threatening disease, particularly in the context of compromised immunity. This organism makes extensive use of mannose in constructing its cell wall, glycoproteins, and glycolipids. Mannose also comprises up to two-thirds of the main cryptococcal virulence factor, a polysaccharide capsule that surrounds the cell. The glycosyltransfer reactions that generate cellular carbohydrate structures usually require activated donors such as nucleotide sugars. GDP-mannose, the mannose donor, is produced in the cytosol by the sequential actions of phosphomannose isomerase, phosphomannomutase, and GDP-mannose pyrophosphorylase. However, most mannose-containing glycoconjugates are synthesized within intracellular organelles. This topological separation necessitates a specific transport mechanism to move this key precursor across biological membranes to the appropriate site for biosynthetic reactions. We have discovered two GDP-mannose transporters in C. neoformans, in contrast to the single such protein reported previously for other fungi. Biochemical studies of each protein expressed in Saccharomyces cerevisiae show that both are functional, with similar kinetics and substrate specificities. Microarray experiments indicate that the two proteins Gmt1 and Gmt2 are transcribed with distinct patterns of expression in response to variations in growth conditions. Additionally, deletion of the GMT1 gene yields cells with small capsules and a defect in capsule induction, while deletion of GMT2 does not alter the capsule. We suggest that C. neoformans produces two GDP-mannose transporters to satisfy its enormous need for mannose utilization in glycan synthesis. Furthermore, we propose that the two proteins have distinct biological roles. This is supported by the different expression patterns of GMT1 and GMT2 in response to environmental stimuli and the dissimilar phenotypes that result when each gene is deleted.

scholarly journals The interplay of phenotype and genotype in Cryptococcus neoformans disease

2020 ◽  
Vol 40 (10) ◽  
Author(s):  
Sophie Altamirano ◽  
Katrina M. Jackson ◽  
Kirsten Nielsen
Keyword(s):  
Patient Outcome ◽  
Cryptococcus Neoformans ◽  
Fungal Pathogen ◽  
Proper Treatment ◽  
Rapid Adaptation ◽  
Complete Understanding ◽  
Phenotypic Changes ◽  
Life Threatening ◽  
Opportunistic Fungal Pathogen

Abstract Cryptococcus neoformans is an opportunistic fungal pathogen that causes life-threatening meningitis primarily in immunocompromised individuals. In order to survive and proliferate during infection, C. neoformans must adapt to a variety of stresses it encounters within the host. Patient outcome depends on the interaction between the pathogen and the host. Understanding the mechanisms that C. neoformans uses to facilitate adaptation to the host and promote pathogenesis is necessary to better predict disease severity and establish proper treatment. Several virulence phenotypes have been characterized in C. neoformans, but the field still lacks a complete understanding of how genotype and phenotype contribute to clinical outcome. Furthermore, while it is known that C. neoformans genotype impacts patient outcome, the mechanisms remain unknown. This lack of understanding may be due to the genetic heterogeneity of C. neoformans and the extensive phenotypic variation observed between and within isolates during infection. In this review, we summarize the current understanding of how the various genotypes and phenotypes observed in C. neoformans correlate with human disease progression in the context of patient outcome and recurrence. We also postulate the mechanisms underlying the genetic and phenotypic changes that occur in vivo to promote rapid adaptation in the host.

scholarly journals A fatal case of meningitis caused by Cryptococcus neoformans var. grubii in an immunocompetent male

2010 ◽  
Vol 5 (01) ◽  
pp. 071-074 ◽  
Author(s):  
Prashant Gupta ◽  
Shruti Malik ◽  
Vineeta Khare ◽  
Gopa Banerjee ◽  
Anurag Mehrotra ◽  
...  
Keyword(s):  
Developing Countries ◽  
Cryptococcus Neoformans ◽  
Cryptococcal Meningitis ◽  
Fatal Case ◽  
Immunocompromised Patients ◽  
Course Of Illness ◽  
Cryptococcal Infection ◽  
Immunocompetent Patients

The incidence of cryptococcal infection is high in developing countries such as India. Cryptococcal meningitis is considered rare in immunocompetent patients and is mainly a disease of immunocompromised patients. Prognosis in immunocompetent patients is generally considered good. We report a fatal case of cryptococcal meningitis in an immunocompetent male caused by Cryptococcus neoformans var. grubii. Whether the patient is immunocompromised or immunocompetent, the outcome of the disease can be severe unless the disease is diagnosed early in the course of illness.

Bilateral Placoid Choroiditis in an HIV-Positive Patient With Cryptococcus neoformans Meningitis and Disseminated Cryptococcal Disease

2020 ◽  
Vol 4 (6) ◽  
pp. 530-533
Author(s):  
Ryan D. Larochelle ◽  
Marissa B. Larochelle ◽  
Yee Yee Aung ◽  
Thinzar Linn ◽  
David Heiden ◽  
...  
Keyword(s):  
Cryptococcus Neoformans ◽  
Opportunistic Infections ◽  
Posterior Pole ◽  
Hiv Positive ◽  
Cryptococcal Infection ◽  
Multifocal Choroiditis ◽  
Cryptococcal Disease ◽  
Unusual Variant ◽  
Life Threatening ◽  
Ophthalmologic Examination

Purpose: We report a presumptive case of bilateral placoid choroiditis secondary to disseminated Cryptococcus neoformans infection and review the literature on choroidal involvement of C neoformans. Methods: A case report is presented. Results: A 35-year-old HIV-positive man presented with disseminated cryptococcal infection. Cryptococcal meningitis was confirmed by lumbar puncture, and skin involvement was confirmed by microscopy of scrapings from a papular, umbilicated, ulcerated lesion. Ophthalmologic examination revealed intact visual acuity, clear vitreous, and multiple yellowish, placoid-appearing choroidal lesions in the posterior pole bilaterally. Conclusions: Multifocal choroiditis caused by C neoformans is an uncommon manifestation of disseminated infection, and placoid yellowish choroidal lesions are an unusual variant. These findings must be differentiated from choroidal tuberculosis and other infections. Multifocal choroiditis typically occurs in AIDS patients and may precede the presentation of meningitis. In such patients, choroidal lesions warrant investigation for systemic, life-threatening opportunistic infections.

scholarly journals Cryptococcal Infection with Ruxolitinib in Primary Myelofibrosis: A Case Report and Literature Review

2021 ◽  
Author(s):  
Zachary Ciochetto ◽  
Njeri Wainaina ◽  
Anna Corey ◽  
Mary Beth Graham ◽  
Muhammad Bilal Abid
Keyword(s):  
Case Report ◽  
Literature Review ◽  
Cryptococcus Neoformans ◽  
Primary Myelofibrosis ◽  
Intracellular Pathogens ◽  
Cryptococcal Infection ◽  
Immunosuppressed Patients ◽  
Life Threatening ◽  
Disseminated Disease ◽  
Immunocompromised Hosts

Cryptococcus neoformans (CN) is an encapsulated yeast that causes disseminated and potentially life-threatening in immunocompromised hosts. We present a patient with primary myelofibrosis on ruxolitinib who developed disseminated disease due to CN. The report underscores the importance of suspecting infections with intracellular pathogens in immunosuppressed patients on ruxolitinib.

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