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Pathogens
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Pathogenesis of Cryptococcus neoformans
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Pathogenesis of Cryptococcus neoformans

A special issue of Pathogens (ISSN 2076-0817).

Deadline for manuscript submissions: closed (31 August 2020) | Viewed by 23323

Special Issue Editors

Dr. Erin McClelland

E-Mail Website
Guest Editor
College of Osteopathic Medicine, Marian University, Indianapolis, IN 46222, USA
Interests: cryptococcus neoformans; medical mycology; host-pathogen interactions; gender-specific differences to infection
Special Issues, Collections and Topics in MDPI journals
Dr. Helene Eisenman Barbour

E-Mail Website
Guest Editor
The Department of Natural Sciences, Baruch College, City University of New York, New York, NY 10010, USA
Interests: Cryptococcus neoformans; melanin; invertebrate model hosts; mycology

Special Issue Information

Dear Colleagues,

Cryptococcus neoformans causes cryptococcosis, primarily in immune compromised hosts. There are ~220,000 new infections and 180,000 deaths annually, a mortality rate of 82%, most in developing countries. In recent years, our understanding of how C. neoformans (and the related organisms, C. gattii and C. grubii) causes disease has increased significantly. Yet, more remains to be discovered.  For this special issue, we would like to summarize the advances to date in our understanding of the pathogenesis of C. neoformans infections, so therefore invite original research articles, case reports, short communications and review papers on all aspects of cryptococcal pathogenesis. Potential topics include (but are not limited to): cellular and molecular mechanisms of pathogenesis, molecular genetics and characterization of cryptococcal isolates, virulence factor mechanisms and discovery, host-pathogen interactions and host defense, Cryptococcus lifecycle and transmission, antifungal therapies and treatments and alternative disease models.

We look forward to reading your contribution.

Dr. Erin McClelland
Dr. Helene Eisenman Barbour
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Pathogens is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Cryptococcus neoformans
  • pathogenesis
  • virulence factors
  • host-pathogen interactions

Published Papers (7 papers)

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Research

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18 pages, 8243 KiB  
Article
A Predicted Mannoprotein Cmp1 Regulates Fungal Virulence in Cryptococcus neoformans
by Lian-Tao Han, Lei Wu and Tong-Bao Liu
Pathogens 2020, 9(11), 881; https://doi.org/10.3390/pathogens9110881 - 24 Oct 2020
Cited by 8 | Viewed by 2225
Abstract
The capsule of the fungal pathogen Cryptococcus neoformans consists of glucuronoxylomannan (GXM), glucuronoxylomannogalactan (GXMGal), and mannoproteins (MPs). MPs are a kind of glycoproteins with low content but high immunogenicity, which can stimulate the immune protection of the host. However, there is not much [...] Read more.
The capsule of the fungal pathogen Cryptococcus neoformans consists of glucuronoxylomannan (GXM), glucuronoxylomannogalactan (GXMGal), and mannoproteins (MPs). MPs are a kind of glycoproteins with low content but high immunogenicity, which can stimulate the immune protection of the host. However, there is not much information about the role of mannoproteins in virulence of the human fungal pathogen C. neoformans. In this study, we reported the identification and functional analysis of a predicted mannoprotein Cmp1 that regulates fungal virulence in C. neoformans. Gene expression pattern analysis indicates that the CMP1 gene was ubiquitously expressed at all stages of cryptococcal development. Subcellular localization analysis indicated that Cmp1 was localized in the cytoplasm of cryptococcal cells. Disruption or overexpression of CMP1 results in impairing capsule formation in Cryptococcus, but it does not affect the melanin production and sensitivity under various stress conditions, nor does it affect the sexual reproduction process of Cryptococcus. Survival assay showed that the pathogenicity of the cmp1Δ mutant or the CMP1 overexpression strain was significantly attenuated in a murine inhalation model of cryptococcosis. In conclusion, our findings implied that the mannoprotein Cmp1 is required for the virulence of C. neoformans. Full article
(This article belongs to the Special Issue Pathogenesis of Cryptococcus neoformans)
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16 pages, 3246 KiB  
Article
Serial Passage of Cryptococcus neoformans in Galleria mellonella Results in Increased Capsule and Intracellular Replication in Hemocytes, but Not Increased Resistance to Hydrogen Peroxide
by Muhammad Fariz Ali, Stephen M. Tansie, John R. Shahan, Rebecca L. Seipelt-Thiemann and Erin E. McClelland
Pathogens 2020, 9(9), 732; https://doi.org/10.3390/pathogens9090732 - 05 Sep 2020
Cited by 8 | Viewed by 2772
Abstract
To gain insight into how pathogens adapt to new hosts, Cryptococcus neoformans (H99W) was serially passaged in Galleria mellonella. The phenotypic characteristics of the passaged strain (P15) and H99W were evaluated. P15 grew faster in hemolymph than H99W, in vitro and in [...] Read more.
To gain insight into how pathogens adapt to new hosts, Cryptococcus neoformans (H99W) was serially passaged in Galleria mellonella. The phenotypic characteristics of the passaged strain (P15) and H99W were evaluated. P15 grew faster in hemolymph than H99W, in vitro and in vivo, suggesting that adaptation had occurred. However, P15 was more susceptible to hydrogen peroxide in vitro, killed fewer mouse macrophages, and had less fungal burden in human ex vivo macrophages than H99W. Analysis of gene expression changes during Galleria infection showed only a few different genes involved in the reactive oxygen species response. As P15 sheds more GXM than H99W, P15 may have adapted by downregulating hemocyte hydrogen peroxide production, possibly through increased capsular glucuronoxylomannan (GXM) shedding. Hemocytes infected with P15 produced less hydrogen peroxide, and hydrogen peroxide production in response to GXM-shedding mutants was correlated with shed GXM. Histopathological examination of infected larvae showed increased numbers and sizes of immune nodules for P15 compared to H99W, suggesting an enhanced, but functionally defective, response to P15. These results could explain why this infection model does not always correlate with murine models. Overall, C. neoformans’ serial passage in G. mellonella resulted in a better understanding of how this yeast evolves under selection. Full article
(This article belongs to the Special Issue Pathogenesis of Cryptococcus neoformans)
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17 pages, 3892 KiB  
Article
Monitoring Glycolysis and Respiration Highlights Metabolic Inflexibility of Cryptococcus neoformans
by Sophie Lev, Cecilia Li, Desmarini Desmarini, David Liuwantara, Tania C. Sorrell, Wayne J. Hawthorne and Julianne T. Djordjevic
Pathogens 2020, 9(9), 684; https://doi.org/10.3390/pathogens9090684 - 21 Aug 2020
Cited by 10 | Viewed by 3822
Abstract
Cryptococcus neoformans is a human fungal pathogen that adapts its metabolism to cope with limited oxygen availability, nutrient deprivation and host phagocytes. To gain insight into cryptococcal metabolism, we optimized a protocol for the Seahorse Analyzer, which measures extracellular acidification rate (ECAR) and [...] Read more.
Cryptococcus neoformans is a human fungal pathogen that adapts its metabolism to cope with limited oxygen availability, nutrient deprivation and host phagocytes. To gain insight into cryptococcal metabolism, we optimized a protocol for the Seahorse Analyzer, which measures extracellular acidification rate (ECAR) and oxygen consumption rate (OCR) as indications of glycolytic and respiratory activities. In doing so we achieved effective immobilization of encapsulated cryptococci, established Rotenone/Antimycin A and 2-deoxyglucose as effective inhibitors of mitochondrial respiration and glycolysis, respectively, and optimized a microscopy-based method of data normalization. We applied the protocol to monitor metabolic changes in the pathogen alone and in co-culture with human blood-derived monocytes. We also compared metabolic flux in wild-type C. neoformans, its isogenic 5-PP-IP5/IP7-deficient metabolic mutant kcs1∆, the sister species of C. neoformans, Cryptococcus deuterogattii/VGII, and two other yeasts, Saccharomyces cerevisiae and Candida albicans. Our findings show that in contrast to monocytes and C. albicans, glycolysis and respiration are tightly coupled in C. neoformans and C. deuterogattii, as no compensatory increase in glycolysis occurred following inhibition of respiration. We also demonstrate that kcs1∆ has reduced metabolic activity that correlates with reduced mitochondrial function. Metabolic inflexibility in C. neoformans is therefore consistent with its obligate aerobe status and coincides with phagocyte tolerance of ingested cryptococcal cells. Full article
(This article belongs to the Special Issue Pathogenesis of Cryptococcus neoformans)
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Review

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15 pages, 1322 KiB  
Review
Dangerous Liaisons: Interactions of Cryptococcus neoformans with Host Phagocytes
by Elizabeth A. Gaylord, Hau Lam Choy and Tamara L. Doering
Pathogens 2020, 9(11), 891; https://doi.org/10.3390/pathogens9110891 - 27 Oct 2020
Cited by 18 | Viewed by 4346
Abstract
Cryptococcus neoformans is an opportunistic fungal pathogen and a leading cause of death in immunocompromised individuals. The interactions of this yeast with host phagocytes are critical to disease outcome, and C. neoformans is equipped with an array of factors to modulate these processes. [...] Read more.
Cryptococcus neoformans is an opportunistic fungal pathogen and a leading cause of death in immunocompromised individuals. The interactions of this yeast with host phagocytes are critical to disease outcome, and C. neoformans is equipped with an array of factors to modulate these processes. Cryptococcal infection begins with the deposition of infectious particles into the lungs, where the fungal cells deploy various antiphagocytic factors to resist internalization by host cells. If the cryptococci are still engulfed, they can survive and proliferate within host cells by modulating the phagolysosome environment in which they reside. Lastly, cryptococcal cells may escape from phagocytes by host cell lysis, nonlytic exocytosis, or lateral cell-to-cell transfer. The interactions between C. neoformans and host phagocytes also influence the dissemination of this pathogen to the brain, where it may cross the blood-brain barrier and cause an often-fatal meningoencephalitis. In this review, we highlight key cryptococcal factors involved in various stages of cryptococcal-host interaction and pathogenesis. Full article
(This article belongs to the Special Issue Pathogenesis of Cryptococcus neoformans)
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14 pages, 1771 KiB  
Review
Pathogenic Delivery: The Biological Roles of Cryptococcal Extracellular Vesicles
by Haroldo C. de Oliveira, Rafael F. Castelli, Flavia C. G. Reis, Juliana Rizzo and Marcio L. Rodrigues
Pathogens 2020, 9(9), 754; https://doi.org/10.3390/pathogens9090754 - 16 Sep 2020
Cited by 11 | Viewed by 4109
Abstract
Extracellular vesicles (EVs) are produced by all domains of life. In fungi, these structures were first described in Cryptococcus neoformans and, since then, they were characterized in several pathogenic and non-pathogenic fungal species. Cryptococcal EVs participate in the export of virulence factors that [...] Read more.
Extracellular vesicles (EVs) are produced by all domains of life. In fungi, these structures were first described in Cryptococcus neoformans and, since then, they were characterized in several pathogenic and non-pathogenic fungal species. Cryptococcal EVs participate in the export of virulence factors that directly impact the Cryptococcus–host interaction. Our knowledge of the biogenesis and pathogenic roles of Cryptococcus EVs is still limited, but recent methodological and scientific advances have improved our understanding of how cryptococcal EVs participate in both physiological and pathogenic events. In this review, we will discuss the importance of cryptococcal EVs, including early historical studies suggesting their existence in Cryptococcus, their putative mechanisms of biogenesis, methods of isolation, and possible roles in the interaction with host cells. Full article
(This article belongs to the Special Issue Pathogenesis of Cryptococcus neoformans)
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11 pages, 562 KiB  
Review
On the History and Applications of Congenic Strains in Cryptococcus Research
by Benjamin J. Chadwick and Xiaorong Lin
Pathogens 2020, 9(9), 750; https://doi.org/10.3390/pathogens9090750 - 15 Sep 2020
Cited by 5 | Viewed by 2152
Abstract
Congenic strains have been utilized in numerous model organisms to determine the genetic underpinning of various phenotypic traits. Congenic strains are usually derived after 10 backcrosses to a recipient parent, at which point they are 99.95% genetically identical to the parental strain. In [...] Read more.
Congenic strains have been utilized in numerous model organisms to determine the genetic underpinning of various phenotypic traits. Congenic strains are usually derived after 10 backcrosses to a recipient parent, at which point they are 99.95% genetically identical to the parental strain. In recent decades, congenic pairs have provided an invaluable tool for genetics and molecular biology research in the Cryptococcus neoformans species complex. Here, we summarize the history of Cryptococcus congenic pairs and their application in Cryptococcus research on topics including the impact of the mating type locus on unisexual reproduction, virulence, tissue tropism, uniparental mitochondrial inheritance, and the genetic underpinning of other various traits. We also discuss the limitations of these approaches and other biological questions, which could be explored by employing congenic pairs. Full article
(This article belongs to the Special Issue Pathogenesis of Cryptococcus neoformans)
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9 pages, 513 KiB  
Review
Current Perspectives on Uniparental Mitochondrial Inheritance in Cryptococcus neoformans
by Amber R. Matha and Xiaorong Lin
Pathogens 2020, 9(9), 743; https://doi.org/10.3390/pathogens9090743 - 10 Sep 2020
Cited by 4 | Viewed by 2886
Abstract
The mitochondrion is a vital organelle in most eukaryotic cells. It contains its own DNA which differs from nuclear DNA, since it is often inherited from only one parent during sexual reproduction. In anisogamous mammals, this is largely due to the fact that [...] Read more.
The mitochondrion is a vital organelle in most eukaryotic cells. It contains its own DNA which differs from nuclear DNA, since it is often inherited from only one parent during sexual reproduction. In anisogamous mammals, this is largely due to the fact that the oocyte has over 1000 times more copies of mitochondrial DNA than the sperm. However, in the isogamous fungus Cryptococcus neoformans, uniparental mitochondrial inheritance (UMI) still occurs during sexual reproduction. It is proposed that UMI might have evolved in the last common ancestor of eukaryotes. Thus, understanding the fundamental process of UMI in lower eukaryotes may give insights into how the process might have evolved in eukaryotic ancestors. In this review, we discuss the current knowledge regarding the cellular features as well as the molecular underpinnings of UMI in Cryptococcus during the mating process, and open questions that need to be answered to solve the mystery of UMI in this eukaryotic microbe. Full article
(This article belongs to the Special Issue Pathogenesis of Cryptococcus neoformans)
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