scholarly journals Mitochondrial Genome Polymorphisms in the Human Pathogenic Fungus Cryptococcus neoformans

2020 ◽  
Vol 11 ◽  
Author(s):  
Yue Wang ◽  
Jianping Xu
Keyword(s):  
Mitochondrial Genome ◽  
Cryptococcus Neoformans ◽  
Pathogenic Fungus ◽  
Human Pathogenic Fungus

scholarly journals The capsule ofCryptococcus neoformansmodulates phagosomal pH through its acid-base properties

2018 ◽  
Author(s):  
Carlos M. De Leon-Rodriguez ◽  
Man Shun Fu ◽  
M. Osman Corbali ◽  
Radames J.B. Cordero ◽  
Arturo Casadevall
Keyword(s):  
Cryptococcus Neoformans ◽  
Capsular Polysaccharide ◽  
Glucuronic Acid ◽  
Pathogenic Fungus ◽  
Weak Acid ◽  
Phagocytic Cells ◽  
Acid Base ◽  
Encapsulated Cells ◽  
Human Pathogenic Fungus ◽  
Base Properties

AbstractPhagosomal acidification is a critical cellular mechanism for the inhibition and killing of ingested microbes by phagocytic cells. The acidic environment activates microbicidal proteins and creates an unfavorable environment for the growth of many microbes. Consequently, numerous pathogenic microbes have developed strategies for countering phagosomal acidification through various mechanisms that include interference with phagosome maturation. The human pathogenic fungusCryptococcus neoformansresides in acidic phagosome after macrophage ingestion that actually provides a favorable environment for replication since the fungus replicates faster at acidic pH. We hypothesized that the glucuronic acid residues in the capsular polysaccharide had the capacity to affect phagosome acidity through their acid-base properties. A ratiometric fluorescence comparison of imaged phagosomes containingC. neoformansto those containing beads showed that the latter were significantly more acidic. Similarly, phagosomes containing non-encapsulatedC. neoformanscells were more acidic than those containing encapsulated cells. Acid-base titrations of isolatedC. neoformanspolysaccharide revealed that it behaves as a weak acid with maximal buffering capacity around pH 4-5. We interpret these results as indicating that the glucuronic acid residues in theC. neoformanscapsular polysaccharide can buffer phagosomal acidification. Interference with phagosomal acidification represents a new function for the cryptococcal capsule in virulence and suggests the importance of considering the acid-base properties of microbial capsules in the host-microbe interaction for other microbes with charged residues in their capsules.ImportanceCryptococcus neoformansis the causative agent of cryptococcosis, a devastating fungal disease that affects thousands of individuals worldwide. This fungus has the capacity to survive inside phagocytic cells, which contributes to persistence of infection and dissemination. One of the major mechanisms of host phagocytes is to acidify the phagosomal compartment after ingestion of microbes. This study shows that the capsule ofC. neoformanscan interfere with full phagosomal acidification by serving as a buffer.

scholarly journals Peroxisomal and Mitochondrial β-Oxidation Pathways Influence the Virulence of the Pathogenic Fungus Cryptococcus neoformans

2012 ◽  
Vol 11 (8) ◽  
pp. 1042-1054 ◽  
Author(s):  
Matthias Kretschmer ◽  
Joyce Wang ◽  
James W. Kronstad
Keyword(s):  
Carbon Source ◽  
Cryptococcus Neoformans ◽  
Virulence Factor ◽  
Fungal Pathogens ◽  
Pathogenic Fungus ◽  
Subsequent Work ◽  
Content Type ◽  
Capsule Production ◽  
Human Pathogenic Fungus ◽  
Host Tissues

ABSTRACTAn understanding of the connections between metabolism and elaboration of virulence factors during host colonization by the human-pathogenic fungusCryptococcus neoformansis important for developing antifungal therapies. Lipids are abundant in host tissues, and fungal pathogens in the phylum basidiomycota possess both peroxisomal and mitochondrial β-oxidation pathways to utilize this potential carbon source. In addition, lipids are important signaling molecules in both fungi and mammals. In this report, we demonstrate that defects in the peroxisomal and mitochondrial β-oxidation pathways influence the growth ofC. neoformanson fatty acids as well as the virulence of the fungus in a mouse inhalation model of cryptococcosis. Disease attenuation may be due to the cumulative influence of altered carbon source acquisition or processing, interference with secretion, changes in cell wall integrity, and an observed defect in capsule production for the peroxisomal mutant. Altered capsule elaboration in the context of a β-oxidation defect was unexpected but is particularly important because this trait is a major virulence factor forC. neoformans. Additionally, analysis of mutants in the peroxisomal pathway revealed a growth-promoting activity forC. neoformans, and subsequent work identified oleic acid and biotin as candidates for such factors. Overall, this study reveals that β-oxidation influences virulence inC. neoformansby multiple mechanisms that likely include contributions to carbon source acquisition and virulence factor elaboration.

scholarly journals Identification of ENA1 as a Virulence Gene of the Human Pathogenic Fungus Cryptococcus neoformans through Signature-Tagged Insertional Mutagenesis

2009 ◽  
Vol 8 (3) ◽  
pp. 315-326 ◽  
Author(s):  
Alexander Idnurm ◽  
Felicia J. Walton ◽  
Anna Floyd ◽  
Jennifer L. Reedy ◽  
Joseph Heitman
Keyword(s):  
Cryptococcus Neoformans ◽  
Fungal Pathogens ◽  
Insertional Mutagenesis ◽  
Pathogenic Fungus ◽  
Mammalian Host ◽  
New Genes ◽  
Strain Collection ◽  
Mutant Strains ◽  
Human Pathogenic Fungus

ABSTRACT A library of more than 4,500 signature-tagged insertion mutants of the human pathogenic fungus Cryptococcus neoformans was generated, and a subset was screened in a murine inhalation model to identify genes required for virulence. New genes that regulate aspects of C. neoformans virulence were also identified by screening the entire library for in vitro phenotypes related to the ability to cause disease, including melanin production, growth at high temperature, and growth under conditions of nutrient limitation. A screen of 10% of the strain collection in mice identified an avirulent mutant strain with an insertion in the ENA1 gene, which is predicted to encode a fungus-specific sodium or potassium P-type ATPase. The results of the deletion of the gene and complementation experiments confirmed its key role in mammalian virulence. ena1 mutant strains exhibited no change in sensitivity to high salt concentrations but were sensitive to alkaline pH conditions, providing evidence that the fungus may have to survive at elevated pH during infection of the mammalian host. The mutation of the well-characterized virulence factor calcineurin (CNA1) also rendered C. neoformans strains sensitive to elevated pH. ENA1 transcripts in wild-type and cna1 mutant strains were upregulated in response to high pH, and cna1 ena1 double mutant strains exhibited increased sensitivity to elevated pH, indicating that at least two pathways in the fungus mediate survival under alkaline conditions. Signature-tagged mutagenesis is an effective strategy for the discovery of new virulence genes in fungal pathogens of animals.

scholarly journals Evidence that the Human Pathogenic Fungus Cryptococcus neoformans var. grubii May Have Evolved in Africa

PLoS ONE ◽  
2011 ◽  
Vol 6 (5) ◽  
pp. e19688 ◽  
Author(s):  
Anastasia P. Litvintseva ◽  
Ignazio Carbone ◽  
Jenny Rossouw ◽  
Rameshwari Thakur ◽  
Nelesh P. Govender ◽  
...  
Keyword(s):  
Cryptococcus Neoformans ◽  
Pathogenic Fungus ◽  
Human Pathogenic Fungus

Cryptococcus neoformans methionine synthase: expression analysis and requirement for virulence

Microbiology ◽  
2004 ◽  
Vol 150 (9) ◽  
pp. 3013-3023 ◽  
Author(s):  
Renata C. Pascon ◽  
Tonya M. Ganous ◽  
Joanne M. Kingsbury ◽  
Gary M. Cox ◽  
John H. McCusker
Keyword(s):  
Cryptococcus Neoformans ◽  
Pathogenic Fungus ◽  
Calcineurin Inhibitors ◽  
Methionine Synthase ◽  
Environmental Condition ◽  
Metabolic Intermediate ◽  
Capsule Formation ◽  
Phenotypic Differences ◽  
Human Pathogenic Fungus ◽  
Transcriptional Induction

This paper describes (i) the expression profile of the methionine synthase gene (MET6) in the human pathogenic fungus Cryptococcus neoformans and (ii) the phenotypes of a C. neoformans met6 mutant. In contrast to the MET3 gene, which showed no significant change in expression in any environmental condition tested, the MET6 gene showed a substantial induction in response to methionine and a dramatic transcriptional induction in response to homocysteine. Like a met3 mutant, the met6 mutant was a methionine auxotroph. However, relative to a met3 mutant, the met6 mutant grew very slowly and was less heat-shock resistant. In contrast to a met3 mutant, the met6 mutant lost viability when starved of methionine, and it was deficient in capsule formation. Like a met3 mutant, the met6 mutant was avirulent. In contrast to a met3 mutant, the met6 mutant was hypersensitive to fluconazole and to the calcineurin inhibitors FK506 and cyclosporin A. A synergistic fungicidal effect was also found between each of these drugs and met6. The phenotypic differences between the met3 and met6 mutants may be due to the accumulation in met6 mutants of homocysteine, a toxic metabolic intermediate that inhibits sterol biosynthesis.

Fitness distribution and transgressive segregation across 40 environments in a hybrid progeny population of the human-pathogenic yeast Cryptococcus neoformans

Genome ◽  
2008 ◽  
Vol 51 (4) ◽  
pp. 272-281 ◽  
Author(s):  
Morvarid Shahid ◽  
Susan Han ◽  
Heather Yoell ◽  
Jianping Xu
Keyword(s):  
Cryptococcus Neoformans ◽  
Biological Effects ◽  
Pathogenic Fungus ◽  
Transgressive Segregation ◽  
Variable Number ◽  
Hybrid Progeny ◽  
Pathogenic Yeast ◽  
Human Fungal Pathogen ◽  
Different Temperatures ◽  
Human Pathogenic Fungus

The opportunistic human fungal pathogen Cryptococcus neoformans includes two varieties, C. neoformans var. grubii and C. neoformans var. neoformans, which correspond to serotypes A and D, respectively. Recent population genetic studies revealed that multiple natural hybridizations have occurred recently between these two divergent lineages. However, the biological effects of such hybridizations are little understood. In this study, we used colony size as a proxy for vegetative fitness to examine the phenotypic effects of hybridization between these two lineages in a laboratory cross. Two genetically diverged parental strains that differed in their growth at different temperatures and on different media as well as in their susceptibility to the common antifungal drug fluconazole were chosen. A total of 269 progeny were obtained and their vegetative growth was determined in 40 environments that differed in nutrients, temperature, and fluconazole concentration. Our analyses indicated little evidence for outbreeding depression or heterosis in the average vegetative fitness of the hybrid progeny population. The progeny, each of the three environmental variables, and their two-way, three-way, and four-way interactions all contributed significantly to the overall vegetative fitness variation. Interestingly, a variable number of progeny displayed evidence of transgressive segregation in vegetative fitness among the tested environments. Our study suggests that hybridization could play a significant role in the phenotypic evolution of this important human-pathogenic fungus.

scholarly journals Role for Chitin and Chitooligomers in the Capsular Architecture of Cryptococcus neoformans

2009 ◽  
Vol 8 (10) ◽  
pp. 1543-1553 ◽  
Author(s):  
Fernanda L. Fonseca ◽  
Leonardo Nimrichter ◽  
Radames J. B. Cordero ◽  
Susana Frases ◽  
Jessica Rodrigues ◽  
...  
Keyword(s):  
Cell Wall ◽  
Cryptococcus Neoformans ◽  
Pathogenic Fungus ◽  
Monosaccharide Composition ◽  
Altered Expression ◽  
Functional Activities ◽  
Differential Reactivity ◽  
Human Pathogenic Fungus

ABSTRACT Molecules composed of β-1,4-linked N-acetylglucosamine (GlcNAc) and deacetylated glucosamine units play key roles as surface constituents of the human pathogenic fungus Cryptococcus neoformans. GlcNAc is the monomeric unit of chitin and chitooligomers, which participate in the connection of capsular polysaccharides to the cryptococcal cell wall. In the present study, we evaluated the role of GlcNAc-containing structures in the assembly of the cryptococcal capsule. The in vivo expression of chitooligomers in C. neoformans varied depending on the infected tissue, as inferred from the differential reactivity of yeast forms to the wheat germ agglutinin (WGA) in infected brain and lungs of rats. Chromatographic and dynamic light-scattering analyses demonstrated that glucuronoxylomannan (GXM), the major cryptococcal capsular component, interacts with chitin and chitooligomers. When added to C. neoformans cultures, chitooligomers formed soluble complexes with GXM and interfered in capsular assembly, as manifested by aberrant capsules with defective connections with the cell wall and no reactivity with a monoclonal antibody to GXM. Cultivation of C. neoformans in the presence of an inhibitor of glucosamine 6-phosphate synthase resulted in altered expression of cell wall chitin. These cells formed capsules that were loosely connected to the cryptococcal wall and contained fibers with decreased diameters and altered monosaccharide composition. These results contribute to our understanding of the role played by chitin and chitooligosaccharides on the cryptococcal capsular structure, broadening the functional activities attributed to GlcNAc-containing structures in this biological system.

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