scholarly journals A Predicted Mannoprotein Cmp1 Regulates Fungal Virulence in Cryptococcus neoformans

Pathogens ◽  
2020 ◽  
Vol 9 (11) ◽  
pp. 881
Author(s):  
Lian-Tao Han ◽  
Lei Wu ◽  
Tong-Bao Liu
Keyword(s):  
Cryptococcus Neoformans ◽  
Fungal Pathogen ◽  
Gene Expression Pattern ◽  
Fungal Virulence ◽  
Human Fungal Pathogen ◽  
Overexpression Strain ◽  
Reproduction Process ◽  
Localization Analysis ◽  
Survival Assay

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.

scholarly journals Zinc Finger Proteins in the Human Fungal Pathogen Cryptococcus neoformans

2020 ◽  
Vol 21 (4) ◽  
pp. 1361
Author(s):  
Yuan-Hong Li ◽  
Tong-Bao Liu
Keyword(s):  
Cryptococcus Neoformans ◽  
Zinc Finger ◽  
Fungal Pathogen ◽  
Ion Homeostasis ◽  
Zinc Finger Proteins ◽  
Morphological Development ◽  
Human Fungal Pathogen ◽  
Essential Trace Elements

Zinc is one of the essential trace elements in eukaryotes and it is a critical structural component of a large number of proteins. Zinc finger proteins (ZNFs) are zinc-finger domain-containing proteins stabilized by bound zinc ions and they form the most abundant proteins, serving extraordinarily diverse biological functions. In recent years, many ZNFs have been identified and characterized in the human fungal pathogen Cryptococcus neoformans, a fungal pathogen causing fatal meningitis mainly in immunocompromised individuals. It has been shown that ZNFs play important roles in the morphological development, differentiation, and virulence of C. neoformans. In this review, we, first, briefly introduce the ZNFs and their classification. Then, we explain the identification and classification of the ZNFs in C. neoformans. Next, we focus on the biological role of the ZNFs functionally characterized so far in the sexual reproduction, virulence factor production, ion homeostasis, pathogenesis, and stress resistance in C. neoformans. We also discuss the perspectives on future function studies of ZNFs in C. neoformans.

scholarly journals A fungal arrestin protein contributes to cell cycle progression and pathogenesis

2019 ◽  
Author(s):  
Calla L. Telzrow ◽  
Connie B. Nichols ◽  
Natalia Castro-Lopez ◽  
Floyd L. Wormley ◽  
J. Andrew Alspaugh
Keyword(s):  
Cell Cycle ◽  
Cryptococcus Neoformans ◽  
Fungal Pathogen ◽  
Cell Cycle Progression ◽  
Lipid Synthesis ◽  
Adaptor Protein ◽  
Cellular Responses ◽  
Fungal Virulence ◽  
Human Fungal Pathogen ◽  
Mutant Phenotypes

ABSTRACTArrestins, a structurally specialized and functionally diverse group of proteins, are central regulators of adaptive cellular responses in eukaryotes. Previous studies on fungal arrestins have demonstrated their capacity to modulate diverse cellular processes through their adaptor functions, facilitating the localization and function of other proteins. However, the mechanisms by which arrestin-regulated processes are involved in fungal virulence remain unexplored. We have identified a small family of four arrestins - Ali1, Ali2, Ali3, and Ali4 - in the human fungal pathogen Cryptococcus neoformans. Using complementary microscopy, proteomic, and reverse genetic techniques, we have defined a role for Ali1 as a novel contributor to cytokinesis, a fundamental cell cycle-associated process. We observed that Ali1 strongly interacts with proteins involved in lipid synthesis, and that ali1Δ mutant phenotypes are rescued by supplementation with lipid precursors that are used to build cellular membranes. From these data, we hypothesize that Ali1 contributes to cytokinesis by serving as an adaptor protein, facilitating the localization of enzymes that modify the plasma membrane during cell division, specifically the fatty acid synthases, Fas1 and Fas2. Finally, we assessed the contributions of the C. neoformans arrestin family to virulence, to better understand the mechanisms by which arrestin-regulated adaptive cellular responses influence fungal infection. We observed that the C. neoformans arrestin family contributes to virulence, and that the individual arrestin proteins likely fulfill distinct functions that are important for disease progression.IMPORTANCETo survive in unpredictable conditions, all organisms must adapt to stressors by regulating adaptive cellular responses. Arrestin proteins are conserved regulators of adaptive cellular responses in eukaryotes. Studies that have been limited to mammals and model fungi have demonstrated that disruption of arrestin-regulated pathways is detrimental for viability. The human fungal pathogen Cryptococcus neoformans causes more than 180,000 infection-related deaths annually, especially among immunocompromised patients. In addition to being genetically-tractable, C. neoformans has a small arrestin family of four members, lending itself to a comprehensive characterization of its arrestin family. This study serves as a functional analysis of arrestins in a pathogen, particularly in the context of fungal fitness and virulence. We investigate the functions of one arrestin protein, Ali1, and define its novel contributions to cytokinesis. We additionally explore the virulence contributions of the C. neoformans arrestin family and find that they contribute to disease establishment and progression.

scholarly journals A Fungal Arrestin Protein Contributes to Cell Cycle Progression and Pathogenesis

mBio ◽  
2019 ◽  
Vol 10 (6) ◽  
Author(s):  
Calla L. Telzrow ◽  
Connie B. Nichols ◽  
Natalia Castro-Lopez ◽  
Floyd L. Wormley ◽  
J. Andrew Alspaugh
Keyword(s):  
Cell Cycle ◽  
Cryptococcus Neoformans ◽  
Fungal Pathogen ◽  
Reverse Genetics ◽  
Lipid Synthesis ◽  
Adaptor Protein ◽  
Cellular Responses ◽  
Fungal Virulence ◽  
Content Type ◽  
Human Fungal Pathogen

ABSTRACT Arrestins, a structurally specialized and functionally diverse group of proteins, are central regulators of adaptive cellular responses in eukaryotes. Previous studies on fungal arrestins have demonstrated their capacity to modulate diverse cellular processes through their adaptor functions, facilitating the localization and function of other proteins. However, the mechanisms by which arrestin-regulated processes are involved in fungal virulence remain unexplored. We have identified a small family of four arrestins, Ali1, Ali2, Ali3, and Ali4, in the human fungal pathogen Cryptococcus neoformans. Using complementary microscopy, proteomic, and reverse genetics techniques, we have defined a role for Ali1 as a novel contributor to cytokinesis, a fundamental cell cycle-associated process. We observed that Ali1 strongly interacts with proteins involved in lipid synthesis, and that ali1Δ mutant phenotypes are rescued by supplementation with lipid precursors that are used to build cellular membranes. From these data, we hypothesize that Ali1 contributes to cytokinesis by serving as an adaptor protein, facilitating the localization of enzymes that modify the plasma membrane during cell division, specifically the fatty acid synthases Fas1 and Fas2. Finally, we assessed the contributions of the C. neoformans arrestin family to virulence to better understand the mechanisms by which arrestin-regulated adaptive cellular responses influence fungal infection. We observed that the C. neoformans arrestin family contributes to virulence, and that the individual arrestin proteins likely fulfill distinct functions that are important for disease progression. IMPORTANCE To survive under unpredictable conditions, all organisms must adapt to stressors by regulating adaptive cellular responses. Arrestin proteins are conserved regulators of adaptive cellular responses in eukaryotes. Studies that have been limited to mammals and model fungi have demonstrated that the disruption of arrestin-regulated pathways is detrimental for viability. The human fungal pathogen Cryptococcus neoformans causes more than 180,000 infection-related deaths annually, especially among immunocompromised patients. In addition to being genetically tractable, C. neoformans has a small arrestin family of four members, lending itself to a comprehensive characterization of its arrestin family. This study serves as a functional analysis of arrestins in a pathogen, particularly in the context of fungal fitness and virulence. We investigate the functions of one arrestin protein, Ali1, and define its novel contributions to cytokinesis. We additionally explore the virulence contributions of the C. neoformans arrestin family and find that they contribute to disease establishment and progression.

scholarly journals Role of clathrin-mediated endocytosis in the use of heme and hemoglobin by the fungal pathogen Cryptococcus neoformans

2018 ◽  
Vol 21 (3) ◽  
pp. e12961 ◽  
Author(s):  
Gaurav Bairwa ◽  
Mélissa Caza ◽  
Linda Horianopoulos ◽  
Guanggan Hu ◽  
James Kronstad
Keyword(s):  
Cryptococcus Neoformans ◽  
Fungal Pathogen

Broadening the spectrum of fluorescent protein tools for use in the encapsulated human fungal pathogen Cryptococcus neoformans

2020 ◽  
Vol 138 ◽  
pp. 103365
Author(s):  
Garrick W.K. Spencer ◽  
Sheena M.H. Chua ◽  
Paige E. Erpf ◽  
Maha S.I. Wizrah ◽  
Taylor G. Dyba ◽  
...  
Keyword(s):  
Cryptococcus Neoformans ◽  
Fungal Pathogen ◽  
Fluorescent Protein ◽  
Human Fungal Pathogen

scholarly journals Cryptococcus neoformans Evades Pulmonary Immunity by Modulating Xylose Precursor Transport

2020 ◽  
Vol 88 (8) ◽  
Author(s):  
Lucy X. Li ◽  
Camaron R. Hole ◽  
Javier Rangel-Moreno ◽  
Shabaana A. Khader ◽  
Tamara L. Doering
Keyword(s):  
Cryptococcus Neoformans ◽  
Mutant Strain ◽  
Fungal Pathogen ◽  
Wild Type ◽  
Content Type ◽  
Helper Cell Type ◽  
Lymphoid Structures ◽  
Type Infection

ABSTRACT Cryptococcus neoformans is a fungal pathogen that kills almost 200,000 people each year and is distinguished by abundant and unique surface glycan structures that are rich in xylose. A mutant strain of C. neoformans that cannot transport xylose precursors into the secretory compartment is severely attenuated in virulence in mice yet surprisingly is not cleared. We found that this strain failed to induce the nonprotective T helper cell type 2 (Th2) responses characteristic of wild-type infection, instead promoting sustained interleukin 12p40 (IL-12p40) induction and increased IL-17A (IL-17) production. It also stimulated dendritic cells to release high levels of proinflammatory cytokines, a behavior we linked to xylose expression. We further discovered that inducible bronchus-associated lymphoid tissue (iBALT) forms in response to infection with either wild-type cryptococci or the mutant strain with reduced surface xylose; although iBALT formation is slowed in the latter case, the tissue is better organized. Finally, our temporal studies suggest that lymphoid structures in the lung restrict the spread of mutant fungi for at least 18 weeks after infection, which is in contrast to ineffective control of the pathogen after infection with wild-type cells. These studies demonstrate the role of xylose in modulation of host response to a fungal pathogen and show that cryptococcal infection triggers iBALT formation.

scholarly journals Erg6 affects membrane composition and virulence of the human fungal pathogen Cryptococcus neoformans

2020 ◽  
Vol 140 ◽  
pp. 103368 ◽  
Author(s):  
Fabiana Freire M. Oliveira ◽  
Hugo Costa Paes ◽  
Luísa Defranco F. Peconick ◽  
Fernanda L. Fonseca ◽  
Clara Luna Freitas Marina ◽  
...  
Keyword(s):  
Cryptococcus Neoformans ◽  
Fungal Pathogen ◽  
Membrane Composition ◽  
Human Fungal Pathogen

scholarly journals The Role of Oxidoreductase-Like Protein Olp1 in Sexual Reproduction and Virulence of Cryptococcus neoformans

2020 ◽  
Vol 8 (11) ◽  
pp. 1730
Author(s):  
Qi-Kun Yu ◽  
Lian-Tao Han ◽  
Yu-Juan Wu ◽  
Tong-Bao Liu
Keyword(s):  
Sexual Reproduction ◽  
Cryptococcus Neoformans ◽  
Expression Patterns ◽  
Fungal Virulence ◽  
Growth Defects ◽  
Human Fungal Pathogen ◽  
Yeast Extract Peptone Dextrose ◽  
Virulence Attenuation ◽  
Protein Encoding ◽  
Fungal Mating

Cryptococcus neoformans is a basidiomycete human fungal pathogen causing lethal meningoencephalitis, mainly in immunocompromised patients. Oxidoreductases are a class of enzymes that catalyze redox, playing a crucial role in biochemical reactions. In this study, we identified one Cryptococcus oxidoreductase-like protein-encoding gene OLP1 and investigated its role in the sexual reproduction and virulence of C. neoformans. Gene expression patterns analysis showed that the OLP1 gene was expressed in each developmental stage of Cryptococcus, and the Olp1 protein was located in the cytoplasm of Cryptococcus cells. Although it produced normal major virulence factors such as melanin and capsule, the olp1Δ mutants showed growth defects on the yeast extract peptone dextrose (YPD) medium supplemented with lithium chloride (LiCl) and 5-fluorocytosine (5-FC). The fungal mating analysis showed that Olp1 is also essential for fungal sexual reproduction, as olp1Δ mutants show significant defects in hyphae growth and basidiospores production during bisexual reproduction. The fungal nuclei imaging showed that during the bilateral mating of olp1Δ mutants, the nuclei failed to undergo meiosis after fusion in the basidia, indicating that Olp1 is crucial for regulating meiosis during mating. Moreover, Olp1 was also found to be required for fungal virulence in C. neoformans, as the olp1Δ mutants showed significant virulence attenuation in a murine inhalation model. In conclusion, our results showed that the oxidoreductase-like protein Olp1 is required for both fungal sexual reproduction and virulence in C. neoformans.

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