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Basic principles of the virulence of Cryptococcus.

ABSTRACT: Among fungal pathogens, Cryptococcus neoformans has gained great importance among the scientific community of several reasons. This fungus is the causative agent of cryptococcosis, a disease mainly associated to HIV immunosuppression and characterized by the appearance of meningoencephalitis. Cryptococcal meningitis is responsible for hundreds of thousands of deaths every year. Research of the pathogenesis and virulence mechanisms of this pathogen has focused on three main different areas: Adaptation to the host environment (nutrients, pH, and free radicals), mechanism of immune evasion (which include phenotypic variations and the ability to behave as a facultative intracellular pathogen), and production of virulence factors. Cryptococcus neoformans has two phenotypic characteristics, the capsule and synthesis of melanin that have a profound effect in the virulence of the yeast because they both have protective effects and induce host damage as virulence factors. Finally, the mechanisms that result in dissemination and brain invasion are also of key importance to understand cryptococcal disease. In this review, I will provide a brief overview of the main mechanisms that makes C. neoformans a pathogen in susceptible patients. Abbreviations: RNS: reactive nitrogen species; BBB: brain blood barrier; GXM: glucuronoxylomannan; GXMGal: glucuronoxylomannogalactan.

SUBMITTER: Zaragoza O

PROVIDER: S-EPMC6550552 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Basic principles of the virulence of <i>Cryptococcus</i>.

Zaragoza Oscar O

Virulence 20191201 1

Among fungal pathogens, <i>Cryptococcus neoformans</i> has gained great importance among the scientific community of several reasons. This fungus is the causative agent of cryptococcosis, a disease mainly associated to HIV immunosuppression and characterized by the appearance of meningoencephalitis. Cryptococcal meningitis is responsible for hundreds of thousands of deaths every year. Research of the pathogenesis and virulence mechanisms of this pathogen has focused on three main different areas ...[more]

PMID: 31119976

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Project description:Fungal opportunistic pathogens colonize various environments, from plants and wood to human and animal tissue. Regarding human pathogens, one great challenge during contrasting niche occupation is the adaptation to different conditions, such as temperature, osmolarity, salinity, pressure, oxidative stress and nutritional availability, which may constitute sources of stress that need to be tolerated and overcome. As an opportunistic pathogen, C. neoformans faces exactly these situations during the transition from the environment to the human host, encountering nutritional constraints. Our previous and current research on amino acid biosynthetic pathways indicates that amino acid permeases are regulated by the presence of the amino acids, nitrogen and temperature. Saccharomyces cerevisiae and Candida albicans have twenty-four and twenty-seven genes encoding amino acid permeases, respectively; conversely, they are scarce in number in Basidiomycetes (C. neoformans, Coprinopsis cinerea and Ustilago maydis), where nine to ten permease genes can be found depending on the species. In this study, we have demonstrated that two amino acid permeases are essential for virulence in C. neoformans. Our data showed that C. neoformans uses two global and redundant amino acid permeases, Aap4 and Aap5 to respond correctly to thermal and oxidative stress. Double deletion of these permeases causes growth arrest in C. neoformans at 37°C and in the presence of hydrogen peroxide. The inability to uptake amino acid at a higher temperature and under oxidative stress also led to virulence attenuation in vivo. Our data showed that thermosensitivity caused by the lack of permeases Aap4 and Aap5 can be remedied by alkaline conditions (higher pH) and salinity. Permeases Aap4 and Aap5 are also required during fluconazole stress and they are the target of the plant secondary metabolite eugenol, a potent antifungal inhibitor that targets amino acid permeases. In summary, our work unravels (i) interesting physiological property of C. neoformans regarding its amino acid uptake system; (ii) an important aspect of virulence, which is the need for amino acid permeases during thermal and oxidative stress resistance and, hence, host invasion and colonization; and (iii) provides a convenient prototype for antifungal development, which are the amino acid permeases Aap4/Aap5 and their inhibitor.

Project description:Insertional mutagenesis was applied to Cryptococcus neoformans to identify genes associated with virulence attributes. Using biolistic transformation, we generated 4,300 nourseothricin (NAT)-resistant strains, of which 590 exhibited stable resistance. We focused on mutants with defects in established virulence factors and identified two with reduced growth at 37 degrees C, four with reduced production of the antioxidant pigment melanin, and two with an increased sensitivity to nitric oxide (NO). The NAT insertion and mutant phenotypes were genetically linked in five of eight mutants, and the DNA flanking the insertions was characterized. For the strains with altered growth at 37 degrees C and altered melanin production, mutations were in previously uncharacterized genes, while the two NO-sensitive strains bore insertions in the flavohemoglobin gene FHB1, whose product counters NO stress. Because of the frequent instability of nourseothricin resistance associated with biolistic transformation, Agrobacterium-mediated transformation was tested. This transkingdom DNA delivery approach produced 100% stable nourseothricin-resistant transformants, and three melanin-defective strains were identified from 576 transformants, of which 2 were linked to NAT in segregation analysis. One of these mutants contained a T-DNA insertion in the promoter of the LAC1 (laccase) gene, which encodes a key enzyme required for melanin production, while the second contained an insertion in the promoter of the CLC1 gene, encoding a voltage-gated chloride channel. Clc1 and its homologs are required for ion homeostasis, and in their absence Cu+ transport into the secretory pathway is compromised, depriving laccase and other Cu(+)-dependent proteins of their essential cofactor. The NAT resistance cassette was optimized for cryptococcal codon usage and GC content and was then used to disrupt a mitogen-activated protein kinase gene, a predicted gene, and two putative chloride channel genes to analyze their contributions to fungal physiology. Our findings demonstrate that both insertional mutagenesis methods can be applied to gene identification, but Agrobacterium-mediated transformation is more efficient and generates exclusively stable insertion mutations.

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Basic principles of the virulence of Cryptococcus.

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Basic principles of the virulence of <i>Cryptococcus</i>.

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