UMMS Affiliation

Department of Medicine. Division of Infectious Diseases and Immunology

Publication Date

2018-11-20

Document Type

Article

Disciplines

Cells | Enzymes and Coenzymes | Fungi | Genetic Phenomena | Immunology and Infectious Disease | Pathogenic Microbiology

Abstract

Chitin is an essential component of the cell wall of Cryptococcus neoformans conferring structural rigidity and integrity under diverse environmental conditions. Chitin deacetylase genes encode the enyzmes (chitin deacetylases [Cdas]) that deacetylate chitin, converting it to chitosan. The functional role of chitosan in the fungal cell wall is not well defined, but it is an important virulence determinant of C. neoformans Mutant strains deficient in chitosan are completely avirulent in a mouse pulmonary infection model. C. neoformans carries genes that encode three Cdas (Cda1, Cda2, and Cda3) that appear to be functionally redundant in cells grown under vegetative conditions. Here we report that C. neoformans Cda1 is the principal Cda responsible for fungal pathogenesis. Point mutations were introduced in the active site of Cda1 to generate strains in which the enzyme activity of Cda1 was abolished without perturbing either its stability or localization. When used to infect CBA/J mice, Cda1 mutant strains produced less chitosan and were attenuated for virulence. We further demonstrate that C. neoformans Cda genes are transcribed differently during a murine infection from what has been measured in vitro

IMPORTANCE Cryptococcus neoformans is unique among fungal pathogens that cause disease in a mammalian host, as it secretes a polysaccharide capsule that hinders recognition by the host to facilitate its survival and proliferation. Even though it causes serious infections in immunocompromised hosts, reports of infection in hosts that are immunocompetent are on the rise. The cell wall of a fungal pathogen, its synthesis, composition, and pathways of remodelling are attractive therapeutic targets for the development of fungicides. Chitosan, a polysaccharide in the cell wall of C. neoformans is one such target, as it is critical for pathogenesis and absent in the host. The results we present shed light on the importance of one of the chitin deacetylases that synthesize chitosan during infection and further implicates chitosan as being a critical factor for the pathogenesis of C. neoformans.

Keywords

catalytic site, cell wall localization, chitin deacetylase, chitosan, fungal virulence, metal binding site

Rights and Permissions

Copyright © 2018 Upadhya et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.

DOI of Published Version

10.1128/mBio.02087-18

Source

MBio. 2018 Nov 20;9(6). pii: mBio.02087-18. doi: 10.1128/mBio.02087-18. Link to article on publisher's site

Journal/Book/Conference Title

mBio

Related Resources

Link to Article in PubMed

PubMed ID

30459196

Creative Commons License

Creative Commons Attribution 4.0 License
This work is licensed under a Creative Commons Attribution 4.0 License.

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