Cryptococcus neoformans Cda1 and Its Chitin Deacetylase Activity Are Required for Fungal Pathogenesis

• Published in: mBio Vol. 9; no. 6
• Main Authors: Upadhya, Rajendra, Baker, Lorina G, Lam, Woei C, Specht, Charles A, Donlin, Maureen J, Lodge, Jennifer K
• Format: Journal Article
• Language: English
• Published: United States American Society for Microbiology 20.11.2018
• Subjects: Amidohydrolases - genetics; Amidohydrolases - metabolism; Animals; catalytic site; cell wall localization; Chitin - metabolism; chitin deacetylase; chitosan; Cryptococcosis - microbiology; Cryptococcus neoformans - enzymology; Cryptococcus neoformans - genetics; Cryptococcus neoformans - pathogenicity; Female; Fungal Proteins - genetics; Fungal Proteins - metabolism; fungal virulence; Gene Expression Regulation, Fungal; Host-Microbe Biology; metal binding site; Mice; Mice, Inbred CBA; Point Mutation; Virulence; Virulence Factors - genetics; chitin deacetylase; chitosan; cell wall localization; fungal virulence; catalytic site; metal binding site
• ISSN: 2161-2129; 2150-7511
• DOI: 10.1128/mbio.02087-18

Chitin is an essential component of the cell wall of 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 Mutant strains deficient in chitosan are completely avirulent in a mouse pulmonary infection model. 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 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 Cda genes are transcribed differently during a murine infection from what has been measured 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 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 .