Cryptococcus neoformans Cda1 and Its Chitin Deacetylase Activity Are Required for Fungal Pathogenesis
Rajendra Upadhya,Lorina G. Baker,Woei C. Lam,Charles A. Specht,Maureen J. Donlin,Jennifer K. Lodge +5 more
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TLDR
Chitin is an essential component of the cell wall of Cryptococcus neoformans conferring structural rigidity and integrity under diverse environmental conditions and further implicates chitosan as being a critical factor for the pathogenesis of C. neo formans.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. IMPORTANCECryptococcus 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.read more
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Treatment strategies for cryptococcal infection: challenges, advances and future outlook
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Deacetylation of chitin oligomers increases virulence in soil-borne fungal pathogens.
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Cryptococcus gattii VGIII isolates causing infections in HIV/AIDS patients in Southern California: identification of the local environmental source as arboreal
Deborah J. Springer,R.B. Billmyre,Elan E. Filler,Kerstin Voelz,R Pursall,Piotr A. Mieczkowski,Robert A. Larsen,RC May,Scott G. Filler,Joseph Heitman,Fred S. Dietrich +10 more
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TL;DR: In this article, a microarray analysis was performed to identify genes upregulated in mature infection cushions (IC), and the expression data were validated by RT-qPCR analysis performed in vitro and in planta, proteomic analysis of the IC secretome.
References
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Action of Microbial Chitinases on Chitosan with Different Degrees of Deacetylation
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Induction of T helper type 1 responses by a polysaccharide deacetylase from Cryptococcus neoformans.
Carmelo Biondo,Concetta Beninati,Mauro Bombaci,Luciano Messina,Giuseppe Mancuso,Angelina Midiri,Roberta Galbo,Giuseppe Teti +7 more
TL;DR: A 25-kDa cryptococcal deacetylase (d25) was found to induce cell proliferation, as well as secretion of interleukin 2 and gamma interferon, but not interleucin 4, in spleen cells from d25-immunized or Cryptococcus neoformans-infected mice.