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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TL;DR: Wang et al. as discussed by the authors summarized the latest knowledge of CDAs, especially for heterologous expression systems and directed evolution strategies, which may contribute to the industrial production and future application of chitin deacetylases.
References
More filters
Journal ArticleDOI
T-Coffee: A novel method for fast and accurate multiple sequence alignment.
TL;DR: A new method for multiple sequence alignment that provides a dramatic improvement in accuracy with a modest sacrifice in speed as compared to the most commonly used alternatives but avoids the most serious pitfalls caused by the greedy nature of this algorithm.
Journal ArticleDOI
Estimation of the current global burden of cryptococcal meningitis among persons living with HIV/AIDS.
Benjamin J. Park,Kathleen Wannemuehler,Barbara J. Marston,Nelesh P. Govender,Peter G. Pappas,Tom Chiller +5 more
TL;DR: The first attempt to estimate the global burden of cryptococcal meningitis finds the number of cases and deaths to be very high, with most occurring in sub-Saharan Africa.
Journal ArticleDOI
Global burden of disease of HIV-associated cryptococcal meningitis: An updated analysis
Radha Rajasingham,Rachel M. Smith,Benjamin J. Park,Joseph N Jarvis,Nelesh P. Govender,Nelesh P. Govender,Nelesh P. Govender,Tom Chiller,David W. Denning,Angela Loyse,David R. Boulware +10 more
TL;DR: The analysis highlights the substantial ongoing burden of HIV-associated cryptococcal disease, primarily in sub-Saharan Africa, which is a metric of HIV treatment programme failure; timely HIV testing and rapid linkage to care remain an urgent priority.
Journal ArticleDOI
T-Coffee: a web server for the multiple sequence alignment of protein and RNA sequences using structural information and homology extension
Paolo Di Tommaso,Sébastien Moretti,Ioannis Xenarios,Miquel Orobitg,Alberto Montanyola,Jia-Ming Chang,Jean-François Taly,Cedric Notredame +7 more
TL;DR: A new interface for T-Coffee, a consistency-based multiple sequence alignment program, is introduced that provides an easy and intuitive access to the most popular functionality of the package.
Journal ArticleDOI
A rare genotype of Cryptococcus gattii caused the cryptococcosis outbreak on Vancouver Island (British Columbia, Canada)
Sarah E. Kidd,Ferry Hagen,R L Tscharke,M Huynh,Karen H Bartlett,Murray Fyfe,Laura MacDougall,Teun Boekhout,Kyung J. Kwon-Chung,Wieland Meyer +9 more
TL;DR: The emergence of this usually tropical pathogen on Vancouver Island highlights the changing distribution of this genotype and emphasizes the importance of an ongoing collaborative effort to monitor the global epidemiology of this yeast.