Cryptococcus neoformans Cda1 and Its Chitin Deacetylase Activity Are Required for Fungal Pathogenesis.
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2018-11
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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 vitroIMPORTANCECryptococcus 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.
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Upadhya, Rajendra, Lorina G Baker, Woei C Lam, Charles A Specht, Maureen J Donlin and Jennifer K Lodge (2018). Cryptococcus neoformans Cda1 and Its Chitin Deacetylase Activity Are Required for Fungal Pathogenesis. mBio, 9(6). pp. e02087–e02018. 10.1128/mbio.02087-18 Retrieved from https://hdl.handle.net/10161/34739.
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Rajendra Upadhya
My research focuses on fungal disease and virulence pathways in the model yeast Cryptococcus neoformans. During my initial training in Dr. Ian Willis' lab at the Albert Einstein College of Medicine, NY, I discovered a novel yeast protein that is a major regulator of RNA polymerase III transcription and consequently affects cell growth and proliferation. Later, I used this expertise to functionally characterize the genome of Toxoplasma gondii, where I created a number of genome-based methodologies to define the Toxoplasma genomeWe are primarily interested in the characterization of fungal cell walls and how they influence fungal virulence and disease. Fungal cell wall biosynthesis and architecture are good targets for creating new antifungals since the cell wall is important for the yeast but missing in the host. We revealed that cell wall chitosan is necessary for maintaining cell wall integrity in Cryptococcus and is also important for fungal virulence by applying several genomic, molecular biology, and cell biology approaches to the Cryptococcus genome. Chitosan deficient mutants are avirulent in mice due to their good clearance from the host. This efficient clearance from the host is accompanied by the activation of a protective immunological response, which protects the mice from infection with a virulent wild-type strain later on. As a result, one of our primary goals is to better understand the biogenesis of chitosan in C. neoformans and C. gattii. We discovered that C. neoformans and C. gattii have different mechanisms for controlling chitosan synthesis. Cda1 and Cda2 are both engaged in fugal pathogenesis in C. neoformans, however Cda3 is the sole one implicated in C. gattii virulence. We have observed that different growth circumstances influence the amount of chitosan in the cell wall. In mice, these chitosan-deficient wild-type strains induced protective immunity against C. neoformans infection. Interestingly, the nature of the host immune response varied considerably between chitosan deficient mutants and wild-type that have been grown under different conditions to alter their chitosan levels. These mutants and wild-type strains with varied levels of chitosan allow us to explore the mechanisms of protective immunity evoked by C. neoformans cda1Δ2Δ3Δ.
Jennifer Lodge
Jennifer Lodge, Ph.D., a professor of molecular genetics and microbiology, is Duke’s vice president for Research & Innovation.
As the university’s chief research and innovation officer, Lodge leads oversight of Duke’s $1.2 billion annual research portfolio, including grants administration, ethical practices and commercialization. Lodge works with campus and medical center research staff, faculty and trainees, and is a key figure in Duke’s connection with external partners.
Before coming to Duke in January 2022, Lodge served as vice chancellor for research and senior associate dean for research for the School of Medicine at Washington University in St. Louis (WUSTL). There, she was responsible for WUSTL’s research development, ethics, education, compliance and research administration systems, and earned a reputation for encouraging innovation and entrepreneurship.
Lodge’s own research is on the human pathogenic fungus Cryptococcus neoformans. Her lab has been funded continuously by NIH for more than two decades, with as many as three prestigious R01 grants at one time. Her lab in the Duke University School of Medicine continues to explore the biochemical processes by which this fungus builds its cell walls. Such knowledge could lead to new antifungal therapies and vaccines.
Lodge is a fellow of the American Academy of Microbiology, the American Association for the Advancement of Science (AAAS) and the National Academy of Inventors. She is also the former chair of the Group on Research at the American Association of Medical Colleges (AAMC).
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