title: Mathematical modeling of pathogenicity of Cryptococcus neoformans.
abstract: Cryptococcus neoformans (Cn) is the most common cause of fungal meningitis worldwide. In infected patients, growth of the fungus can occur within the phagolysosome of phagocytic cells, especially in non-activated macrophages of immunocompromised subjects. Since this environment is characteristically acidic, Cn must adapt to low pH to survive and efficiently cause disease. In the present work, we designed, tested, and experimentally validated a theoretical model of the sphingolipid biochemical pathway in Cn under acidic conditions. Simulations of metabolic fluxes and enzyme deletions or downregulation led to predictions that show good agreement with experimental results generated post hoc and reconcile intuitively puzzling results. This study demonstrates how biochemical modeling can yield testable predictions and aid our understanding of fungal pathogenesis through the design and computational simulation of hypothetical experiments.
authors.affiliation: Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC, USA.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Garcia
authors.forename: John
authors.initials: J
authors.lastname: Shea
authors.forename: Fernando
authors.initials: F
authors.lastname: Alvarez-Vasquez
authors.forename: Asfia
authors.initials: A
authors.lastname: Qureshi
authors.forename: Chiara
authors.initials: C
authors.lastname: Luberto
authors.forename: Eberhard O
authors.initials: EO
authors.lastname: Voit
authors.forename: Maurizio
authors.initials: M
authors.lastname: Del Poeta
mesh_terms: D002518:Ceramides / Q000378:metabolism; D019295:Computational Biology / Q000379:methods; D003455:Cryptococcus neoformans / Q000378:metabolism* / Q000472:pathogenicity*; D003593:Cytoplasm / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism; D006056:Golgi Apparatus / Q000378:metabolism; D006863:Hydrogen-Ion Concentration; D008928:Mitochondria / Q000378:metabolism; D008954:Models, Biological; D008962:Models, Theoretical; D013107:Sphingolipids / Q000378:metabolism; D049490:Systems Biology; D014774:Virulence
chemical_list: D002518:Ceramides; D013107:Sphingolipids