Mathematical modeling of pathogenicity of Cryptococcus neoformans.
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.
Garcia
Jacqueline
J
Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC, USA.
Shea
John
J
Alvarez-Vasquez
Fernando
F
Qureshi
Asfia
A
Luberto
Chiara
C
Voit
Eberhard O
EO
Del Poeta
Maurizio
M
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
D002518:Ceramides; D013107:Sphingolipids