title: Cryptococcus neoformans requires a functional glycolytic pathway for disease but not persistence in the host.
abstract: Cryptococcus neoformans is an important fungal pathogen of immunocompromised individuals, with a close relative, Cryptococcus gattii, emerging as a serious threat for the immunocompetent. During initial infection, C. neoformans colonizes the airspaces of the lungs, resulting in pneumonia, and subsequently migrates to the central nervous system (CNS). We sought to understand fungal carbon utilization during colonization of these fundamentally different niches within the host, in particular the roles of gluconeogenesis and glycolysis. We created mutants at key points in the gluconeogenesis/glycolysis metabolic pathways that are restricted for growth on lactate and glucose, respectively. A phosphoenolpyruvate carboxykinase mutant (the pck1Δ mutant), blocked for entry of 2- and 3-carbon substrates into gluconeogenesis and attenuated for virulence in a murine inhalation model, showed wild-type (WT) persistence in a rabbit cerebrospinal fluid (CSF) model of cryptococcosis. Conversely, both the pyruvate kinase (pyk1Δ) and the hexose kinase I and II (hxk1Δ/hxk2Δ) mutants, which show impaired glucose utilization, exhibited severely attenuated virulence in the murine inhalation model of cryptococcosis and decreased persistence in the CNS in both the rabbit CSF and the murine inhalation models while displaying adequate persistence in the lungs of mice. These data suggest that glucose utilization is critical for virulence of C. neoformans and persistence of the yeast in the CNS.
authors.affiliation: Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Price
authors.forename: Marisol
authors.initials: M
authors.lastname: Betancourt-Quiroz
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Price
authors.forename: Dena L
authors.initials: DL
authors.lastname: Toffaletti
authors.forename: Haily
authors.initials: H
authors.lastname: Vora
authors.forename: Guanggan
authors.initials: G
authors.lastname: Hu
authors.forename: James W
authors.initials: JW
authors.lastname: Kronstad
authors.forename: John R
authors.initials: JR
authors.lastname: Perfect
mesh_terms: D000818:Animals; D003453:Cryptococcosis / Q000382:microbiology*; D003455:Cryptococcus neoformans / Q000378:metabolism* / Q000472:pathogenicity*; D004195:Disease Models, Animal; D005260:Female; D017353:Gene Deletion; D005800:Genes, Fungal; D005943:Gluconeogenesis; D005947:Glucose / Q000378:metabolism; D006019:Glycolysis; D006801:Humans; D019344:Lactic Acid / Q000378:metabolism; D008297:Male; D051379:Mice; D011817:Rabbits; D012376:Rodent Diseases / Q000382:microbiology / Q000473:pathology; D014774:Virulence; D037521:Virulence Factors / Q000235:genetics
chemical_list: D037521:Virulence Factors; D019344:Lactic Acid; D005947:Glucose