title: PI3K signaling of autophagy is required for starvation tolerance and virulenceof Cryptococcus neoformans.
abstract: Autophagy is a process by which cells recycle cytoplasm and defective organelles during stress situations such as nutrient starvation. It can also be used by host cells as an immune defense mechanism to eliminate infectious pathogens. Here we describe the use of autophagy as a survival mechanism and virulence-associated trait by the human fungal pathogen Cryptococcus neoformans. We report that a mutant form of C. neoformans lacking the Vps34 PI3K (vps34Delta), which is known to be involved in autophagy in ascomycete yeast, was defective in the formation of autophagy-related 8-labeled (Atg8-labeled) vesicles and showed a dramatic attenuation in virulence in mouse models of infection. In addition, autophagic vesicles were observed in WT but not vps34Delta cells after phagocytosis by a murine macrophage cell line, and Atg8 expression was exhibited in WT C. neoformans during human infection of brain. To dissect the contribution of defective autophagy in vps34Delta C. neoformans during pathogenesis, a strain of C. neoformans in which Atg8 expression was knocked down by RNA interference was constructed and these fungi also demonstrated markedly attenuated virulence in a mouse model of infection. These results demonstrated PI3K signaling and autophagy as a virulence-associated trait and survival mechanism during infection with a fungal pathogen. Moreover, the data show that molecular dissection of such pathogen stress-response pathways may identify new approaches for chemotherapeutic interventions.
authors.affiliation: Section of Infectious Diseases, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois 60612, USA.
authors.forename: Guowu
authors.initials: G
authors.lastname: Hu
authors.forename: Moshe
authors.initials: M
authors.lastname: Hacham
authors.forename: Scott R
authors.initials: SR
authors.lastname: Waterman
authors.forename: John
authors.initials: J
authors.lastname: Panepinto
authors.forename: Soowan
authors.initials: S
authors.lastname: Shin
authors.forename: Xiaoguang
authors.initials: X
authors.lastname: Liu
authors.forename: Jack
authors.initials: J
authors.lastname: Gibbons
authors.forename: Tibor
authors.initials: T
authors.lastname: Valyi-Nagy
authors.forename: Keisuke
authors.initials: K
authors.lastname: Obara
authors.forename: H Ari
authors.initials: HA
authors.lastname: Jaffe
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Ohsumi
authors.forename: Peter R
authors.initials: PR
authors.lastname: Williamson
mesh_terms: D000818:Animals; D001343:Autophagy; D002460:Cell Line; D003455:Cryptococcus neoformans / Q000472:pathogenicity*; D008264:Macrophages / Q000276:immunology; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D014774:Virulence
chemical_list: D019869:Phosphatidylinositol 3-Kinases