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PMID: 18259613 Published · ppublish English Journal Article Research Support, N.I.H., Extramural

PI3K signaling of autophagy is required for starvation tolerance and virulenceof Cryptococcus neoformans.

The Journal of clinical investigation ·Vol. 118 ·No. 3 ·2008-03-00 ·Pages 1186-97

Hu G, Hacham M, Waterman SR, Panepinto J, Shin S, Liu X, Gibbons J, Valyi-Nagy T, Obara K, Jaffe HA, Ohsumi Y, Williamson PR

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.

MeSH Terms
Animals Autophagy Cell Line Cryptococcus neoformans/pathogenicity Macrophages/immunology Mice Phosphatidylinositol 3-Kinases/physiology Signal Transduction/physiology Virulence
Chemicals
Phosphatidylinositol 3-Kinases
Authors & Affiliations
12 authors, click to expand affiliations / ORCID
Hu Guowu
Section of Infectious Diseases, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois 60612, USA.
Hacham Moshe
Waterman Scott R
Panepinto John
Shin Soowan
Liu Xiaoguang
Gibbons Jack
Valyi-Nagy Tibor
Obara Keisuke
Jaffe H Ari
Ohsumi Yoshinori
Williamson Peter R
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Article Info
Journal
The Journal of clinical investigation
Abbr.
J Clin Invest
ISSN
0021-9738
DOI
10.1172/JCI32053
Published
2008-03-00
Pages
1186-97
Language
English
Region
United States
NLM ID
7802877
PMCID
PMC2230655
Subset
IM
Grants
NIAID NIH HHS · AI45995 · United States
NIAID NIH HHS · R01 AI049371 · United States
NIAID NIH HHS · R01 AI045995 · United States
NIAID NIH HHS · AI47087 · United States
NIAID NIH HHS · AI49371 · United States
External Links
PubMed source DOI: 10.1172/JCI32053 PMC Full Text View journal details
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