Global Reprogramming of Host Kinase Signaling in Response to Fungal Infection

Aseem Pandey, Sheng Li Ding, Qing Ming Qin, Rahul Gupta, Gabriel Gomez, Furong Lin, Xuehuan Feng, Luciana Fachini da Costa, Sankar P. Chaki, Madhu Katepalli, Elizabeth D. Case, Erin J. van Schaik, Tabasum Sidiq, Omar Khalaf, Angela Arenas, Koichi S. Kobayashi, James E. Samuel, Gonzalo M. Rivera, Robert C. Alaniz, Sing Hoi SzeXiaoning Qian, William J. Brown, Allison Rice-Ficht, William K. Russell, Thomas A. Ficht, Paul de Figueiredo

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

Abstract

Cryptococcus neoformans (Cn) is a deadly fungal pathogen whose intracellular lifestyle is important for virulence. Host mechanisms controlling fungal phagocytosis and replication remain obscure. Here, we perform a global phosphoproteomic analysis of the host response to Cryptococcus infection. Our analysis reveals numerous and diverse host proteins that are differentially phosphorylated following fungal ingestion by macrophages, thereby indicating global reprogramming of host kinase signaling. Notably, phagocytosis of the pathogen activates the host autophagy initiation complex (AIC) and the upstream regulatory components LKB1 and AMPKα, which regulate autophagy induction through their kinase activities. Deletion of Prkaa1, the gene encoding AMPKα1, in monocytes results in resistance to fungal colonization of mice. Finally, the recruitment of AIC components to nascent Cryptococcus-containing vacuoles (CnCVs) regulates the intracellular trafficking and replication of the pathogen. These findings demonstrate that host AIC regulatory networks confer susceptibility to infection and establish a proteomic resource for elucidating host mechanisms that regulate fungal intracellular parasitism.

Original languageEnglish (US)
Pages (from-to)637-649.e6
JournalCell Host and Microbe
Volume21
Issue number5
DOIs
StatePublished - May 10 2017

Keywords

  • AMPKα
  • Cryptococcus neoformans
  • autophagy initiation complex
  • fungal pathogen
  • host factors
  • host-pathogen interaction
  • kinase signaling
  • phagocytosis
  • phosphoproteomics
  • proteomics

ASJC Scopus subject areas

  • Parasitology
  • Microbiology
  • Virology

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