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Global Reprogramming of Host Kinase Signaling in Response to Fungal Infection

Aseem Pandey1, Sheng Li Ding2, Qing-Ming Qin3

  • 1Department of Microbial Pathogenesis and Immunology, Texas A&M Health Science Center, College Station, Texas 77843, USA; Norman Borlaug Center, Texas A&M University, College Station, Texas 77843, USA; Department of Veterinary Pathobiology, College of Veterinary Medicine, Texas A&M University, College Station, Texas 77843, USA.

Cell Host & Microbe
|May 12, 2017
PubMed

Insights

Host autophagy initiation complex (AIC) activation by Cryptococcus neoformans (Cn) promotes fungal infection. Inhibiting AIC regulatory networks, like AMPKα, confers resistance to this deadly fungal pathogen.

Area of Science:

  • Host-pathogen interactions
  • Immunology
  • Molecular biology

Background:

  • Cryptococcus neoformans (Cn) is a significant fungal pathogen, with its intracellular survival crucial for virulence.
  • Host cellular mechanisms governing fungal phagocytosis and intracellular replication are not well understood.

Purpose of the Study:

  • To investigate the host's global phosphoproteomic response to Cryptococcus infection.
  • To identify host signaling pathways and proteins involved in controlling fungal intracellular parasitism.

Main Methods:

  • Global phosphoproteomic analysis of host macrophages infected with Cryptococcus neoformans.
  • Kinase activity assays and genetic manipulation (e.g., Prkaa1 deletion in monocytes).

Main Results:

  • Significant differential phosphorylation of numerous host proteins indicates global kinase signaling reprogramming upon fungal ingestion.
  • Phagocytosis of Cn activates the host autophagy initiation complex (AIC) via LKB1 and AMPKα.
  • Deletion of Prkaa1 (encoding AMPKα1) in monocytes leads to resistance against fungal colonization in mice.
  • Recruitment of AIC components to Cryptococcus-containing vacuoles (CnCVs) influences fungal trafficking and replication.

Conclusions:

  • Host AIC regulatory networks are critical for susceptibility to Cryptococcus neoformans infection.
  • Targeting AIC regulatory pathways presents a potential strategy to combat fungal intracellular parasitism.
  • This study provides a proteomic resource for understanding host-pathogen interactions in fungal infections.
Keywords:
AMPKαCryptococcus neoformansautophagy initiation complexfungal pathogenhost factorshost-pathogen interactionkinase signalingphagocytosisphosphoproteomicsproteomics

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