Identification of the fungal ligand triggering cytotoxic PRR-mediated NK cell killing of Cryptococcus and Candida

Nature Communications
Shu Shun LiChristopher H Mody

Abstract

Natural killer (NK) cells use the activating receptor NKp30 as a microbial pattern-recognition receptor to recognize, activate cytolytic pathways, and directly kill the fungi Cryptococcus neoformans and Candida albicans. However, the fungal pathogen-associated molecular pattern (PAMP) that triggers NKp30-mediated killing remains to be identified. Here we show that β-1,3-glucan, a component of the fungal cell wall, binds to NKp30. We further demonstrate that β-1,3-glucan stimulates granule convergence and polarization, as shown by live cell imaging. Through Src Family Kinase signaling, β-1,3-glucan increases expression and clustering of NKp30 at the microbial and NK cell synapse to induce perforin release for fungal cytotoxicity. Rather than blocking the interaction between fungi and NK cells, soluble β-1,3-glucan enhances fungal killing and restores defective cryptococcal killing by NK cells from HIV-positive individuals, implicating β-1,3-glucan to be both an activating ligand and a soluble PAMP that shapes NK cell host immunity.

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Citations

Jan 11, 2019·Cancers·Alexander David Barrow, Marco Colonna
Mar 2, 2019·Journal of Leukocyte Biology·Christopher H ModyShu Shun Li
Mar 3, 2019·Nature Reviews. Gastroenterology & Hepatology·Mathias L Richard, Harry Sokol
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Jan 30, 2020·The Journal of Infectious Diseases·Alessandra MaroldaOliver Kurzai
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May 28, 2019·Frontiers in Immunology·Alexander David BarrowMarco Colonna
Oct 14, 2020·Antimicrobial Agents and Chemotherapy·María Velasco-de AndrésFrancisco Lozano
Dec 6, 2020·Biochimica Et Biophysica Acta. Reviews on Cancer·Xiali QinHailong Cao
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Feb 2, 2021·FEMS Microbiology Reviews·Antonia LastBernhard Hube
Mar 6, 2021·International Journal of Biological Macromolecules·Lijuan WuChenyang Zhao
Apr 30, 2021·Frontiers in Immunology·Stéphane IsnardJean-Pierre Routy
Apr 26, 2021·Clinical Immunology : the Official Journal of the Clinical Immunology Society·Margaret R DunneThomas R Rogers
Aug 24, 2021·Frontiers in Microbiology·Binghua SunJin-Hua Li

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Methods Mentioned

BETA
atomic force spectroscopy
flow cytometry
AFM
ELISA
confocal microscopy
Atomic Force Microscopy

Software Mentioned

Volocity
ImageJ
GraphPad
JPK Data Processing
SoftWoRx
EBImage
RStudio
R
GraphPad Prism

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