Identiﬁcation of the fungal ligand triggering
cytotoxic PRR-mediated NK cell killing of
Cryptococcus and Candida
Shu Shun Li
, Henry Ogbomo
, Michael K. Mansour
, Richard F. Xiang
, Lian Szabo
, Fay Munro
, Roy A. Mariuzza
, Matthias Amrein
, Jatin M. Vyas
, Stephen M. Robbins
Christopher H. Mody
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.
Department of Microbiology, Immunology and Infectious Diseases, University of Calgary, Calgary T2N 4N1, Canada.
The Calvin, Phoebe and Joan Snyder
Institute for Chronic Diseases, University of Calgary, Calgary T2N 4N1, Canada.
Department of Medicine Division of Infectious Diseases, Massachusetts
General Hospital, Boston, MA 02114, USA.
Department of Medicine, University of Calgary, Calgary T2N 4N1, Canada.
Department of Cell Biology and
Anatomy, University of Calgary, Calgary T2N 4N1, Canada.
Department of Cell Biology & Molecular Genetics, University of Maryland, College Park, MD
Department of Biochemistry and Molecular Biology, University of Calgary, Calgary T2N 4N1, Canada.
Southern Alberta Cancer Research
Institute, University of Calgary, Calgary T2N 4N1, Canada. Shu Shun Li and Henry Ogbomo contributed equally to this work Correspondence and requests for
materials should be addressed to C.H.M. (email: email@example.com)