Hyphal Als proteins act as CR3 ligands to promote immune responses against Candida albicans

Tingting Zhou, Norma V. Solis, Michaela Marshall, Qing Yao, Rachel Garleb, Mengli Yang, Eric Pearlman, Scott G. Filler and Haoping Liu ()
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Tingting Zhou: University of California
Norma V. Solis: Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center
Michaela Marshall: University of California
Qing Yao: California Institute of Technology
Rachel Garleb: University of California
Mengli Yang: University of California
Eric Pearlman: University of California
Scott G. Filler: Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center
Haoping Liu: University of California

Nature Communications, 2024, vol. 15, issue 1, 1-13

Abstract: Abstract Patients with decreased levels of CD18 (β2 integrins) suffer from life-threatening bacterial and fungal infections. CD11b, the α subunit of integrin CR3 (CD11b/CD18, αMβ2), is essential for mice to fight against systemic Candida albicans infections. Live elongating C. albicans activates CR3 in immune cells. However, the hyphal ligands that activate CR3 are not well defined. Here, we discovered that the C. albicans Als family proteins are recognized by the I domain of CD11b in macrophages. This recognition synergizes with the β-glucan-bound lectin-like domain to activate CR3, thereby promoting Syk signaling and inflammasome activation. Dectin-2 activation serves as the “outside-in signaling” for CR3 activation at the entry site of incompletely sealed phagosomes, where a thick cuff of F-actin forms to strengthen the local interaction. In vitro, CD18 partially contributes to IL-1β release from dendritic cells induced by purified hyphal Als3. In vivo, Als3 is vital for C. albicans clearance in mouse kidneys. These findings uncover a novel family of ligands for the CR3 I domain that promotes fungal clearance.

Date: 2024
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DOI: 10.1038/s41467-024-48093-8

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