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

Tingting Zhou1, Norma V Solis2, Michaela Marshall3

  • 1Department of Biological Chemistry, University of California, Irvine, CA, USA.

Nature Communications
|May 9, 2024
PubMed

Insights

Researchers discovered that Candida albicans Als proteins activate immune cell CR3 receptors, crucial for fighting fungal infections. This finding reveals new targets for enhancing immune response against C. albicans.

Area of Science:

  • Immunology
  • Microbiology
  • Cell Biology

Background:

  • Decreased CD18 (β2 integrins) levels lead to severe bacterial and fungal infections.
  • CD11b, part of integrin CR3 (CD11b/CD18), is vital for combating systemic Candida albicans infections in mice.
  • While live C. albicans activates CR3, the specific hyphal ligands remain unidentified.

Purpose of the Study:

  • To identify the hyphal ligands of Candida albicans that activate the CR3 receptor in immune cells.
  • To elucidate the mechanism by which CR3 activation by C. albicans contributes to immune responses.
  • To investigate the role of CD11b/CD18 and Als3 in fungal clearance.

Main Methods:

  • Investigated the interaction between C. albicans Als family proteins and the CD11b I domain in macrophages.
  • Assessed CR3 activation, Syk signaling, and inflammasome activation.
  • Utilized Dectin-2 activation as an indicator of outside-in signaling.
  • Conducted in vitro experiments with dendritic cells and purified hyphal Als3.
  • Evaluated the in vivo role of Als3 in C. albicans clearance in mouse kidneys.

Main Results:

  • Discovered that C. albicans Als proteins are recognized by the CD11b I domain on macrophages.
  • CR3 activation by Als proteins synergizes with β-glucan binding, promoting Syk signaling and inflammasome activation.
  • Dectin-2 activation facilitates CR3 activation at phagosome entry sites, involving F-actin formation.
  • In vitro, CD18 partially mediates IL-1β release induced by hyphal Als3.
  • In vivo, Als3 is essential for C. albicans clearance in mouse kidneys.

Conclusions:

  • Identified Als family proteins as novel ligands for the CR3 I domain.
  • Demonstrated a new mechanism of CR3 activation involving Als proteins and Dectin-2 signaling.
  • Highlighted the critical role of Als3 in host defense against C. albicans infection.
  • Uncovered a pathway that promotes fungal clearance, offering potential therapeutic targets.

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