The Role of Cell Receptors in Modulating Immune Defense Against Fungal Infections

People are constantly exposed to a vast number of fungal spores daily, including potentially harmful ones like Aspergillus fumigatus. Typically, the immune system efficiently neutralizes these spores, preventing illness. However, individuals with weakened immune systems—due to conditions such as cancer, organ transplants, or chronic diseases—are at increased risk of developing serious fungal infections like aspergillosis.

Understanding the immune mechanisms involved in combating fungal pathogens is crucial for developing effective treatments. A key area of research focuses on C-type lectin receptors (CLRs), a family of proteins that serve as sensors to detect and initiate immune responses against microbial invaders. Most CLRs function by activating immune cells, similar to pressing a gas pedal, leading to a robust attack on the pathogen. In contrast, the dendritic cell immunoreceptor (Dcir) acts like a brake, providing a regulatory function that limits excessive inflammation.

Recent studies by researchers at Chiba University, Japan, led by Associate Professor Shinobu Saijo and Assistant Professor Fabio Seiti Yamada Yoshikawa, have shed light on Dcir’s specific role during fungal infections. Published in the journal Frontiers in Immunology on August 4, 2025, this research used mouse models to explore how Dcir influences the immune response to Aspergillus fumigatus.

The experiments demonstrated that mice lacking Dcir (Dcir-knockout mice) could clear fungal infections more effectively from their lungs and spleen than normal mice. This improved clearance was found to depend on neutrophils, a type of immune cell critically involved in fighting fungal pathogens. When neutrophils were depleted, the enhanced protection seen in Dcir-deficient mice disappeared, confirming their key role.

Further in vitro analyses revealed that neutrophils from Dcir-knockout mice exhibited increased ability to kill fungal hyphae—the filamentous growth form of fungi—through a process known as degranulation. This process involves releasing enzymes that can destroy large pathogens that cannot be ingested. The heightened degranulation activity was linked to increased intracellular calcium levels and the activation of the signaling protein PLCγ2. When the degranulation pathway was blocked pharmacologically, the enhanced antifungal effect was lost, both in laboratory tests and in live mice.

These findings suggest that Dcir acts as a negative regulator, essentially applying brakes to neutrophil degranulation and consequently limiting the immune response against A. fumigatus. By modulating this receptor, scientists could potentially enhance the body’s natural ability to fight fungal infections.

Dr. Saijo emphasized the importance of these discoveries, stating that targeting Dcir could offer new therapeutic strategies for treating aspergillosis. Future research aims to investigate whether genetic differences in the Dcir gene influence susceptibility to fungal infections in humans and to identify specific molecules on the fungus recognized by Dcir. Ultimately, this work might lead to improved treatments for individuals at high risk of fungal disease.

Understanding how immune regulators like Dcir modulate host defenses opens new avenues for improving antifungal therapies and managing immune responses more effectively.