Blocking immune ‘Brake’ Protein Enhances Defense Against Deadly Fungus
New research published August 4, 2025, in Frontiers in Immunology reveals that blocking a specific receptor protein, Dcir (also known as Clec4a2), significantly improves the immune systemS ability to fight off aspergillus fumigatus, a fungus that causes the potentially fatal infection aspergillosis. The study, led by researchers including Dr. Fabio Seiti Yamada Yoshikawa and Dr. Juro Saijo, identifies Dcir as a negative regulator of neutrophil activity, essentially acting as an “immune brake” that limits the body’s defense against the fungus.
Initial experiments demonstrated that mice genetically engineered to lack the Dcir receptor (Dcir-knockout mice) were markedly more effective at clearing A. fumigatus from both their lungs and spleens compared to normal, wild-type mice. To pinpoint the mechanism behind this improved immunity, the team focused on neutrophils - the primary immune cells responsible for combating this type of fungal infection. Crucially,they found that the protective benefit of Dcir deficiency was entirely dependent on the presence of these neutrophils; depleting them in the Dcir-knockout mice eliminated the enhanced fungal clearance.
Further inquiry, using neutrophils isolated from the Dcir-knockout mice in vitro, revealed that the increased protection stemmed from enhanced fungal killing via degranulation. “Neutrophils eliminate pathogens via phagocytosis, programmed cell death, oxidative stress, and degranulation,” explains Dr. Yoshikawa. Degranulation is a potent process where neutrophils release enzymes to destroy pathogens too large to engulf. The researchers observed significantly higher degranulation activity in neutrophils from Dcir-deficient mice, linking this to increased intracellular calcium mobilization and activation of the signaling protein PLCγ2.
Confirming the importance of this pathway, blocking degranulation with a drug reversed the protective effect of Dcir deficiency, both in laboratory experiments and within the mouse model. This demonstrates that Dcir’s primary role is to restrain neutrophil degranulation, thereby limiting the immune response to A. fumigatus.
“The identification of Dcir as a receptor involved in the host defense to Aspergillus fumigatus suggests that it can be a potential target for pharmacological interventions, helping in the treatment of patients affected by this infection,” notes Dr. Saijo. The findings broaden understanding of C-type lectin receptor (CLR) functions in host defense and open new avenues for improving the management of aspergillosis.
Future research will investigate whether genetic variations in the Dcir gene correlate with aspergillosis severity in humans, and identify the specific molecules on Aspergillus that Dcir recognizes. The ultimate goal is to develop improved treatment options for individuals at higher risk of fungal infection.
Source: Yoshikawa, F. S. Y., et al. (2025). The C-type lectin receptor Dcir (Clec4a2) restrains Aspergillus fumigatus elimination by limiting the degranulatory activity of neutrophils. Frontiers in Immunology.doi.org/10.3389/fimmu.2025.1639400.