Blocking immune ‘Brake’ Protein Enhances Defense Againstโ Deadly โคFungus
Newโ research published August โ4, 2025, in Frontiers in Immunology โ reveals that โblockingโฃ a specific receptor protein, Dcir (also known as Clec4a2), significantly improves the immune systemS ability to fight offโ aspergillus fumigatus, a fungus that โcauses 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 โbody’s defense against the fungus.
Initial experiments demonstrated that mice genetically engineered to lackโค 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. โขTo pinpoint the โmechanismโฃ behind this improved immunity, the team focused on neutrophils โ- the primary immune cells responsible for combating this type of fungal โinfection.โฃ Crucially,they โfound that the protective benefit of Dcir deficiency was entirely dependent on the presence of these neutrophils; depleting them in the Dcir-knockout mice eliminated โฃthe enhanced fungal clearance.
Further โคinquiry, using neutrophils isolatedโข from the Dcir-knockout mice in vitro, revealed that the increased protection stemmed from enhanced fungal killing via degranulation. “Neutrophils eliminate pathogens viaโค phagocytosis, programmed cell death, oxidative stress, and degranulation,” explains Dr. Yoshikawa. Degranulation isโ a potent process where neutrophils release enzymes to destroy pathogens too large to engulf. The researchersโข observed significantly higher degranulation activity in neutrophils from Dcir-deficientโ mice, linking this to increased โintracellular calciumโฃ mobilization and โactivation of the signaling protein PLCฮณ2.
Confirming the importance of this โpathway, blocking โคdegranulation with a drugโข reversed the protective effect of Dcir deficiency, both in laboratory experiments and within the mouse model. This โขdemonstrates that Dcir’sโฃ primary role is to restrain neutrophil degranulation, therebyโ limiting the immune responseโค to A.โ fumigatus.
“The identification of Dcir as aโ receptor involved in the host defense to Aspergillus fumigatus suggests โthat it can beโ aโค 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 defenseโ and open new โavenues โfor improving the management ofโค aspergillosis.
Future research willโข investigate whether genetic variations โin the Dcir gene correlate with aspergillosis severity in humans, โand identifyโค the specific molecules on Aspergillus โthat Dcir recognizes. The โultimate โgoal is to develop improved treatment options for individuals at higher risk of fungal infection.
Source: Yoshikawa, F. S. Y.,โ et al. (2025). The C-typeโ lectin receptor Dcir (Clec4a2) restrains Aspergillus fumigatus eliminationโ by limiting the degranulatory โactivity of neutrophils. Frontiers in Immunology.doi.org/10.3389/fimmu.2025.1639400.
