Every year, a total of around 2 million people worldwide develop Invasive pulmonary aspergillosis (IPA), with a crude annual mortality rate of 85.2% as published in 2024 (D. Denning)¹. Aspergillus fumigatus, the causative agent itself usually stays in its air-borne, spore-forming form and transforms into a life-threatening pathogen, particularly in immuno-compromised patients. On the other hand, natural killer (NK) cells serve as the initial line of defense in the human body. The function of NK cells against A. fumigatus in the human body remains a puzzle. We have previously reported that NK cells establish a stable immunological synapse with A. fumigatus, and CD56 is a pathogen recognition receptor on human NK cells². CD226 (DNAM-1), a cell-surface glycoprotein, plays vital roles in several diseases ranging from autoimmune diseases to cancer to viral infections. Additionally, it has been published that CD226 serves as an activating receptor for NK cells and is involved in the immunological synapse (IS) formation. However, it is not clear yet if this is only true for NK-cell-cancer-cell interaction or also in the NK-cell-fungus interaction. In our research, we are working to unlock the mechanism by visualizing the interface of CD226- A. fumigatus interaction. Our findings have already indicated that, unlike CD56, CD226 does not significantly relocate at the interaction site. Furthermore, our results suggest that the interaction between CD226 and A. fumigatus occurs through a direct mechanism. A CRISPR-Cas-engineered knock-out CD226 NK cells is assisting us to envisage the significance of CD226 in fungal infections.

References:
1. Denning, W. D., Global incidence and mortality of severe fungal disease. Lancet Infect Dis, (2024). https://doi.org/10.1016/S1473-3099(23)00692-8
2. Ziegler, S., Weiss, E., Schmitt, AL. et al. CD56 Is a Pathogen Recognition Receptor on Human Natural Killer Cells. Sci Rep 7, 6138 (2017). https://doi.org/10.1038/s41598-017-06238-4