Impact of CD11c + Cells in Conducting Airway Lumen on Aspergillus fumigatus Conidia Deposition in Neutropenic Mice

Mariia Valentinovna Pavelchenko^1,2Svyatoslav Sergeevich Shalyapin^1,3Sergey Alexandrovich Portnov^1,3Andrey Bogorodskiy²Elena Bolkhovitina¹Vitalii Pavlovich Shevchenko⁴Alexander M. Sapozhnikov¹Valentin Ivanovich Borshchevskiy²Marina Alexandrovna Shevchenko^1*

• ¹Institute of Bioorganic Chemistry (RAS), Moscow, Moscow Oblast, Russia
• ²Moscow Institute of Physics and Technology, Dolgoprudny, Moscow Oblast, Russia
• ³National Research Nuclear University MEPhI, Moscow, Moscow Oblast, Russia
• ⁴Tikhonov Moscow Institute of Electronics and Mathematics, National Research University Higher School of Economics, Moscow, Moscow Oblast, Russia

Inhaled conidia of opportunistic fungi Aspergillus fumigatus settle in the airway mucosa and alveolar spaces, and different immune cells typically provide crucial defense against fungal germination. But for immunocompromised patients, the lack of sufficient proinflammatory immune response often leads to invasive aspergillosis, with current treatments limited by insufficient understanding of precise conidial distribution patterns in the airways. Therefore, we employed advanced imaging techniques, including immunohistochemistry, optical clearing, and confocal laser-scanning microscopy, to map A. fumigatus conidial distribution in both immunocompetent and neutropenic mouse airways. We developed a 3D airway model distinguishing the main bronchus, intermediate bronchi, and terminal bronchioles, enabling quantitative analysis of conidial location. Additionally, we analyzed interactions of CD11c+ cells with conidia in the conducting airway mucosa. Our findings revealed that while the majority of conidia reached the alveolar space in both groups, neutropenic mice showed significantly higher conidial concentrations in bronchial branches, particularly in the main bronchus, compared to immunocompetent mice. Simultaneously, in conducting airway mucosa of neutropenic mice, CD11+ cells ingested an elevated number of conidia compared to immunocompetent mice. Thus, detailed mapping of conidial distribution patterns provides crucial insights into spatial aspects of antifungal treatment in neutropenic patients. The enhanced contribution of CD11c+ cells to conidia internalization in the conducting airway mucosa of neutropenic mice demonstrated in the present study, emphasizes the potential of these cells in developing more effective, cell-targeted antifungal treatments.