Dalia Sheta, Zeinab Mokhtari, Marlene Strobel, Yidong Yu, Pia Wittmann, Zahraa Abboud, Michael Kern, Jorge Amich, Nora Trinks, Sebastian Reinhard, Sina Hirsch, Ivan Aleksić, Vasileios Drosos, Eslam S. Ibrahim, Kerstin Guenther, Knut Ohlsen, Martin Fraunholz, Christian Stigloher, A. M. López, Sascha Schaeuble, Natalie Nieuwenhuizen, Tobias Koehler, Oliver Kurzai, Antoine-Emmanuel Saliba, Panagiota Arampatzi, Alexander J. Westermann, Paul Jordan, Oliver Werz, Juergen Loeffler, Gianni Panagiotou, Hermann Einsele, Markus Sauer, Katrin Heinze, Manfred B. Lutz, Heike M. Hermanns, Ulrich Terpitz, Andreas Beilhack
bioRxiv · 2026 · Preprint
Invasive pulmonary aspergillosis (IPA) is a life-threatening complication in immunocompromised individuals, including recipients of allogeneic hematopoietic cell transplantation (allo-HCT). While systemic neutropenia is traditionally considered the primary risk factor for IPA, we demonstrate that tissue-resident alveolar macrophages (AMs), rather than recruited neutrophils, dictate survival during the critical early window after transplantation. Utilizing an ultra-low dose Aspergillus fumigatus infection model that mimics physiological exposure, we identify alveolar macrophages (AMs) as key players in pulmonary antifungal defense. In immunocompromised mice, AMs conferred protection against lethal invasive aspergillosis by day 6, but not day 4 post-allo-HCT. To enhance AM function at the earlier time point, we tested cytokine-based interventions and show that M-CSF, but not IL-34, which both bind to the CSF-1 receptor, promotes migratory activity, phagolysosomal function and fungal killing in both mouse and human primary tissue-resident AMs. In allo-HCT recipient mice, M-CSF treatment preserved lung tissue integrity, suppressed pro-inflammatory cytokines, and protected mice from lethal invasive aspergillosis. The M-CSF-driven protective effect was abrogated upon AM depletion. Our findings demonstrate a critical role of tissue-resident AMs in pulmonary antifungal immunity and suggest that therapeutic modulation of AM activity via M-CSF may offer a promising strategy to combat severe fungal infections in immunocompromised patients.
@article{sheta_mcsf_2026,
title = {M-CSF-stimulated alveolar macrophages safeguard from invasive aspergillosis},
doi = {10.64898/2026.07.06.736478},
abstract = {Invasive pulmonary aspergillosis (IPA) is a life-threatening complication in immunocompromised individuals, including recipients of allogeneic hematopoietic cell transplantation (allo-HCT). While systemic neutropenia is traditionally considered the primary risk factor for IPA, we demonstrate that tissue-resident alveolar macrophages (AMs), rather than recruited neutrophils, dictate survival during the critical early window after transplantation. Utilizing an ultra-low dose Aspergillus fumigatus infection model that mimics physiological exposure, we identify alveolar macrophages (AMs) as key players in pulmonary antifungal defense. In immunocompromised mice, AMs conferred protection against lethal invasive aspergillosis by day 6, but not day 4 post-allo-HCT. To enhance AM function at the earlier time point, we tested cytokine-based interventions and show that M-CSF, but not IL-34, which both bind to the CSF-1 receptor, promotes migratory activity, phagolysosomal function and fungal killing in both mouse and human primary tissue-resident AMs. In allo-HCT recipient mice, M-CSF treatment preserved lung tissue integrity, suppressed pro-inflammatory cytokines, and protected mice from lethal invasive aspergillosis. The M-CSF-driven protective effect was abrogated upon AM depletion. Our findings demonstrate a critical role of tissue-resident AMs in pulmonary antifungal immunity and suggest that therapeutic modulation of AM activity via M-CSF may offer a promising strategy to combat severe fungal infections in immunocompromised patients.},
journal = {bioRxiv},
author = {Sheta, Dalia and Mokhtari, Zeinab and Strobel, Marlene and Yu, Yidong and Wittmann, Pia and Abboud, Zahraa and Kern, Michael and Amich, Jorge and Trinks, Nora and Reinhard, Sebastian and Hirsch, Sina and Aleksić, Ivan and Drosos, Vasileios and Ibrahim, Eslam S. and Guenther, Kerstin and Ohlsen, Knut and Fraunholz, Martin and Stigloher, Christian and López, A. M. and Schaeuble, Sascha and Nieuwenhuizen, Natalie and Koehler, Tobias and Kurzai, Oliver and Saliba, Antoine-Emmanuel and Arampatzi, Panagiota and Westermann, Alexander J. and Jordan, Paul and Werz, Oliver and Loeffler, Juergen and Panagiotou, Gianni and Einsele, Hermann and Sauer, Markus and Heinze, Katrin and Lutz, Manfred B. and Hermanns, Heike M. and Terpitz, Ulrich and Beilhack, Andreas},
year = {2026},
pubstate = {preprint},
}