Abstract
Respiratory viral infections, such as influenza and COVID-19, pose significant global health challenges. For patients with invasive pulmonary aspergillosis, a subsequent viral infection can lead to markedly worse clinical outcomes. Although amphotericin B (AmB) remains a cornerstone antifungal therapy, our investigation demonstrates that it paradoxically enhances the entry of influenza A virus and SARS-CoV-2. Mechanistically, AmB directly binds to and activates glucocerebrosidase, leading to ceramide accumulation and RAB7 upregulation in the late endosomes, thereby enhancing late endosomal maturation and fusion with viruses. In animal models, AmB treatment enhances viral infection in both influenza A virus–infected mice and SARS-CoV-2–challenged hamsters, resulting in accelerated weight loss, higher viral loads, and aggravated tissue damage. Consistently, in our propensity score-matched cohort of patients with culture-confirmed invasive pulmonary aspergillosis (2016–2025, n = 1,072), systemic use of AmB is associated with a significantly higher incidence of subsequent viral infection compared to other antifungals (21.55% vs. 7.76%, P = 0.003), which is further supported by multivariable analysis confirming AmB as an independent risk factor (adjusted OR = 3.45, 95% CI 2.20–5.41, P = 7.174 × 10-8). In summary, our findings provide crucial clinical evidence to guide antifungal therapy and reveal glucocerebrosidase as a potential target for developing novel antiviral strategies.
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Data availability
The mass spectrometry proteomics data generated in this study have been deposited in the ProteomeXchange Consortium under accession codes PXD064601 and PXD064637. The targeted lipidomics data are provided in Supplementary Data 1. Raw lipidomics instrument files are unavailable due to third-party intellectual property restrictions associated with the service provider (LipidALL Technologies), but the provided quantitative dataset is sufficient to interpret and validate the reported findings. Patient clinical data are not publicly available to strictly comply with data privacy laws and ethical regulations protecting patient confidentiality. However, de-identified clinical data will be made available to researchers upon reasonable request. Access requests should be submitted to the corresponding author and must include a research proposal and a signed Data Use Agreement. The corresponding author will review requests in accordance with the ethics committee’s requirements and respond within 4 weeks. All other data supporting the findings of this study are available within the article, its Supplementary Information, or the Source Data file. Source data are provided with this paper.
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Acknowledgements
We thank Dr. Linqi Zhang and Dr. Xuanling Shi from Tsinghua University for providing the plasmids CMV/R‑HA and CMV/R‑N1NA; Dr. Ning Jiao and Dr. Xiaodong Dou from Peking University for their discussions on the experimental framework; Dr. Hui Wang from Peking University People’s Hospital for her comments on the manuscript; Dr. Xiaoying Gu and Dr. Rongling Zhang from China-Japan Friendship Hospital for their suggestions on statistical analysis; Dr. Fei Zhu from Xiangya Hospital for assistance with chemical structures; and Wenqing He from China Medical University for help with figure preparation and data verification. The work was supported by the National Natural Science Foundation of China (Nos. 82241056 and 82530002 to B.C., Nos. 82170015 and 82570008 to Z.W., No. 824B2001 to W.Z.), the Chinese Academy of Medical Sciences (CAMS) Innovation Fund for Medical Sciences (Nos. CIFMS 2021-I2M-1-048 and 2024-I2M-ZD-011 to B.C.), the Excellence & Innovation Initiative of China-Japan Friendship Hospital (No. ZRZC2025-KCB03 to Z.W.), the New Cornerstone Science Foundation (to B.C.), and the Fundamental Research Funds for the Central Universities (No. APL24200210010302003 to W.Z.).
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B.C., Z.W., and P.W. conceived and supervised the study. Z.W. and M.L. designed the experimental framework. D.H., W.Z., Y.H., Y.Y., W.W., and Y.L. carried out the in vitro cellular experiments. H.L., Q.F., X.L., and Yun Z. performed the molecular biology assays. Z.X., W.T., and Ying Z. executed the animal infection studies. D.H., J.Z., X.Z., and D.P. collected and analyzed the clinical coinfection data. D.H. and W.Z. conducted data analysis and drafted the manuscript. B.C., Z.W., and W.Z. obtained funding for the study. All authors contributed to the manuscript preparation and approved the final version.
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He, D., Zuo, W., Xiang, Z. et al. Amphotericin B promotes respiratory viral entry by enhancing late endosomal maturation and fusion via glucocerebrosidase-mediated ceramide remodeling. Nat Commun (2026). https://doi.org/10.1038/s41467-026-70095-x
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DOI: https://doi.org/10.1038/s41467-026-70095-x
