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<p>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<sup>-8</sup>). In summary, our findings provide crucial clinical evidence to guide antifungal therapy and reveal glucocerebrosidase as a potential target for developing novel antiviral strategies.</p>

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Amphotericin B promotes respiratory viral entry by enhancing late endosomal maturation and fusion via glucocerebrosidase-mediated ceramide remodeling

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月9日

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  • Di He,
  • Wenting Zuo,
  • Zhiguang Xiang,
  • Jiankang Zhao,
  • Wei Tong,
  • Hongyan Li,
  • Qing Fang,
  • Xin Li,
  • Yun Zhang,
  • Ying Zheng,
  • Xianxia Zhuo,
  • Danni Pu,
  • Yijiao Huang,
  • Yingying Yuan,
  • Weiyang Wang,
  • Yameng Lu,
  • Min Luo,
  • Peigang Wang,
  • Zai Wang,
  • Bin Cao

摘要

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.