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.