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

Summary

This multi-scale study shows that amphotericin B directly activates glucocerebrosidase, increases ceramide, and accelerates late endosomal maturation/fusion, thereby enhancing influenza and SARS-CoV-2 entry. Concordant animal and propensity-matched clinical data indicate higher subsequent viral infection risk in amphotericin-treated invasive aspergillosis patients.

Key Findings

• Amphotericin B directly binds to and activates glucocerebrosidase, increasing ceramide and RAB7-driven late endosomal maturation/fusion to enhance influenza and SARS-CoV-2 entry.
• In vivo, amphotericin B increased viral loads, accelerated weight loss, and aggravated tissue damage in influenza-infected mice and SARS-CoV-2-challenged hamsters.
• In a propensity score–matched cohort of invasive pulmonary aspergillosis (n=1,072), systemic amphotericin B was associated with a higher incidence of subsequent viral infection vs other antifungals (21.55% vs 7.76%, P=0.003; adjusted OR 3.45, 95% CI 2.20–5.41).

Clinical Implications

In high-risk respiratory settings, consider antifungal stewardship that minimizes amphotericin B use when alternative agents are suitable, and intensify viral monitoring if amphotericin is required. The glucocerebrosidase–ceramide axis emerges as a potential target to mitigate viral entry.

Limitations

• Observational clinical component cannot eliminate residual confounding; not a randomized clinical trial.
• Generalizability across fungal indications, dosing regimens, and broader patient populations requires confirmation.

Future Directions

Prospective comparative studies of antifungal regimens during respiratory virus seasons; interventional studies targeting glucocerebrosidase/ceramide pathways to blunt viral entry.