Nguyen Dung, Laidlaw Stephen M, Dong Xiaofeng, Wand Matthew, Horton Amanda, Sutton Mark, Tree Julia, Milligan Rachel, Erdmann Maximillian, Matthews David, Davidson Andrew D, Rahman Khondaker Miraz, Hiscox Julian A, Carroll Miles
Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.
Pandemic Sciences Institute, University of Oxford, Oxford, United Kingdom.
J Virol. 2025 Jul 22;99(7):e0051925. doi: 10.1128/jvi.00519-25. Epub 2025 Jun 4.
Severe coronavirus disease 2019 (COVID-19) patients who require hospitalization are at high risk of invasive pulmonary mucormycosis. Amphotericin B (AmB), which is the first-line therapy for invasive pulmonary mucormycosis, has been shown to promote or inhibit replication of a spectrum of viruses. In this study, we first predicted that AmB and nystatin had strong interactions with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) proteins using screening, indicative of drugs with potential therapeutic activity against this virus. Subsequently, we investigated the impact of AmB, nystatin, natamycin, fluconazole, and caspofungin on SARS-CoV-2 infection and replication . Results showed that AmB and nystatin actually increased SARS-CoV-2 replication in Vero E6, Calu-3, and Huh7 cells. At optimal concentrations, AmB and nystatin increase SARS-CoV-2 replication by up to 100- and 10-fold in Vero E6 and Calu-3 cells, respectively. The other antifungals tested had no impact on SARS-CoV-2 infection . Drug kinetic studies indicate that AmB enhances SARS-CoV-2 infection by promoting viral entry into cells. Additionally, knockdown of genes encoding for interferon-induced transmembrane (IFITM) proteins 1, 2, and 3 suggests AmB enhances SARS-CoV-2 cell entry by overcoming the antiviral effect of the IFITM3 protein. This study further elucidates the role of IFITM3 in viral entry and highlights the potential dangers of treating COVID-19 patients, with invasive pulmonary mucormycosis, using AmB.IMPORTANCEAmB and nystatin are common treatments for fungal infections but were predicted to strongly interact with SARS-CoV-2 proteins, indicating their potential modulation or inhibition against the virus. However, our tests revealed that these antifungals, in fact, enhance SARS-CoV-2 infection by facilitating viral entry into cells. The magnitude of enhancement could be up to 10- or 100-fold, depending on cell lines used. These findings indicate that AmB and nystatin have the potential to enhance disease when given to patients infected with SARS-CoV-2 and therefore should not be used for treatment of fungal infections in active COVID-19 cases.
需要住院治疗的重症2019冠状病毒病（COVID-19）患者发生侵袭性肺毛霉病的风险很高。两性霉素B（AmB）是侵袭性肺毛霉病的一线治疗药物，已显示可促进或抑制多种病毒的复制。在本研究中，我们首先通过筛选预测AmB和制霉菌素与严重急性呼吸综合征冠状病毒2（SARS-CoV-2）蛋白有强烈相互作用，表明这些药物具有抗该病毒的潜在治疗活性。随后，我们研究了AmB、制霉菌素、游霉素、氟康唑和卡泊芬净对SARS-CoV-2感染和复制的影响。结果显示，AmB和制霉菌素实际上增加了SARS-CoV-2在Vero E6、Calu-3和Huh7细胞中的复制。在最佳浓度下，AmB和制霉菌素分别使SARS-CoV-2在Vero E6和Calu-3细胞中的复制增加高达100倍和10倍。所测试的其他抗真菌药物对SARS-CoV-2感染没有影响。药物动力学研究表明，AmB通过促进病毒进入细胞来增强SARS-CoV-2感染。此外，对编码干扰素诱导跨膜（IFITM）蛋白1、2和3的基因进行敲低表明，AmB通过克服IFITM3蛋白的抗病毒作用来增强SARS-CoV-2进入细胞的能力。本研究进一步阐明了IFITM3在病毒进入中的作用，并突出了使用AmB治疗患有侵袭性肺毛霉病的COVID-19患者的潜在危险。重要性AmB和制霉菌素是真菌感染的常用治疗药物，但预测它们与SARS-CoV-2蛋白有强烈相互作用，表明它们对该病毒有潜在的调节或抑制作用。然而，我们的测试表明，这些抗真菌药物实际上通过促进病毒进入细胞来增强SARS-CoV-2感染。增强的程度可能高达10倍或100倍，具体取决于所使用的细胞系。这些发现表明，给感染SARS-CoV-2的患者使用AmB和制霉菌素可能会加重病情，因此不应将其用于治疗活动性COVID-19病例中的真菌感染。
