斯坦福大学医学院Jan E. Carette研究组揭示了MFSD6是肠病毒D68的一种进入受体。这一研究成果于2025年3月25日发表在国际顶尖学术期刊《自然》上。

课题组人员利用基因组规模的CRISPR筛选，鉴定了特征不明确的多通膜转运蛋白MFSD6作为EV-D68的宿主进入因子。敲除MFSD6表达可消除EV-D68在细胞系和呼吸细胞、神经细胞等原代细胞中的感染。MFSD6定位于质膜上，是病毒进入宿主细胞所必需的。MFSD6通过其第三个细胞外环（L3）直接与EV-D68颗粒结合。课题组测定了EV-D68与L3在2.1 分辨率，显示交互界面。通过将MFSD6（L3）修饰为Fc而设计的诱饵受体阻断了EV-D68对人原代肺上皮细胞的感染，并在EV-D68感染的致死性motheme模型中提供了近乎完全的保护。总之，他们的研究结果表明MFSD6是EV-D68的一个进入受体，并支持靶向MFSD6作为对抗这种具有大流行潜力的新兴病原体感染的潜在机制。

据了解，由于全球疫苗接种运动，脊髓灰质炎病毒已接近被消灭，人们的注意力已转移到其他可抑制脊髓灰质炎样麻痹综合征（现称为急性弛缓性脊髓炎）的肠道病毒主题1-3。特别是，肠病毒D68 （EV-D68）被认为是近年来AFM流行病爆发的主要驱动因素，但对EV-D68宿主相互作用知之甚少。EV-D68是一种呼吸道病毒，但在极少数情况下，可扩散到中枢神经系统，导致严重的神经发病。

附：英文原文

Title: MFSD6 is an entry receptor for enterovirus D68

Author: Varanese, Lauren, Xu, Lily, Peters, Christine E., Pintilie, Grigore, Roberts, David S., Raj, Suyash, Liu, Mengying, Ooi, Yaw Shin, Diep, Jonathan, Qiao, Wenjie, Richards, Christopher M., Callaway, Jeremy, Bertozzi, Carolyn R., Jabs, Sabrina, de Vries, Erik, van Kuppeveld, Frank J. M., Nagamine, Claude M., Chiu, Wah, Carette, Jan E.

Issue&Volume: 2025-03-25

Abstract: With the near eradication of poliovirus due to global vaccination campaigns, attention has shifted to other enteroviruses that can cause polio-like paralysis syndrome (now termed acute flaccid myelitis (AFM))1–3. In particular, enterovirus D68 (EV-D68) is believed to be the main driver of epidemic outbreaks of AFM in recent years4, yet not much is known about EV-D68 host interactions. EV-D68 is a respiratory virus5 but, in rare cases, can spread to the central nervous system to cause severe neuropathogenesis. Here, we used genome-scale CRISPR screens to identify the poorly characterized multipass membrane transporter MFSD6 as a host entry factor for EV-D68. Knockout of MFSD6 expression abrogated EV-D68 infection in cell lines and primary cells corresponding to respiratory and neural cells. MFSD6 localized to the plasma membrane and was required for viral entry into host cells. MFSD6 bound directly to EV-D68 particles via its third extracellular loop (L3). We determined the cryo-EM structure of EV-D68 in complex with L3 at 2.1 resolution, revealing the interaction interface. A decoy receptor, engineered by fusing MFSD6(L3) to Fc, blocked EV-D68 infection of human primary lung epithelial cells, and provided near complete protection in a lethal mouse model of EV-D68 infection. Collectively, our results reveal MFSD6 as an entry receptor for EV-D68, and support targeting MFSD6 as a potential mechanism to combat infections by this emerging pathogen with pandemic potential.

DOI: 10.1038/s41586-025-08908-0

Source: https://www.nature.com/articles/s41586-025-08908-0