近期推送的北京大學(xué)基礎(chǔ)醫(yī)學(xué)院病原生物學(xué)系與感染病研究中心的向?qū)捿x課題組在Nature Communications發(fā)表最新研究成果，成功揭示胚胎干細(xì)胞獨(dú)特的自我保護(hù)免受病毒感染的分子機(jī)制的文章（詳請點擊）得到很大的反響。

現(xiàn)將同步發(fā)表nature communications上關(guān)于胚胎干細(xì)胞抗病毒新機(jī)制的研究的點評也轉(zhuǎn)載于此，以期讓廣大病毒學(xué)同仁對此領(lǐng)域有更深入了解。

郭德銀（廣州國家實驗室，研究員）

哺乳動物細(xì)胞中，以干擾素（IFN）為核心的先天免疫應(yīng)答是抵御病毒感染的第一道防線。然而，早期胚胎和胚胎干細(xì)胞（embryonic stem cells, ESCs）中的 IFN免疫應(yīng)答存在顯著缺陷，其抗病毒機(jī)制與分化成熟細(xì)胞有明顯不同。近年來，針對ESCs抗病毒機(jī)制的研究取得一些進(jìn)展：ESCs 可以通過組成型表達(dá)部分重要的 ISGs 基因抑制病毒感染；通過RNA 干擾（RNAi）途徑抑制病毒 RNA 復(fù)制；依賴內(nèi)源性 RTase 和 RNase H 活性的天然抗病毒機(jī)制ERASE等。盡管如此，對于多能干細(xì)胞抗病毒機(jī)制的整體認(rèn)識尚處于初期階段，在 ESCs 等多能性干細(xì)胞中是否還存在新的抗病毒機(jī)制仍然是亟待解決的重要科學(xué)問題。

在本研究中，向?qū)捿x教授團(tuán)隊揭示了囊泡相關(guān)膜蛋白5（VAMP5）在ESCs中作為宿主限制因子發(fā)揮抗病毒作用，而且不依賴于其已知的囊泡運(yùn)輸和膜融合功能。研究證實了VAMP5對冠狀病毒的廣譜抑制活性，包括SARS-CoV-2及其變異株（Alpha、Delta和Omicron等）和其它冠狀病毒，如MERS-CoV、CoV-OC43、CoV-NL63以及哺乳動物相關(guān)的豬流行性腹瀉病毒PEDV和小鼠肝炎病毒MHV-A59。該研究還進(jìn)一步證實了VAMP5對黃病毒（寨卡病毒ZIKV、登革病毒DENV2）、流感病毒等的抗病毒作用，因此該研究系統(tǒng)性驗證了VAMP5的廣譜抗病毒活性，為發(fā)展廣譜抗病毒治療策略提供了新的思路。

該研究進(jìn)一步揭示了VAMP5抑制冠狀病毒復(fù)制的分子機(jī)制，發(fā)現(xiàn)其定位于冠狀病毒復(fù)制所依賴的雙膜囊泡（DMVs），通過C端結(jié)構(gòu)域與RNA 依賴的 RNA 聚合酶 (RdRp) 復(fù)合體中的非結(jié)構(gòu)蛋白 NSP8結(jié)合。這一相互作用有效破壞了病毒的復(fù)制轉(zhuǎn)錄復(fù)合物功能，進(jìn)而抑制病毒負(fù)鏈RNA合成，從而阻斷病毒復(fù)制。值得注意的是，盡管小鼠和大鼠VAMP5的C端序列與人源蛋白差異顯著，其抗病毒功能仍高度保守，提示該機(jī)制在進(jìn)化中的重要性，為理解干細(xì)胞抗病毒防御提供了新視角。

這項工作不僅闡明了VAMP5在ESCs中抵抗冠狀病毒的分子機(jī)制，更強(qiáng)調(diào)了VAMP5在ESCs微環(huán)境中的多重生物學(xué)功能，揭示了胚胎干細(xì)胞如何在不依賴IFN的情況下通過宿主限制因子保護(hù)自身免受病原體損傷。這一研究也提示，在胚胎干細(xì)胞獨(dú)特的抗病毒防御體系中，可能有更多的關(guān)鍵宿主因子發(fā)揮作用，該領(lǐng)域尚有大量未知機(jī)制待深入探索。

Commentary on Dong et al., Nature Communications (2025) （克利夫蘭醫(yī)學(xué)中心，吳賢芳教授）

Dong et al. (Nat Commun, 2025) present a compelling study identifying VAMP5—a vesicle-associated membrane protein—as a previously unrecognized intrinsic antiviral effector in embryonic stem cells (ESCs). Using a combination of transcriptomic profiling, virological assays, and molecular interaction studies, the authors show that VAMP5 is highly enriched in ESCs and confers resistance to coronaviruses, including SARS-CoV-2. Mechanistically, VAMP5 localizes to double-membrane vesicles (DMVs), the specialized sites where many positive-strand RNA viruses, such as SARS-CoV-2, establish their replication complexes. VAMP5 directly interacts with the viral nonstructural protein NSP8, disrupting the assembly or stability of the replication-transcription complex and thereby inhibiting the synthesis of negative-strand viral RNA—a critical step for viral genome amplification.

Strikingly, genetic deletion of VAMP5 in ESCs led to a robust increase in viral replication, yet without affecting the core properties of ESCs such as pluripotency or differentiation potential. This finding underscores the specificity and non-disruptive nature of VAMP5-mediated antiviral defense—one that allows stem cells to maintain developmental fidelity while remaining protected from viral invasion.

These findings resonate strongly with our earlier work (Wu et al., Cell, 2017), which demonstrated that pluripotent and multipotent stem cells intrinsically express a network of antiviral proteins, including members of the IFITM family, to suppress viral infection. Crucially, these antiviral responses operate independently of canonical interferon signaling, which is largely muted or even absent in ESCs. Instead, ESCs appear to have evolved cell-intrinsic, constitutive defense programs that provide immediate protection without triggering pro-inflammatory or differentiation-disruptive cascades.

The collective significance of these studies lies in highlighting a stem-cell-specific antiviral strategy-distinct from that of differentiated somatic cells-centered on constitutively expressed antiviral factors and rapid, non-inflammatory control of viral replication. This paradigm offers several important advantages:

1.Preservation of pluripotency: Activation of classical IFN signaling pathways is known to disrupt pluripotency gene networks and trigger unwanted differentiation or apoptosis. By contrast, ESCs and likely other multipotent stem cells avoid these risks by relying on preformed antiviral proteins that do not perturb their transcriptional identity.

2.Rapid and preemptive defense: In contrast to somatic cells, which require pathogen recognition and cytokine induction to mount antiviral responses, stem cells maintain a "ready-to-act" antiviral state. This is especially crucial during early embryogenesis, when viral exposure can have catastrophic developmental consequences.

3.Protection of the progenitor reservoir: Because stem cells are the origin of all tissues, their loss due to infection poses an existential threat to the organism. A tightly regulated, low-noise antiviral system allows for sustained protection without compromising the long-term regenerative potential of the stem cell pool.

4.Adaptation to immune privilege: Many stem cell compartments-including the inner cell mass, germline precursors, and certain adult niches-exist in relatively immune-privileged environments. Intrinsic antiviral immunity may represent an evolutionary adaptation to protect these cells in contexts where classical immune effector functions are limited or suppressed.

Together, the findings of Dong et al. and our previous study reveal that stem cells utilize a fundamentally different antiviral logic, built around constitutive preparedness rather than inducible inflammation. This strategy not only ensures the survival of the stem cell population under viral threat but may also provide insights into the design of virus-resistant stem cell lines for therapeutic applications. Moreover, the identification of VAMP5 adds to a growing list of stem cell-intrinsic restriction factors and highlights how organelle dynamics-especially involving DMVs and vesicular trafficking-may be co-opted as a line of antiviral defense in pluripotent cells.

As our understanding deepens, it will be critical to investigate how these intrinsic programs are regulated during development and how they intersect with metabolic and epigenetic states of stem cells. Additionally, this body of work opens new avenues for engineering synthetic immunity in stem cells and their derivatives, potentially improving the safety of cell-based therapies in infectious disease settings.