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Lymphocytic choriomeningitis virus (LCMV) is an enveloped and segmented negative-sense RNA virus classified within the family of the order. LCMV is associated with fatal disease in immunocompromised populations and, as the prototypical arenavirus member, acts as a model for the many highly pathogenic members of the family, such as Junín, Lassa, and Lujo viruses, all of which are associated with devastating hemorrhagic fevers. To enter cells, the LCMV envelope fuses with late endosomal membranes, for which two established requirements are low pH and interaction between the LCMV glycoprotein (GP) spike and secondary receptor CD164. LCMV subsequently uncoats, where the RNA genome-associated nucleoprotein (NP) separates from the Z protein matrix layer, releasing the viral genome into the cytosol. To further examine LCMV endosome escape, we performed an siRNA screen which identified host cell potassium ion (K) channels as important for LCMV infection, with pharmacological inhibition confirming K channel involvement during the LCMV entry phase completely abrogating productive infection. To better understand the K-mediated block in infection, we tracked incoming virions along their entry pathway under physiological conditions, where uncoating was signified by separation of NP and Z proteins. In contrast, K channel blockade prevented uncoating, trapping virions within Rab7 and CD164-positive endosomes, identifying K as a third LCMV entry requirement. K did not increase GP-CD164 binding or alter GP-CD164-dependent fusion. Thus, we propose that K mediates uncoating by modulating NP-Z interactions within the virion interior. These results suggest K channels represent a potential anti-arenaviral target.IMPORTANCEArenaviruses can cause fatal human disease for which approved preventative or therapeutic options are not available. Here, using the prototypical LCMV, we identified K channels as critical for arenavirus infection, playing a vital role during the entry phase of the infection cycle. We showed that blocking K channel function resulted in entrapment of LCMV particles within late endosomal compartments, thus preventing productive replication. Our data suggest K is required for LCMV uncoating and genome release by modulating interactions between the viral nucleoprotein and the matrix protein layer inside the virus particle.

淋巴细胞性脉络丛脑膜炎病毒（LCMV）是一种有包膜的分节段负链RNA病毒，归类于该目下的科。LCMV在免疫功能低下人群中会引发致命疾病，并且作为原型沙粒病毒成员，可作为该科许多高致病性成员（如胡宁病毒、拉沙病毒和卢乔病毒，所有这些病毒都与毁灭性的出血热有关）的模型。为了进入细胞，LCMV包膜与晚期内体膜融合，对此已确定的两个要求是低pH值以及LCMV糖蛋白（GP）刺突与辅助受体CD164之间的相互作用。随后LCMV脱壳，其中与RNA基因组相关的核蛋白（NP）与Z蛋白基质层分离，将病毒基因组释放到细胞质中。为了进一步研究LCMV从内体逃逸的过程，我们进行了一项小干扰RNA筛选，确定宿主细胞钾离子（K⁺）通道对LCMV感染很重要，药物抑制证实K⁺通道在LCMV进入阶段发挥作用，完全消除了有效感染。为了更好地理解K⁺介导的感染阻断作用，我们在生理条件下追踪进入的病毒粒子沿其进入途径的情况，其中脱壳表现为NP和Z蛋白的分离。相比之下，K⁺通道阻断阻止了脱壳，将病毒粒子捕获在Rab7和CD164阳性内体中，确定K⁺是LCMV进入的第三个要求。K⁺不会增加GP - CD164结合或改变GP - CD164依赖性融合。因此，我们提出K⁺通过调节病毒粒子内部的NP - Z相互作用来介导脱壳。这些结果表明K⁺通道代表了一个潜在的抗沙粒病毒靶点。

重要性

沙粒病毒可导致致命的人类疾病，目前尚无获批的预防或治疗方案。在此，我们利用原型LCMV，确定K⁺通道对沙粒病毒感染至关重要，在感染周期的进入阶段发挥着关键作用。我们表明，阻断K⁺通道功能会导致LCMV颗粒被困在晚期内体区室中，从而阻止有效复制。我们的数据表明，K⁺是LCMV脱壳和基因组释放所必需的，它通过调节病毒粒子内部病毒核蛋白与基质蛋白层之间的相互作用来实现。