STAT2-dependent restriction of Zika virus by human macrophages but not dendritic cells

Zika virus (ZIKV) is an emerging mosquito-borne flavivirus that poses significant threats to global public health. Macrophages and dendritic cells are both key sentinel cells in the host immune response and play critical roles in the pathogenesis of flavivirus infections. Recent studies showed that ZIKV could productively infect monocyte-derived dendritic cells (moDCs), but the role of macrophages in ZIKV infection remains incompletely understood. In this study, we first compared ZIKV infection in monocyte-derived macrophages (MDMs) and moDCs derived from the same donors. We demonstrated that while both MDMs and moDCs were susceptible to epidemic (Puerto Rico) and pre-epidemic (Uganda) strains of ZIKV, virus replication was largely restricted in MDMs but not in moDCs. ZIKV induced significant apoptosis in moDCs but not MDMs. The restricted virus replication in MDMs was not due to inefficient virus entry but was related to post-entry events in the viral replication cycle. In stark contrast with moDCs, ZIKV failed to inhibit STAT1 and STAT2 phosphorylation in MDMs. This resulted in the lack of efficient antagonism of the host type I interferon-mediated antiviral responses. Importantly, depletion of STAT2 but not STAT1 in MDMs significantly rescued the replication of ZIKV and the prototype flavivirus yellow fever virus. Overall, our findings revealed a differential interplay between macrophages and dendritic cells with ZIKV. While dendritic cells may be exploited by ZIKV to facilitate virus replication, macrophages restricted ZIKV infection.

寨卡病毒（ZIKV）是一种新兴的蚊媒黄病毒，对全球公共卫生构成重大威胁。巨噬细胞和树突状细胞均为主体的关键哨兵细胞，在黄病毒感染的发病机制中扮演着至关重要的角色。近期研究表明，寨卡病毒能够高效感染由单核细胞衍生的树突状细胞（moDCs），然而巨噬细胞在寨卡病毒感染中的作用尚不完全明了。在本研究中，我们首先比较了来自同一供体的单核细胞衍生的巨噬细胞（MDMs）和moDCs的寨卡病毒感染情况。我们证实，尽管MDMs和moDCs对流行（波多黎各）和前流行（乌干达）的寨卡病毒株均具有易感性，但病毒复制主要受到MDMs的限制，而在moDCs中则未受到限制。寨卡病毒在moDCs中诱导了显著的细胞凋亡，但在MDMs中并未观察到。MDMs中病毒复制的限制并非源于病毒进入效率低下，而是与病毒复制周期中的后进入事件相关。与moDCs形成鲜明对比的是，寨卡病毒未能抑制MDMs中的STAT1和STAT2磷酸化。这导致了宿主I型干扰素介导的抗病毒反应的有效拮抗缺失。值得注意的是，在MDMs中耗竭STAT2而非STAT1显著挽救了寨卡病毒和原型黄病毒（黄热病毒）的复制。总体而言，我们的研究结果揭示了巨噬细胞与树突状细胞与寨卡病毒之间的差异化相互作用。尽管树突状细胞可能被寨卡病毒利用以促进病毒复制，但巨噬细胞限制了寨卡病毒的感染。