Department of Viroscience, Erasmus University Medical Center, Rotterdam, the Netherlands.
Department of Cell Biology, Erasmus University Medical Center, Rotterdam, the Netherlands.
PLoS Negl Trop Dis. 2024 Mar 27;18(3):e0012074. doi: 10.1371/journal.pntd.0012074. eCollection 2024 Mar.
Seoul orthohantavirus (SEOV) is a rat-borne zoonotic virus that is transmitted via inhalation of aerosolized infectious excreta, and can cause hemorrhagic fever with renal syndrome (HFRS) in humans worldwide. In rats, SEOV predominantly exists as a persistent infection in the absence of overt clinical signs. Lack of disease in rats is attributed to downregulation of pro-inflammatory and upregulation of regulatory host responses. As lung microvascular endothelial cells (LMECs) represent a primary target of infection in both human and rats, infections in these cells provide a unique opportunity to study the central role of LMECs in the dichotomy between pathogenicity in both species. In this study, host responses to SEOV infection in primary human and rat LMECs were directly compared on a transcriptional level. As infection of rat LMECs was more efficient than human LMECs, the majority of anti-viral defense responses were observed earlier in rat LMECs. Most prominently, SEOV-induced processes in both species included responses to cytokine stimulus, negative regulation of innate immune responses, responses to type I and II interferons, regulation of pattern recognition receptor signaling and MHC-I signaling. However, over time, in the rat LMECs, responses shifted from an anti-viral state towards a more immunotolerant state displayed by a PD-L1, B2M-, JAK2-focused interaction network aiding in negative regulation of cytotoxic CD8-positive T cell activation. This suggests a novel mechanism by which species-specific orthohantavirus-induced endothelium and T cell crosstalk may play a crucial role in the development of acute disease in humans and persistence in rodents.
首尔病毒（SEOV）是一种通过吸入气溶胶化的传染性排泄物传播的啮齿动物源性人畜共患病病毒，可在全球范围内导致肾综合征出血热（HFRS）。在大鼠中，SEOV 主要以无明显临床症状的持续性感染形式存在。大鼠缺乏疾病是由于促炎反应下调和调节性宿主反应上调所致。由于肺微血管内皮细胞（LMECs）是人类和大鼠感染的主要靶细胞，因此这些细胞的感染为研究 LMECs 在两种物种的致病性之间的二分法中的核心作用提供了独特的机会。在这项研究中，直接在转录水平上比较了原发性人源和大鼠 LMEC 中 SEOV 感染的宿主反应。由于大鼠 LMEC 的感染效率高于人 LMEC，因此在大鼠 LMEC 中更早观察到大多数抗病毒防御反应。最为明显的是，SEOV 在两种物种中诱导的过程均包括对细胞因子刺激的反应、先天免疫反应的负调节、I 型和 II 型干扰素的反应、模式识别受体信号和 MHC-I 信号的调节。然而，随着时间的推移，大鼠 LMEC 中的反应从抗病毒状态转变为更具免疫耐受状态，这表现为 PD-L1、B2M、JAK2 为重点的相互作用网络，有助于负调节细胞毒性 CD8 阳性 T 细胞的激活。这表明，特定物种的 orthohantavirus 诱导的内皮细胞和 T 细胞串扰可能在人类急性疾病的发展和啮齿动物的持续存在中发挥关键作用的新机制。
