Department of Viroscience, Erasmus Medical Center, Rotterdam, The Netherlands.
HerpeslabNL of the Department of Viroscience, Erasmus Medical Center, Rotterdam, The Netherlands.
Sci Rep. 2024 Aug 29;14(1):20095. doi: 10.1038/s41598-024-71050-w.
Usutu (USUV), West Nile (WNV), and Zika virus (ZIKV) are neurotropic arthropod-borne viruses (arboviruses) that cause severe neurological disease in humans. However, USUV-associated neurological disease is rare, suggesting a block in entry to or infection of the brain. We determined the replication, cell tropism and neurovirulence of these arboviruses in human brain tissue using a well-characterized human fetal organotypic brain slice culture model. Furthermore, we assessed the efficacy of interferon-β and 2'C-methyl-cytidine, a synthetic nucleoside analogue, in restricting viral replication. All three arboviruses replicated within the brain slices, with WNV reaching the highest titers, and all primarily infected neuronal cells. USUV- and WNV-infected cells exhibited a shrunken morphology, not associated with detectable cell death. Pre-treatment with interferon-β inhibited replication of all arboviruses, while 2'C-methyl-cytidine reduced only USUV and ZIKV titers. Collectively, USUV can infect human brain tissue, showing similarities in tropism and neurovirulence as WNV and ZIKV. These data suggest that a blockade to infection of the human brain may not be the explanation for the low clinical incidence of USUV-associated neurological disease. However, USUV replicated more slowly and to lower titers than WNV, which could help to explain the reduced severity of neurological disease resulting from USUV infection.
乌苏图（USUV）、西尼罗河（WNV）和寨卡病毒（ZIKV）是神经亲和性虫媒病毒（arboviruses），会导致人类严重的神经系统疾病。然而，与 USUV 相关的神经系统疾病较为罕见，这表明该病毒进入或感染大脑的过程受阻。我们使用经过充分验证的人类胎儿器官型脑切片培养模型，确定了这些 arboviruses 在人类脑组织中的复制、细胞嗜性和神经毒力。此外，我们评估了干扰素-β和 2'C-甲基胞苷（一种合成核苷类似物）在限制病毒复制方面的功效。三种 arboviruses 均可在脑切片中复制，WNV 达到的滴度最高，且主要感染神经元细胞。感染 USUV 和 WNV 的细胞表现出皱缩的形态，与可检测到的细胞死亡无关。干扰素-β预处理可抑制所有 arboviruses 的复制，而 2'C-甲基胞苷仅降低 USUV 和 ZIKV 的滴度。总之，USUV 可以感染人类脑组织，其嗜性和神经毒力与 WNV 和 ZIKV 相似。这些数据表明，感染人脑的阻断可能不是 USUV 相关神经系统疾病临床发病率低的原因。然而，USUV 的复制速度比 WNV 慢，滴度也更低，这可以帮助解释 USUV 感染导致的神经系统疾病严重程度降低。
