Department of Viroscience, Erasmus Medical Center, Dr. Molewaterplein 40, Rotterdam, 3015 GD, The Netherlands.
Department of Medical Microbiology, Leiden University Medical Centre, Leiden, the Netherlands.
J Neuroinflammation. 2024 Sep 27;21(1):236. doi: 10.1186/s12974-024-03228-y.
West Nile virus (WNV) and Usutu virus (USUV) are closely related flaviviruses with differing capacities to cause neurological disease in humans. WNV is thought to use a transneural route of neuroinvasion along motor neurons and causes severe motor deficits. The potential for use of transneural routes of neuroinvasion by USUV has not been investigated experimentally, and evidence from the few clinical case reports of USUV-associated neuroinvasive disease is lacking. We hypothesised that, compared with WNV, USUV is less able to infect motor neurons, and therefore determined the susceptibility of human induced pluripotent stem cell (iPSC)-derived spinal cord motor neurons to infection. Both viruses could grow to high titres in iPSC-derived neural cultures. However, USUV could not productively infect motor neurons due to restriction by the antiviral response, which was not induced upon WNV infection. Inhibition of the antiviral response allowed for widespread infection and transportation of USUV along motor neurons within a compartmented culture system. These results show a stark difference in the ability of these two viruses to evade initiation of intrinsic antiviral immunity. Our data suggests that USUV cannot infect motor neurons in healthy individuals but in case of immunodeficiency may pose a risk for motor-related neurological disease and transneural invasion.
西尼罗河病毒（WNV）和乌苏图病毒（USUV）是密切相关的黄病毒，它们在引起人类神经疾病方面的能力不同。WNV 被认为通过沿运动神经元的跨神经元途径进行神经入侵，并导致严重的运动功能障碍。USUV 通过跨神经元途径进行神经入侵的潜力尚未经过实验研究，并且缺乏关于 USUV 相关神经侵袭性疾病的少数临床病例报告的证据。我们假设，与 WNV 相比，USUV 感染运动神经元的能力较弱，因此确定了人诱导多能干细胞（iPSC）衍生的脊髓运动神经元对感染的易感性。两种病毒都可以在 iPSC 衍生的神经培养物中生长到高滴度。然而，由于抗病毒反应的限制，USUV 不能有效地感染运动神经元，而 WNV 感染不会诱导这种反应。抗病毒反应的抑制允许 USUV 在分隔培养系统中沿运动神经元广泛感染和运输。这些结果显示了这两种病毒逃避内在抗病毒免疫起始的能力存在明显差异。我们的数据表明，USUV 不能感染健康个体中的运动神经元，但在免疫缺陷的情况下，可能会对与运动相关的神经疾病和跨神经元入侵构成风险。
