■越来越多的研究报告说,许多2019年冠状病毒病(COVID-19)患者和接种疫苗的个体出现了中枢神经系统(CNS)症状,血清中的大多数抗体没有病毒中和能力。我们检验了以下假设:由严重急性呼吸综合征冠状病毒2(SARS-CoV-2)的刺突蛋白诱导的非中和性抗S1-111IgG可能会对CNS产生负面影响。
■经过14天的适应,分组的ApoE-/-小鼠通过皮下注射用不同的刺突蛋白衍生肽(与KLH偶联)或KLH免疫四次(第0天,第7天,第14天,第28天)。抗体水平,神经胶质细胞的状态,基因表达,前脉冲抑制,运动活动,从第21天开始评估空间工作记忆。
■在免疫后在其血清和脑匀浆中测量到抗S1-111IgG水平的增加。至关重要的是,抗S1-111IgG增加小胶质细胞的密度,激活的小胶质细胞,海马中的星形胶质细胞,在S1-111免疫小鼠中,我们观察到类似精神运动的行为表型,感觉运动门控缺陷和自发性受损。转录组分析显示,S1-111免疫小鼠的上调基因主要与突触可塑性和精神障碍有关。
■我们的结果表明,刺突蛋白诱导的非中和抗体抗S1-111IgG通过激活神经胶质细胞和调节突触可塑性在模型小鼠中引起一系列精神病样变化。预防抗S1-111IgG(或其他非中和抗体)的产生可能是减少COVID-19患者和接种疫苗个体中枢神经系统表现的潜在策略。
UNASSIGNED: An increasing number of studies have reported that numerous patients with coronavirus disease 2019 (COVID-19) and vaccinated individuals have developed central nervous system (CNS) symptoms, and that most of the antibodies in their sera have no virus-neutralizing ability. We tested the hypothesis that non-neutralizing anti-S1-111 IgG induced by the spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) could negatively affect the CNS.
UNASSIGNED: After 14-day acclimation, the grouped ApoE-/- mice were immunized four times (day 0, day 7, day 14, day 28) with different spike-protein-derived peptides (coupled with KLH) or KLH via subcutaneous injection. Antibody level, state of glial cells, gene expression, prepulse inhibition, locomotor activity, and spatial working memory were assessed from day 21.
UNASSIGNED: An increased level of anti-S1-111 IgG was measured in their sera and brain homogenate after the immunization. Crucially, anti-S1-111 IgG increased the density of microglia, activated microglia, and astrocytes in the hippocampus, and we observed a psychomotor-like behavioral phenotype with defective sensorimotor gating and impaired spontaneity among S1-111-immunized mice. Transcriptome profiling showed that up-regulated genes in S1-111-immunized mice were mainly associated with synaptic plasticity and mental disorders.
UNASSIGNED: Our results show that the non-neutralizing antibody anti-S1-111 IgG induced by the spike protein caused a series of psychotic-like changes in model mice by activating glial cells and modulating synaptic plasticity. Preventing the production of anti-S1-111 IgG (or other non-neutralizing antibodies) may be a potential strategy to reduce CNS manifestations in COVID-19 patients and vaccinated individuals.