Up to 25% of individuals infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) exhibit postacute cognitive sequelae. Although millions of cases of coronavirus disease 2019 (COVID-19)-mediated memory dysfunction are accumulating worldwide, the underlying mechanisms and how vaccination lowers risk are unknown. Interleukin-1 (IL-1), a key component of innate immune defense against SARS-CoV-2 infection, is elevated in the hippocampi of individuals with COVID-19. Here we show that intranasal infection of C57BL/6J mice with SARS-CoV-2 Beta variant leads to central nervous system infiltration of Ly6C^hi monocytes and microglial activation. Accordingly, SARS-CoV-2, but not H1N1 influenza virus, increases levels of brain IL-1β and induces persistent IL-1R1-mediated loss of hippocampal neurogenesis, which promotes postacute cognitive deficits. Vaccination with a low dose of adenoviral-vectored spike protein prevents hippocampal production of IL-1β during breakthrough SARS-CoV-2 infection, loss of neurogenesis and subsequent memory deficits. Our study identifies IL-1β as one potential mechanism driving SARS-CoV-2-induced cognitive impairment in a new mouse model that is prevented by vaccination.

高达 25% 的严重急性呼吸综合征冠状病毒 2 (SARS-CoV-2) 感染者会出现急性后认知后遗症。尽管全球范围内数以百万计的 2019 冠状病毒病 (COVID-19) 介导的记忆功能障碍病例正在积累，但其潜在机制以及疫苗接种如何降低风险尚不清楚。白细胞介素-1 (IL-1) 是针对 SARS-CoV-2 感染的先天免疫防御的关键组成部分，在 COVID-19 患者的海马体中含量升高。在这里，我们发现，C57BL/6J 小鼠鼻内感染 SARS-CoV-2 Beta 变体会导致中枢神经系统 Ly6C ^hi单核细胞浸润和小胶质细胞激活。因此，SARS-CoV-2（而非 H1N1 流感病毒）会增加大脑 IL-1β 的水平，并诱导 IL-1R1 介导的海马神经发生持续丧失，从而促进急性后认知缺陷。低剂量腺病毒载体刺突蛋白疫苗可防止突破性 SARS-CoV-2 感染期间海马产生 IL-1β、神经发生丧失和随后的记忆缺陷。我们的研究发现，IL-1β 是在新小鼠模型中驱动 SARS-CoV-2 诱导的认知障碍的一种潜在机制，而这种认知障碍可以通过疫苗接种来预防。