揭开精神分裂症的病毒假说:机制与证据的全面综述

Unravelling the Viral Hypothesis of Schizophrenia: A Comprehensive Review of Mechanisms and Evidence.

作者信息

Sighencea Mădălina Georgeta, Trifu Simona Corina

机构信息

Doctoral School, "Carol Davila" University of Medicine and Pharmacy Bucharest, 020021 Bucharest, Romania.

Department of Psychiatry, "Carol Davila" University of Medicine and Pharmacy Bucharest, 020021 Bucharest, Romania.

出版信息

Int J Mol Sci. 2025 Aug 1;26(15):7429. doi: 10.3390/ijms26157429.

Abstract

Schizophrenia is a challenging multifactorial neuropsychiatric disease that involves interactions between genetic susceptibility and environmental insults. Increasing evidence implicates viral infections as significant environmental contributors, particularly during sensitive neurodevelopmental periods. This review synthesises current findings on the viral hypothesis of schizophrenia, encompassing a wide array of neurotropic viruses, including influenza viruses, herpesviruses (HSV-1 and 2, CMV, VZV, EBV, HHV-6 and 8), hepatitis B and C viruses, HIV, HERVs, HTLV, Zika virus, BoDV, coronaviruses (including SARS-CoV-2), and others. These pathogens can contribute to schizophrenia through mechanisms such as direct microinvasion, persistent central nervous system infection, immune-mediated neuroinflammation, molecular mimicry, and the disturbance of the blood-brain barrier. Prenatal exposure to viral infections can trigger maternal immune activation, resulting in cytokine-mediated alterations in the neurological development of the foetus that persist into adulthood. Genetic studies highlight the role of immune-related loci, including major histocompatibility complex polymorphisms, in modulating susceptibility to infection and neurodevelopmental outcomes. Clinical data also support the "mild encephalitis" hypothesis, suggesting that a subset of schizophrenia cases involve low-grade chronic neuroinflammation. Although antipsychotics have some immunomodulatory effects, adjunctive anti-inflammatory therapies show promise, particularly in treatment-resistant cases. Despite compelling associations, pathogen-specific links remain inconsistent, emphasising the need for longitudinal studies and integrative approaches such as viromics to unravel causal relationships. This review supports a "multi-hit" model in which viral infections interfere with hereditary and immunological susceptibilities, enhancing schizophrenia risk. Elucidating these virus-immune-brain interactions may facilitate the discovery of biomarkers, targeted prevention, and novel therapeutic strategies for schizophrenia.

摘要

精神分裂症是一种具有挑战性的多因素神经精神疾病,涉及遗传易感性与环境损伤之间的相互作用。越来越多的证据表明病毒感染是重要的环境因素,尤其是在敏感的神经发育阶段。本综述综合了关于精神分裂症病毒假说的当前研究结果,涵盖了多种嗜神经病毒,包括流感病毒、疱疹病毒(单纯疱疹病毒1型和2型、巨细胞病毒、水痘带状疱疹病毒、EB病毒、人类疱疹病毒6型和8型)、乙型和丙型肝炎病毒、人类免疫缺陷病毒、内源性逆转录病毒、人类嗜T淋巴细胞病毒、寨卡病毒、博尔纳病病毒、冠状病毒(包括严重急性呼吸综合征冠状病毒2)等。这些病原体可通过直接微侵袭、中枢神经系统持续感染、免疫介导的神经炎症、分子模拟以及血脑屏障破坏等机制导致精神分裂症。产前暴露于病毒感染可引发母体免疫激活,导致细胞因子介导的胎儿神经发育改变,并持续至成年期。遗传学研究强调了免疫相关基因座的作用,包括主要组织相容性复合体多态性,在调节感染易感性和神经发育结局方面的作用。临床数据也支持“轻度脑炎”假说,表明一部分精神分裂症病例涉及低度慢性神经炎症。尽管抗精神病药物具有一些免疫调节作用,但辅助抗炎治疗显示出前景,尤其是在难治性病例中。尽管存在令人信服的关联,但病原体特异性联系仍不一致,这强调了需要进行纵向研究以及采用病毒组学等综合方法来阐明因果关系。本综述支持一种“多重打击”模型,其中病毒感染干扰遗传和免疫易感性,增加精神分裂症风险。阐明这些病毒-免疫-脑相互作用可能有助于发现生物标志物、进行有针对性的预防以及开发针对精神分裂症的新型治疗策略。

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