Hein Zaw Myo, Kumar Suresh, Che Ramli Muhammad Danial, Che Mohd Nassir Che Mohd Nasril
Department of Basic Medical Sciences, College of Medicine, Ajman University, Ajman P.O. Box 346, United Arab Emirates.
Faculty of Medicine, Nursing and Health Sciences, SEGi University, Petaling Jaya 47810, Selangor, Malaysia.
Int J Mol Sci. 2025 Jun 27;26(13):6214. doi: 10.3390/ijms26136214.
The COVID-19 pandemic has revealed the profound and lasting impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on the nervous system. Beyond acute infection, SARS-CoV-2 acts as a potent immunomodulatory agent, disrupting immune homeostasis and contributing to persistent inflammation, autoimmunity, and neurodegeneration. Long COVID, or post-acute sequelae of SARS-CoV-2 infection (PASC), is characterized by a spectrum of neurological symptoms, including cognitive dysfunction, fatigue, neuropathy, and mood disturbances. These are linked to immune dysregulation involving cytokine imbalance, blood-brain barrier (BBB) disruption, glial activation, and T-cell exhaustion. Key biomarkers such as interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), glial fibrillary acidic protein (GFAP), and neurofilament light chain (NFL) correlate with disease severity and chronicity. This narrative review examines the immunopathological mechanisms underpinning the neurological sequelae of long COVID, focusing on neuroinflammation, endothelial dysfunction, and molecular mimicry. We also assess the role of viral variants in shaping neuroimmune outcomes and explore emerging diagnostic and therapeutic strategies, including biomarker-guided and immune-targeted interventions. By delineating how SARS-CoV-2 reshapes neuroimmune interactions, this review aims to support the development of precision-based diagnostics and targeted therapies for long COVID-related neurological dysfunction. Emerging approaches include immune-modulatory agents (e.g., anti-IL-6), neuroprotective drugs, and strategies for repurposing antiviral or anti-inflammatory compounds in neuro-COVID. Given the high prevalence of comorbidities, personalized therapies guided by biomarkers and patient-specific immune profiles may be essential. Advancements in vaccine technologies and targeted biologics may also hold promise for prevention and disease modification. Finally, continued interdisciplinary research is needed to clarify the complex virus-immune-brain axis in long COVID and inform effective clinical management.
2019冠状病毒病（COVID-19）大流行揭示了严重急性呼吸综合征冠状病毒2（SARS-CoV-2）对神经系统产生的深远而持久的影响。除了急性感染外，SARS-CoV-2作为一种强效免疫调节剂，会破坏免疫稳态，并导致持续性炎症、自身免疫和神经退行性变。长期新冠，即SARS-CoV-2感染的急性后遗症（PASC），其特征是一系列神经症状，包括认知功能障碍、疲劳、神经病变和情绪障碍。这些症状与免疫失调有关，涉及细胞因子失衡、血脑屏障（BBB）破坏、神经胶质细胞激活和T细胞耗竭。白细胞介素-6（IL-6）、肿瘤坏死因子-α（TNF-α）、神经胶质纤维酸性蛋白（GFAP）和神经丝轻链（NFL）等关键生物标志物与疾病的严重程度和慢性病程相关。这篇叙述性综述探讨了长期新冠神经后遗症背后的免疫病理机制，重点关注神经炎症、内皮功能障碍和分子模拟。我们还评估了病毒变体在塑造神经免疫结果方面的作用，并探索新出现的诊断和治疗策略，包括生物标志物导向和免疫靶向干预措施。通过阐述SARS-CoV-2如何重塑神经免疫相互作用，本综述旨在支持针对长期新冠相关神经功能障碍开发基于精准医学的诊断方法和靶向治疗。新出现的方法包括免疫调节剂（如抗IL-6）、神经保护药物，以及在神经新冠中重新利用抗病毒或抗炎化合物的策略。鉴于合并症的高患病率，由生物标志物和患者特异性免疫谱指导的个性化治疗可能至关重要。疫苗技术和靶向生物制剂的进展也可能为预防和疾病改善带来希望。最后，需要持续开展跨学科研究，以阐明长期新冠中复杂的病毒-免疫-脑轴，并为有效的临床管理提供依据。
