Michalak Krzysztof Piotr, Michalak Amelia Zofia, Brenk-Krakowska Alicja
Laboratory of Vision Science and Optometry, Physics and Astronomy Faculty, Adam Mickiewicz University in Poznań, Poznań, Poland.
Faculty of Medicine, Poznań University of Medical Sciences, Poznań, Poland.
Front Immunol. 2025 Apr 17;16:1582783. doi: 10.3389/fimmu.2025.1582783. eCollection 2025.
Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has been recognized not only for its acute effects but also for its ability to cause LongCOVID Syndrome (LCS), a condition characterized by persistent symptoms affecting multiple organ systems. This review examines the molecular and immunological mechanisms underlying LCS, with a particular focus on autophagy inhibition, chronic inflammation, oxidative, nitrosative and calcium stress, viral persistence and autoimmunology. Potential pathophysiological mechanisms involved in LCS include (1) autoimmune activation, (2) latent viral persistence, where SARS-CoV-2 continues to influence host metabolism, (3) reactivation of latent pathogens such as Epstein-Barr virus (EBV) or cytomegalovirus (CMV), exacerbating immune and metabolic dysregulation, and (4) possible persistent metabolic and inflammatory dysregulation, where the body fails to restore post-infection homeostasis. The manipulation of cellular pathways by SARS-CoV-2 proteins is a critical aspect of the virus' ability to evade immune clearance and establish long-term dysfunction. Viral proteins such as NSP13, ORF3a and ORF8 have been shown to disrupt autophagy, thereby impairing viral clearance and promoting immune evasion. In addition, mitochondrial dysfunction, dysregulated calcium signaling, oxidative stress, chronic HIF-1α activation and Nrf2 inhibition create a self-sustaining inflammatory feedback loop that contributes to tissue damage and persistent symptoms. Therefore understanding the molecular basis of LCS is critical for the development of effective therapeutic strategies. Targeting autophagy and Nrf2 activation, glycolysis inhibition, and restoration calcium homeostasis may provide novel strategies to mitigate the long-term consequences of SARS-CoV-2 infection. Future research should focus on personalized therapeutic interventions based on the dominant molecular perturbations in individual patients.
严重急性呼吸综合征冠状病毒2（SARS-CoV-2）不仅因其急性影响而被认识，还因其导致长期新冠综合征（LongCOVID Syndrome，LCS）的能力而被关注。长期新冠综合征是一种以影响多个器官系统的持续症状为特征的病症。本综述探讨了长期新冠综合征背后的分子和免疫机制，特别关注自噬抑制、慢性炎症、氧化应激、亚硝化应激和钙应激、病毒持续存在及自身免疫。长期新冠综合征涉及的潜在病理生理机制包括：（1）自身免疫激活；（2）潜伏病毒持续存在，即SARS-CoV-2继续影响宿主代谢；（3）潜伏病原体如爱泼斯坦-巴尔病毒（EBV）或巨细胞病毒（CMV）的重新激活，加剧免疫和代谢失调；（4）可能持续存在的代谢和炎症失调，即身体无法恢复感染后的内稳态。SARS-CoV-2蛋白对细胞通路的操控是该病毒逃避免疫清除并导致长期功能障碍能力的关键方面。诸如NSP13、ORF3a和ORF8等病毒蛋白已被证明会破坏自噬，从而损害病毒清除并促进免疫逃逸。此外，线粒体功能障碍、钙信号失调、氧化应激、慢性低氧诱导因子-1α（HIF-1α）激活和核因子E2相关因子2（Nrf2）抑制会形成一个自我维持的炎症反馈回路，导致组织损伤和持续症状。因此，了解长期新冠综合征的分子基础对于开发有效的治疗策略至关重要。靶向自噬和Nrf2激活、抑制糖酵解以及恢复钙稳态可能为减轻SARS-CoV-2感染的长期后果提供新策略。未来的研究应专注于基于个体患者主要分子扰动的个性化治疗干预措施。
