El Houdi Meriem, Skhoun Hanaa, Guennoun Aya, Dakka Nadia, Ameziane El Hassani Rabii, Ouzzif Zohra, El Baghdadi Jamila
Genetics Unit, Military Hospital Mohammed V, Rabat, Morocco.
Laboratory of Human Pathologies Biology and Genomic Center of Human Pathologies, Department of Biology, Faculty of Sciences, Mohammed V University in Rabat, Rabat, Morocco.
Mol Biol Rep. 2025 Jul 18;52(1):733. doi: 10.1007/s11033-025-10843-2.
Genetic alterations affecting the immune-related pathways can significantly disrupt the innate immune system among patients with COVID-19, contributing to disease severity. Research investigations have shown that common or rare mutations in TLR genes, mainly TLR3 and TLR7, can impair the recognition of viral RNA, leading to an altered interferon response. Moreover, the NF-κB pathway, which represents a vital regulator of inflammatory cytokine production, may also be genetically disturbed, resulting in either insufficient inflammatory signaling or, adversely, excessive cytokine release in the most severe cases. Alterations in the JAK/STAT signaling pathway that mediates the downstream effects of type I interferons and other cytokines, can further compromise the antiviral defenses. The purpose of this review is to outline recent literature describing the current understanding of immunogenetic mechanisms in response to SARS-CoV-2 infection, with an emphasis on TLR and JAK/STAT signaling pathways. We aimed to investigate important variants within the genes related to these cascades and their involvement in COVID-19 severity. We also discussed emerging therapeutic strategies, especially the JAK/STAT modulators and TLR antagonists in severe COVID-19.Despite significant advances in targeting JAK/STAT pathways for the treatment of COVID-19, these approaches can show partial efficacy in monitoring critical inflammatory responses, due to the rapid viral evolution. Moreover, JAK inhibitors, being beneficial in decreasing hyperinflammation, may present potential side effects, particularly linked to immunosuppression. Hence, by integrating genetic profiling and modulation of immunity pathways, novel precision medicine approaches may greatly optimize treatment strategies and COVID-19 patient outcomes.
影响免疫相关通路的基因改变可显著扰乱新冠肺炎患者的固有免疫系统，导致疾病严重程度增加。研究调查表明，TLR基因（主要是TLR3和TLR7）的常见或罕见突变会损害对病毒RNA的识别，导致干扰素反应改变。此外，作为炎症细胞因子产生的重要调节因子的NF-κB通路也可能受到基因干扰，导致炎症信号不足，或者在最严重的情况下，导致细胞因子过度释放。介导I型干扰素和其他细胞因子下游效应的JAK/STAT信号通路的改变，会进一步损害抗病毒防御。本综述的目的是概述最近的文献，描述目前对SARS-CoV-2感染免疫遗传机制的理解，重点是TLR和JAK/STAT信号通路。我们旨在研究与这些级联反应相关的基因中的重要变体及其与新冠肺炎严重程度的关系。我们还讨论了新兴的治疗策略，特别是严重新冠肺炎中的JAK/STAT调节剂和TLR拮抗剂。尽管在针对JAK/STAT通路治疗新冠肺炎方面取得了重大进展，但由于病毒的快速进化，这些方法在监测关键炎症反应方面可能显示出部分疗效。此外，JAK抑制剂虽然有利于减轻过度炎症，但可能会出现潜在的副作用，特别是与免疫抑制有关的副作用。因此，通过整合基因分析和免疫通路调节，新的精准医学方法可能会极大地优化治疗策略和新冠肺炎患者的治疗效果。
