Martinez-Sánchez Mariana Esther, Choreño-Parra José Alberto, Álvarez-Buylla Elena R, Zúñiga Joaquín, Balderas-Martínez Yalbi Itzel
Laboratory of Computational Biology, Instituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas, Mexico City CP 14080, Mexico.
Laboratory of Immunobiology and Genetics, Instituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas, Mexico City CP 14080, Mexico.
Pathogens. 2022 Dec 22;12(1):18. doi: 10.3390/pathogens12010018.
In this model we use a dynamic and multistable Boolean regulatory network to provide a mechanistic explanation of the lymphopenia and dysregulation of CD4+ T cell subsets in COVID-19 and provide therapeutic targets. Using a previous model, the cytokine micro-environments found in mild, moderate, and severe COVID-19 with and without TGF-β and IL-10 was we simulated. It shows that as the severity of the disease increases, the number of antiviral Th1 cells decreases, while the the number of Th1-like regulatory and exhausted cells and the proportion between Th1 and Th1R cells increases. The addition of the regulatory cytokines TFG-β and IL-10 makes the Th1 attractor unstable and favors the Th17 and regulatory subsets. This is associated with the contradictory signals in the micro-environment that activate SOCS proteins that block the signaling pathways. Furthermore, it determined four possible therapeutic targets that increase the Th1 compartment in severe COVID-19: the activation of the IFN-γ pathway, or the inhibition of TGF-β or IL-10 pathways or SOCS1 protein; from these, inhibiting SOCS1 has the lowest number of predicted collateral effects. Finally, a tool is provided that allows simulations of specific cytokine environments and predictions of CD4 T cell subsets and possible interventions, as well as associated secondary effects.
在该模型中，我们使用动态多稳态布尔调控网络来为新冠病毒疾病中淋巴细胞减少和CD4+ T细胞亚群失调提供机制解释，并提供治疗靶点。利用先前的模型，我们模拟了在有或没有转化生长因子-β（TGF-β）和白细胞介素-10（IL-10）的情况下，轻症、中症和重症新冠病毒疾病中的细胞因子微环境。结果显示，随着疾病严重程度增加，抗病毒Th1细胞数量减少，而Th1样调节性和耗竭性细胞数量以及Th1与Th1R细胞之间的比例增加。添加调节性细胞因子TGF-β和IL-10会使Th1吸引子不稳定，并有利于Th17和调节性亚群。这与微环境中激活抑制细胞因子信号传导蛋白（SOCS）从而阻断信号通路的矛盾信号有关。此外，研究确定了在重症新冠病毒疾病中增加Th1区室的四个可能治疗靶点：激活干扰素-γ（IFN-γ）途径，或抑制TGF-β或IL-10途径或SOCS1蛋白；其中，抑制SOCS1的预测副作用数量最少。最后，提供了一个工具，可用于模拟特定细胞因子环境、预测CD4 T细胞亚群及可能的干预措施以及相关的继发效应。
