Simulation and Prediction of the Adaptive Immune Response to Influenza A Virus Infection
Simulation and Prediction of the Adaptive Immune Response to Influenza A Virus Infection
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DOI：
10.1128/jvi.00098-09
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发表时间：
2009-07-15
影响因子：
5.4
通讯作者：
Wu, Hulin
中科院分区：
文献类型：
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作者：
Lee, Ha Youn;Topham, David J.;Wu, Hulin
对原发性流感病毒感染的细胞免疫反应很复杂，涉及多种细胞类型和解剖区室，并且难以直接测量。在这里，我们开发了一个两室模型，可以量化病毒复制和适应性免疫之间的相互作用。通过准确确认 CD4 对抗体持久性的帮助作用以及免疫耗竭实验的后果，证明了模型的保真度。该模型预测，限制病毒感染和/或产生的药物必须在感染后 2 天内施用，早期施用可带来联合治疗的好处，并且肺部的细胞毒性 CD8 T 细胞在病毒清除方面与攻击时存在的中和抗体一样有效。该模型可用于研究明确的生物场景并生成可通过实验检验的假设。例如，当适应性反应依赖于细胞免疫细胞启动时，抗原呈递的调节对病毒清除动力学的影响比病毒中和或细胞毒性的效率更大。这些发现表明，调节抗原呈递或肺驻留细胞毒性细胞的数量以及联合药物干预是对抗高毒力流感病毒的策略。我们进一步比较了替代模型结构，例如，病毒直接激活 B 细胞与通过专业抗原呈递细胞或 CD8 T 细胞的树突状细胞许可激活 B 细胞。
The cellular immune response to primary influenza virus infection is complex, involving multiple cell types and anatomical compartments, and is difficult to measure directly. Here we develop a two-compartment model that quantifies the interplay between viral replication and adaptive immunity. The fidelity of the model is demonstrated by accurately confirming the role of CD4 help for antibody persistence and the consequences of immune depletion experiments. The model predicts that drugs to limit viral infection and/or production must be administered within 2 days of infection, with a benefit of combination therapy when administered early, and cytotoxic CD8 T cells in the lung are as effective for viral clearance as neutralizing antibodies when present at the time of challenge. The model can be used to investigate explicit biological scenarios and generate experimentally testable hypotheses. For example, when the adaptive response depends on cellular immune cell priming, regulation of antigen presentation has greater influence on the kinetics of viral clearance than the efficiency of virus neutralization or cellular cytotoxicity. These findings suggest that the modulation of antigen presentation or the number of lung resident cytotoxic cells and the combination drug intervention are strategies to combat highly virulent influenza viruses. We further compared alternative model structures, for example, B-cell activation directly by the virus versus that through professional antigen-presenting cells or dendritic cell licensing of CD8 T cells.