Quantifying the Early Immune Response and Adaptive Immune Response Kinetics in Mice Infected with Influenza A Virus
Quantifying the Early Immune Response and Adaptive Immune Response Kinetics in Mice Infected with Influenza A Virus
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DOI：
10.1128/jvi.00266-10
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发表时间：
2010-07-01
影响因子：
5.4
通讯作者：
Topham, David J.
中科院分区：
文献类型：
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作者：
Miao, Hongyu;Hollenbaugh, Joseph A.;Topham, David J.
季节性和大流行性甲型流感病毒(IAV)仍然是公共卫生的威胁。然而，我们缺乏对IAV感染的免疫反应动力学的详细和定量的了解，以及哪些生物学参数对感染结果影响最大。为了解决这些问题，我们使用建模方法和实验数据相结合的方法来定量研究对初次IAV感染的先天性和获得性免疫反应。建立了描述靶(上皮)细胞、流感病毒、细胞毒性T淋巴细胞(CTL)以及病毒特异性免疫球蛋白和免疫球蛋白之间的动态相互作用的数学模型。通过对340只小鼠的原发H3N2IAV感染获得的大量数据进行模型拟合，估计了IAV和免疫动力学参数。在可检测到的病毒特异性免疫应答前(第5天前)，感染上皮细胞的半衰期约为1.2天，游离感染性IAV的半衰期约为4小时，适应性免疫应答期间(第5天后)，感染上皮细胞的平均半衰期约为0.5天，游离感染性病毒的平均半衰期约为1.8分钟。在适应阶段，模型拟合证实CD8(+)CTL对限制感染细胞至关重要，而病毒特异性IgM调节游离IAV水平。这可能意味着，CD4T细胞和类别转换的免疫球蛋白抗体与产生IAV特异性记忆和通过更快的二次免疫反应预防未来感染更相关。此外，还进行了模拟研究，以了解生物学参数对IAV清除的相对贡献。本研究为更好地了解和预测流感病毒免疫提供了依据。
Seasonal and pandemic influenza A virus (IAV) continues to be a public health threat. However, we lack a detailed and quantitative understanding of the immune response kinetics to IAV infection and which biological parameters most strongly influence infection outcomes. To address these issues, we use modeling approaches combined with experimental data to quantitatively investigate the innate and adaptive immune responses to primary IAV infection. Mathematical models were developed to describe the dynamic interactions between target (epithelial) cells, influenza virus, cytotoxic T lymphocytes (CTLs), and virus-specific IgG and IgM. IAV and immune kinetic parameters were estimated by fitting models to a large data set obtained from primary H3N2 IAV infection of 340 mice. Prior to a detectable virus-specific immune response (before day 5), the estimated half-life of infected epithelial cells is similar to 1.2 days, and the half-life of free infectious IAV is similar to 4 h. During the adaptive immune response (after day 5), the average half-life of infected epithelial cells is similar to 0.5 days, and the average half-life of free infectious virus is similar to 1.8 min. During the adaptive phase, model fitting confirms that CD8(+) CTLs are crucial for limiting infected cells, while virus-specific IgM regulates free IAV levels. This may imply that CD4 T cells and class-switched IgG antibodies are more relevant for generating IAV-specific memory and preventing future infection via a more rapid secondary immune response. Also, simulation studies were performed to understand the relative contributions of biological parameters to IAV clearance. This study provides a basis to better understand and predict influenza virus immunity.