[论文解读] Cellular reproduction number, generation time and growth rate differ between human- and avian-adapted influenza strains

Ada W. C. Yan, Jie Zhou+4 more|arXiv (Cornell University)|Mar 19, 2019

Influenza Virus Research Studies参考文献 51被引用 3

一句话总结

本研究提出，细胞基本再生数（R₀）、平均世代时间（τG）和初始增长速率（r）是流感病毒适应人类的关键预测因子。通过拟合人源与禽源流感病毒株体外数据的机制模型，作者发现适应人类的毒株表现出更低的R₀、更短的τG和更慢的r，这些差异由病毒内部基因驱动。这些参数可通过高通量检测量化宿主适应性，从而为大流行风险评估提供依据。

ABSTRACT

When analysing in vitro data, growth kinetics of influenza strains are often compared by computing their growth rates, which are sometimes used as proxies for fitness. However, analogous to mechanistic epidemic models, the growth rate can be defined as a function of two parameters: the basic reproduction number (the average number of cells each infected cell infects) and the mean generation time (the average length of a replication cycle). Using a mechanistic model, previously published data from experiments in human lung cells, and newly generated data, we compared estimates of all three parameters for six influenza A strains. Using previously published data, we found that the two human-adapted strains (pre-2009 seasonal H1N1, and pandemic H1N1) had a lower basic reproduction number, shorter mean generation time and slower growth rate than the two avian-adapted strains (H5N1 and H7N9). These same differences were then observed in data from new experiments where two strains were engineered to have different internal proteins (pandemic H1N1 and H5N1), but the same surface proteins (PR8), confirming our initial findings and implying that differences between strains were driven by internal genes. Also, the model predicted that the human-adapted strains underwent more replication cycles than the avian-adapted strains by the time of peak viral load, potentially accumulating mutations more quickly. These results suggest that the in vitro reproduction number, generation time and growth rate differ between human-adapted and avian-adapted influenza strains, and thus could be used to assess host adaptation of internal proteins to inform pandemic risk assessment.

研究动机与目标

• 识别可预测流感毒株宿主适应性的定量体外参数，以弥补当前基于动物的大流行风险评估的局限性。
• 评估细胞基本再生数（R₀）、平均世代时间（τG）和初始增长速率（r）在人类适应与禽类适应流感毒株之间是否存在差异。
• 确定这些参数是否可作为高通量、定量的宿主适应性和大潜伏期预测指标，用于监测和公共卫生决策。
• 探究病毒内部基因在驱动人类与禽类适应毒株之间感染动力学差异中的作用。

提出的方法

• 开发了一种针对人肺细胞中流感感染的机制性常微分方程（ODE）模型，追踪靶细胞（T）、潜伏感染细胞（L）、活跃感染细胞（I）和感染性病毒（Vinf）。
• 模型将R₀估算为 R₀ = (β_inf * T₀ * p_inf * τ_I) / (c + β_inf * T₀)，其中β_inf为感染率，p_inf为病毒产生率，τ_I为感染细胞寿命，c为清除率。
• 平均世代时间τG计算为 τL + [(n_I + 1)/(2n_I)] * τ_I + 1/(c + β_inf * T₀)，综合考虑潜伏期、感染期和病毒清除。
• 初始增长速率r通过在无病平衡点（T₀, 0, 0, 0）附近线性化模型获得。
• 参数估计采用自适应Metropolis-Hastings算法，基于多周期、单周期和空白对照产量的实验数据组合，采用对数正态观测误差，并设定低滴度的阈值。
• 实施了世代追踪扩展，以计算某一时刻来自各代病毒颗粒的比例，从而支持对复制周期的分析。

实验结果

研究问题

• RQ1 人类适应与禽类适应流感毒株在细胞基本再生数（R₀）、平均世代时间（τG）和初始增长速率（r）方面是否存在差异？
• RQ2 这些参数的差异是由内部病毒基因还是表面糖蛋白驱动的？
• RQ3 R₀、τG和r能否作为宿主适应性和大流行潜力的定量、高通量预测指标？
• RQ4 在达到病毒载量峰值时，人类适应与禽类适应毒株在复制周期数和突变累积方面有何差异？

主要发现

• 人类适应毒株（2009年之前季节性H1N1和大流行H1N1）的R₀显著低于禽类适应毒株（H5N1和H7N9）。
• 人类适应毒株表现出比禽类适应毒株更短的平均世代时间（τG），表明其复制周期更快。
• 人类适应毒株的初始增长速率（r）低于禽类适应毒株，与较低的R₀和更短的τG一致。
• 在表面蛋白相同（PR8 HA/NA）但内部蛋白不同（大流行H1N1 vs. H5N1）的改造毒株中，观察到相同的R₀、τG和r差异，证实内部基因驱动了所观察到的动力学差异。
• 模型预测，人类适应毒株在达到病毒载量峰值时经历了比禽类适应毒株更多的复制周期，可能加速突变累积。
• 这三个参数——R₀、τG和r——在人类与禽类适应流感毒株之间系统性不同，表明其在量化宿主适应性及支持大流行风险评估方面具有实用价值。