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Discrete Dynamical Modeling of Influenza Virus Infection Suggests Age-Dependent Differences in Immunity
Journal of Virology ( IF 4.0 ) Pub Date : 2017-12-01 , DOI: 10.1128/jvi.00395-17
Ericka Keef 1 , Li Ang Zhang 2 , David Swigon 3, 4 , Alisa Urbano 5 , G Bard Ermentrout 3 , Michael Matuszewski 2 , Franklin R Toapanta 6 , Ted M Ross 6 , Robert S Parker 2, 4, 7, 8 , Gilles Clermont 2, 4, 7, 8
Affiliation  

Immunosenescence, an age-related decline in immune function, is a major contributor to morbidity and mortality in the elderly. Older hosts exhibit a delayed onset of immunity and prolonged inflammation after an infection, leading to excess damage and a greater likelihood of death. Our study applies a rule-based model to infer which components of the immune response are most changed in an aged host. Two groups of BALB/c mice (aged 12 to 16 weeks and 72 to 76 weeks) were infected with 2 inocula: a survivable dose of 50 PFU and a lethal dose of 500 PFU. Data were measured at 10 points over 19 days in the sublethal case and at 6 points over 7 days in the lethal case, after which all mice had died. Data varied primarily in the onset of immunity, particularly the inflammatory response, which led to a 2-day delay in the clearance of the virus from older hosts in the sublethal cohort. We developed a Boolean model to describe the interactions between the virus and 21 immune components, including cells, chemokines, and cytokines, of innate and adaptive immunity. The model identifies distinct sets of rules for each age group by using Boolean operators to describe the complex series of interactions that activate and deactivate immune components. Our model accurately simulates the immune responses of mice of both ages and with both inocula included in the data (95% accurate for younger mice and 94% accurate for older mice) and shows distinct rule choices for the innate immunity arm of the model between younger and aging mice in response to influenza A virus infection.

IMPORTANCE Influenza virus infection causes high morbidity and mortality rates every year, especially in the elderly. The elderly tend to have a delayed onset of many immune responses as well as prolonged inflammatory responses, leading to an overall weakened response to infection. Many of the details of immune mechanisms that change with age are currently not well understood. We present a rule-based model of the intrahost immune response to influenza virus infection. The model is fit to experimental data for young and old mice infected with influenza virus. We generated distinct sets of rules for each age group to capture the temporal differences seen in the immune responses of these mice. These rules describe a network of interactions leading to either clearance of the virus or death of the host, depending on the initial dosage of the virus. Our models clearly demonstrate differences in these two age groups, particularly in the innate immune responses.



中文翻译:


流感病毒感染的离散动态模型表明免疫力存在年龄依赖性差异



免疫衰老是一种与年龄相关的免疫功能下降,是老年人发病和死亡的主要原因。老年宿主在感染后表现出免疫力延迟和炎症延长,导致过度损伤和更大的死亡可能性。我们的研究应用基于规则的模型来推断老年宿主中免疫反应的哪些组成部分变化最大。两组 BALB/c 小鼠(12 至 16 周和 72 至 76 周)分别感染 2 种接种物:存活剂量为 50 PFU,致死剂量为 500 PFU。在亚致死病例中,在 19 天内测量了 10 个点的数据;在致死病例中,在 7 天内测量了 6 个点的数据,之后所有小鼠均死亡。数据的变化主要在于免疫的开始,特别是炎症反应,这导致亚致死队列中老年宿主清除病毒的时间延迟了两天。我们开发了一个布尔模型来描述病毒与先天免疫和适应性免疫的 21 种免疫成分(包括细胞、趋化因子和细胞因子)之间的相互作用。该模型通过使用布尔运算符来描述激活和停用免疫组件的一系列复杂的相互作用,从而识别每个年龄组的不同规则集。我们的模型准确地模拟了数据中包含两种接种物的两个年龄小鼠的免疫反应(年轻小鼠的准确度为 95%,老年小鼠的准确度为 94%),并显示了模型的先天免疫臂在年轻小鼠之间的不同规则选择以及衰老小鼠对甲型流感病毒感染的反应。


重要性流感病毒感染每年都会导致很高的发病率和死亡率,尤其是老年人。老年人的许多免疫反应往往会延迟发生,并且炎症反应也会延长,从而导致对感染的整体反应减弱。随着年龄的增长而变化的免疫机制的许多细节目前尚不清楚。我们提出了一种基于规则的流感病毒感染宿主内免疫反应模型。该模型适合感染流感病毒的年轻和年老小鼠的实验数据。我们为每个年龄组生成了不同的规则集,以捕获这些小鼠免疫反应中观察到的时间差异。这些规则描述了导致病毒清除或宿主死亡的相互作用网络,具体取决于病毒的初始剂量。我们的模型清楚地证明了这两个年龄组的差异,特别是在先天免疫反应方面。

更新日期:2017-11-15
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