包含抗原和CD8 T细胞之间相互作用的动力基序可能是病毒感染

StephenW

A dynamical motif comprising the interactions between antigens and CD8 T cells may underlie the outcomes of viral infections
Subhasish Baral, Rustom Antia, and Narendra M. Dixit
PNAS August 27, 2019 116 (35) 17393-17398; first published August 14, 2019 https://doi.org/10.1073/pnas.1902178116

    Edited by Michael B. A. Oldstone, Scripps Research Institute, La Jolla, CA, and approved July 23, 2019 (received for review February 5, 2019)

    Article Figures & SI Info & Metrics
    PDF

Significance

Viral infections have different outcomes in different individuals. They could be cleared spontaneously, turn chronic, or cause host death due to tissue damage. Identifying what determines these outcomes has been a longstanding challenge in immunology. Many factors, including viral inoculum size and host genetics, that influence the outcomes have been identified, suggesting that a complex interplay of numerous factors determines the outcomes. In striking contrast, we argue that the outcomes are determined by a dynamical motif comprising a few, essential interactions between viral antigens and CD8 T cells. The other factors influence the outcomes indirectly by modulating these essential interactions. The motif presents a conceptual understanding of the outcomes, explains several confounding experimental observations, and proposes interventions.
Abstract

Some viral infections culminate in very different outcomes in different individuals. They can be rapidly cleared in some, cause persistent infection in others, and cause mortality from immunopathology in yet others. The conventional view is that the different outcomes arise as a consequence of the complex interactions between a large number of different factors (virus, different immune cells, and cytokines). Here, we identify a simple dynamical motif comprising the essential interactions between antigens and CD8 T cells and posit it as predominantly determining the outcomes. Viral antigen can activate CD8 T cells, which in turn, can kill infected cells. Sustained antigen stimulation, however, can cause CD8 T-cell exhaustion, compromising effector function. Using mathematical modeling, we show that the motif comprising these interactions recapitulates all of the outcomes observed. The motif presents a conceptual framework to understand the variable outcomes of infection. It also explains a number of confounding experimental observations, including the variation in outcomes with the viral inoculum size, the evolutionary advantage of exhaustion in preventing lethal pathology, the ability of natural killer (NK) cells to act as rheostats tuning outcomes, and the role of the innate immune response in the spontaneous clearance of hepatitis C. Interventions that modulate the interactions in the motif may present routes to clear persistent infections or limit immunopathology.

    acute infection chronic infection immunopathology mathematical model bistability

StephenW

包含抗原和CD8 T细胞之间相互作用的动力基序可能是病毒感染结果的基础
Subhasish Baral，Rustom Antia和Narendra M. Dixit
PNAS 2019年8月27日116（35）17393-17398;首次发布于2019年8月14日https://doi.org/10.1073/pnas.1902178116

    由Michael B. A. Oldstone编辑，Scripps研究所，La Jolla，CA，并于2019年7月23日批准（收到2019年2月5日审查）

    文章数据和SI信息和指标
    PDF

意义

病毒感染在不同个体中具有不同的结果。它们可以自发清除，转为慢性，或由于组织损伤导致宿主死亡。确定决定这些结果的因素一直是免疫学的长期挑战。已经确定了影响结果的许多因素，包括病毒接种物大小和宿主遗传，这表明许多因素的复杂相互作用决定了结果。与之形成鲜明对比的是，我们认为结果是由动态基序决定的，其中包括病毒抗原和CD8 T细胞之间的一些必要的相互作用。其他因素通过调节这些基本相互作用间接影响结果。该主题提供了对结果的概念性理解，解释了几个混淆的实验观察，并提出了干预措施。
抽象

一些病毒感染在不同个体中导致非常不同的结果。它们可以在某些情况下迅速清除，在其他情况下导致持续感染，并在其他情况下导致免疫病理学死亡。传统观点认为，由于大量不同因子（病毒，不同免疫细胞和细胞因子）之间复杂的相互作用，会产生不同的结果。在这里，我们确定一个简单的动力学基序，包括抗原和CD8 T细胞之间的基本相互作用，并假定它主要决定结果。病毒抗原可激活CD8 T细胞，而CD8 T细胞又可杀死受感染的细胞。然而，持续的抗原刺激可导致CD8 T细胞衰竭，影响效应功能。使用数学建模，我们表明包含这些相互作用的基序概括了所观察到的所有结果。该主题提供了一个概念框架，以了解感染的可变结果。它还解释了许多令人困惑的实验观察结果，包括病毒接种体大小结果的变化，预防致死病理的耗尽的进化优势，自然杀伤（NK）细胞作为变阻器调整结果的能力，以及作用在丙型肝炎的自发清除中的先天免疫应答中，调节基序中相互作用的干预可以提供清除持续感染或限制免疫病理学的途径。

    急性感染慢性感染免疫病理学数学模型双稳态

StephenW

https://www.pnas.org/content/pnas/116/35/17393.full.pdf