Control theory helps to resolve the measles paradox.
Control theory helps to resolve the measles paradox.
复制标题
控制理论有助于解决麻疹悖论。
DOI：
10.1098/rsos.201891
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发表时间：
2021-04-28
影响因子：
3.5
通讯作者：
Spurgeon SK
中科院分区：
文献类型：
--
作者：
Anelone AJN;Hancock EJ;Klein N;Kim P;Spurgeon SK
麻疹病毒（MV）是一种高度传染性的呼吸道麻疹病毒，导致许多残疾和死亡。研究MV感染的一个关键挑战是了解所谓的“麻疹悖论”-在清除急性病毒血症之前，感染进展为严重的免疫抑制，这也在犬瘟热病毒（CDV）感染中观察到。然而，缺乏与体内数据相匹配的模型限制了我们对这种复杂且反直觉现象的理解。最近，在开发适合恒河猴急性麻疹感染数据的模型方面取得了进展。这一进展促使我们的调查，以获得更多的见解，从这个模型的控制机制的悖论。在本文中，我们研究了分析条件确定MV和CDV的病毒清除的控制和鲁棒性，解开复杂的反馈机制的动态急性感染在其自然宿主。我们将控制理论应用于这个模型，以帮助解决麻疹悖论。我们发现免疫抑制对控制和清除病毒很重要。我们还显示了在何种条件下T细胞杀伤成为免疫抑制和病毒清除的主要机制。此外，我们的特征在于T细胞免疫的鲁棒性，以解释MV和CDV控制的相似性和差异。总之，我们的结果与实验数据一致，推进了对麻疹病毒之间病毒清除控制机制的理解，并将有助于开发有效的治疗方法。此外，分析方法和结果有可能促进对一系列病毒感染（如COVID-19）的免疫系统反应的理解。
Measles virus (MV) is a highly contagious respiratory morbillivirus that results in many disabilities and deaths. A crucial challenge in studying MV infection is to understand the so-called ‘measles paradox’—the progression of the infection to severe immunosuppression before clearance of acute viremia, which is also observed in canine distemper virus (CDV) infection. However, a lack of models that match in vivo data has restricted our understanding of this complex and counter-intuitive phenomenon. Recently, progress was made in the development of a model that fits data from acute measles infection in rhesus macaques. This progress motivates our investigations to gain additional insights from this model into the control mechanisms underlying the paradox. In this paper, we investigated analytical conditions determining the control and robustness of viral clearance for MV and CDV, to untangle complex feedback mechanisms underlying the dynamics of acute infections in their natural hosts. We applied control theory to this model to help resolve the measles paradox. We showed that immunosuppression is important to control and clear the virus. We also showed under which conditions T-cell killing becomes the primary mechanism for immunosuppression and viral clearance. Furthermore, we characterized robustness properties of T-cell immunity to explain similarities and differences in the control of MV and CDV. Together, our results are consistent with experimental data, advance understanding of control mechanisms of viral clearance across morbilliviruses, and will help inform the development of effective treatments. Further the analysis methods and results have the potential to advance understanding of immune system responses to a range of viral infections such as COVID-19.
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