Evolution of highly pathogenic H5N1 influenza A virus in the central nervous system of ferrets.
Evolution of highly pathogenic H5N1 influenza A virus in the central nervous system of ferrets.
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DOI：
10.1371/journal.ppat.1011214
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发表时间：
2023-03
期刊：
影响因子：
6.7
通讯作者：
中科院分区：
文献类型：
--
作者：
中枢神经系统（CNS）疾病是人类甲型流感病毒感染最常见的呼吸道外并发症。值得注意的是，人畜共患高致病性禽流感（HPAI）H5 N1病毒感染往往比季节性流感病毒感染更容易引起中枢神经系统疾病。在呼吸道感染的背景下，禽流感病毒的进化已被广泛研究，但中枢神经系统感染的进化过程仍然知之甚少。我们先前已经观察到HPAI A/Indonesia/5/2005（H5 N1）病毒在CNS中复制和传播的能力在个体雪貂之间差异很大。基于这些观察结果，我们试图了解进入和复制的CNS内的病毒种群的进化动力学的影响。首先，我们确定并表征了三个取代-PB 1 E177 G和A652 T和NP I119 M-在感染流感A/印度尼西亚/5/2005（H5 N1）病毒的雪貂的CNS中检测到，该雪貂发展为严重的脑膜脑炎。我们发现，这些取代中的一些，单独或集体，导致体外聚合酶活性增加。然而，在体内，携带CNS相关突变的病毒保留了其感染CNS的能力，但表现出减少分散到其他解剖部位。对鼻甲骨和嗅球中病毒多样性的分析显示，通过该途径进入CNS的病毒群体缺乏遗传瓶颈。此外，携带CNS相关突变的病毒群体在脑干中显示出阳性选择的迹象。这些向中枢神经系统传播的特征与选择性过程的作用一致，强调了H5 N1病毒适应中枢神经系统的潜力。中枢神经系统（CNS）是甲型流感病毒最常见的呼吸道外感染部位之一。在雪貂--一种用于研究流感发病机制的动物模型--中，高致病性禽流感H5 N1病毒可通过嗅觉神经进入中枢神经系统，导致严重的脑膜脑炎的发展。在目前的工作中，我们评估了病毒种群进入和传播整个CNS的进化动力学。我们表明，一旦进入中枢神经系统，H5 N1病毒可以获得突变，增加体外聚合酶活性。在体内，携带这些突变的病毒保留了其感染CNS的能力，但显示出向其他解剖部位的扩散减少。对病毒种群的分析表明，从鼻甲到嗅球的感染并不存在遗传瓶颈，这表明病毒从鼻腔扩散到CNS。在中枢神经系统内部，特别是脑干，我们发现了正选择的迹象。这些发现支持了H5 N1病毒可以通过嗅觉神经有效地侵入中枢神经系统的想法，并具有适应中枢神经系统的潜力。
Central nervous system (CNS) disease is the most common extra-respiratory tract complication of influenza A virus infections in humans. Remarkably, zoonotic highly pathogenic avian influenza (HPAI) H5N1 virus infections are more often associated with CNS disease than infections with seasonal influenza viruses. Evolution of avian influenza viruses has been extensively studied in the context of respiratory infections, but evolutionary processes in CNS infections remain poorly understood. We have previously observed that the ability of HPAI A/Indonesia/5/2005 (H5N1) virus to replicate in and spread throughout the CNS varies widely between individual ferrets. Based on these observations, we sought to understand the impact of entrance into and replication within the CNS on the evolutionary dynamics of virus populations. First, we identified and characterized three substitutions–PB1 E177G and A652T and NP I119M - detected in the CNS of a ferret infected with influenza A/Indonesia/5/2005 (H5N1) virus that developed a severe meningo-encephalitis. We found that some of these substitutions, individually or collectively, resulted in increased polymerase activity in vitro. Nevertheless, in vivo, the virus bearing the CNS-associated mutations retained its capacity to infect the CNS but showed reduced dispersion to other anatomical sites. Analyses of viral diversity in the nasal turbinate and olfactory bulb revealed the lack of a genetic bottleneck acting on virus populations accessing the CNS via this route. Furthermore, virus populations bearing the CNS-associated mutations showed signs of positive selection in the brainstem. These features of dispersion to the CNS are consistent with the action of selective processes, underlining the potential for H5N1 viruses to adapt to the CNS. The central nervous system (CNS) is one of the most common extra-respiratory tract sites of infection for influenza A viruses. In ferrets—an animal model used to study the pathogenesis of influenza—highly pathogenic avian influenza H5N1 virus can enter the CNS via the olfactory nerve, resulting in the development of a severe meningo-encephalitis. In the present work, we evaluated the evolutionary dynamics of the virus populations entering and spreading throughout the CNS. We show that once inside the CNS, H5N1 viruses can acquire mutations that increase the polymerase activity in vitro. In vivo, the virus bearing these mutations retained its capacity to infect the CNS but showed reduced spread to other anatomical sites. Analysis of virus populations revealed that infection from the nasal turbinate to the olfactory bulb did not present a genetic bottleneck, suggesting a diffusive passage of viruses from the nasal cavity to the CNS. Inside the CNS, specifically in the brainstem, we found signs of positive selection. These findings support the idea that H5N1 viruses can invade the CNS efficiently via the olfactory nerve, and have the potential to adapt to the CNS.
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