Deep spatial profiling of Venezuelan equine encephalitis virus reveals increased genetic diversity amidst neuroinflammation and cell death during brain infection.
Deep spatial profiling of Venezuelan equine encephalitis virus reveals increased genetic diversity amidst neuroinflammation and cell death during brain infection.
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DOI：
10.1128/jvi.00827-23
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发表时间：
2023-08-31
影响因子：
5.4
通讯作者：
中科院分区：
文献类型：
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委内瑞拉马脑炎病毒（VEEV）引起一种发热性疾病，可进展为神经系统疾病，在人类病例中可能导致死亡。靶向脑感染的疗法的评估和优化需要了解宿主对VEEV的反应、感染的动力学以及病毒在宿主内进化的潜力。我们假设大脑感染期间的选择性压力可能在时间和空间上不同，因此我们研究了感染后7天（dpi）小鼠大脑8个区域中VEEV TC-83的宿主反应，病毒转录水平和遗传变异的动态。病毒复制在整个大脑中增加，直到5-6 dpi，然后减少，神经元是病毒复制的主要部位。低水平的遗传多样性，注意到1 dpi，随后扩大的VEEV和非同义（NS）突变的遗传多样性达到峰值5 dpi。促炎反应和免疫细胞的流入反映了病毒的水平，并与5 dpi时对神经元的实质性损伤以及小胶质细胞和星形胶质细胞的活化增加相关。Ns突变的流行和动力学表明VEEV在脑内处于选择下，并且进行性神经炎症可能在充当选择性压力中起作用。委内瑞拉马脑炎病毒（VEEV）引起的人类脑炎的治疗是从自然或气溶胶暴露是不可用的，因此，有很大的兴趣，以解决这一差距。与自然感染相反，对气溶胶暴露引起的感染进行治疗需要速效药物，这些药物能够迅速穿透血脑屏障，进入大脑中的感染部位，并减轻耐药性的出现。因此，重要的是不仅要了解VEEV的发病机制，而且要了解脑内病毒种群的运输，病毒在宿主内进化的潜力，以及VEEV如何进化抗性。
Venezuelan equine encephalitis virus (VEEV) causes a febrile illness that can progress to neurological disease with the possibility of death in human cases. The evaluation and optimization of therapeutics that target brain infections demands knowledge of the host’s response to VEEV, the dynamics of infection, and the potential for within-host evolution of the virus. We hypothesized that selective pressures during infection of the brain may differ temporally and spatially and so we investigated the dynamics of the host response, viral transcript levels, and genetic variation of VEEV TC-83 in eight areas of the brain in mice over 7 days post-infection (dpi). Viral replication increased throughout the brain until 5–6 dpi and decreased thereafter with neurons as the main site of viral replication. Low levels of genetic diversity were noted on 1 dpi and were followed by an expansion in the genetic diversity of VEEV and nonsynonymous (Ns) mutations that peaked by 5 dpi. The pro-inflammatory response and the influx of immune cells mirrored the levels of virus and correlated with substantial damage to neurons by 5 dpi and increased activation of microglial cells and astrocytes. The prevalence and dynamics of Ns mutations suggest that the VEEV is under selection within the brain and that progressive neuroinflammation may play a role in acting as a selective pressure. Treatment of encephalitis in humans caused by Venezuelan equine encephalitis virus (VEEV) from natural or aerosol exposure is not available, and hence, there is a great interest to address this gap. In contrast to natural infections, therapeutic treatment of infections from aerosol exposure will require fast-acting drugs that rapidly penetrate the blood-brain barrier, engage sites of infection in the brain and mitigate the emergence of drug resistance. Therefore, it is important to understand not only VEEV pathogenesis, but the trafficking of the viral population within the brain, the potential for within-host evolution of the virus, and how VEEV might evolve resistance.
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影响因子：
3.7
作者：
Kehn-Hall K;Narayanan A;Lundberg L;Sampey G;Pinkham C;Guendel I;Van Duyne R;Senina S;Schultz KL;Stavale E;Aman MJ;Bailey C;Kashanchi F
通讯作者：
Kashanchi F
影响因子：
5.4
作者：
Phillips, Aaron T.;Rico, Amber B.;Olson, Ken E.
通讯作者：
Olson, Ken E.
DOI：
10.1073/pnas.96.24.13910
发表时间：
1999-11-23
影响因子：
11.1
作者：
Drake, JW;Holland, JJ
通讯作者：
Holland, JJ
影响因子：
5.4
作者：
KINNEY, RM;CHANG, GJ;TRENT, DW
通讯作者：
TRENT, DW
影响因子：
7.6
作者：
Jonsson, Colleen B.;Cao, Xufeng;Golden, Jennifer E.
通讯作者：
Golden, Jennifer E.