Entry receptor bias in evolutionarily distant HSV-1 clinical strains drives divergent ocular and nervous system pathologies.
Entry receptor bias in evolutionarily distant HSV-1 clinical strains drives divergent ocular and nervous system pathologies.
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DOI：
10.1016/j.jtos.2021.03.005
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发表时间：
2021-07
期刊：
影响因子：
--
通讯作者：
Shukla D
中科院分区：
文献类型：
--
作者：
Koujah L;Allaham M;Patil CD;Ames JM;Suryawanshi RK;Yadavalli T;Agelidis A;Mun C;Surenkhuu B;Jain S;Shukla D
单纯疱疹病毒1型(HSV-1)感染会导致多种病理变化，包括眼部病变、间质性角膜炎和脑炎。虽然宿主免疫在疾病进展中的作用已被很好地了解，但在人类中，遗传变异在产生优先病毒进入受体使用和由此导致的免疫发病机制中的作用尚不清楚。眼部培养取自表现出不同病理的单纯疱疹病毒性角膜炎(HSK)患者。下一代测序和随后的分析表征了菌株之间的遗传差异，并估计了进化差异。利用小鼠眼部感染模型，评估了菌株变异对眼表损伤和先天免疫传播的表型贡献。眼组织流式细胞术检测免疫细胞群的差异性募集，细胞因子阵列检测引流淋巴结局部免疫反应的程序，组织学检测三叉神经节(TG)的炎症。体外角膜培养和体外研究阐明了遗传变异在改变宿主-病原体相互作用中的作用，导致宿主反应不同。对临床分离株的系统发育分析表明，目前流行的HSV-1毒株之间存在进化差异。发现了引起宿主功能相互作用改变的突变，特别是病毒进入糖蛋白，它产生了对疱疹病毒进入介体的受体偏爱，疱疹病毒介体是一种免疫调节剂，参与了HSK等免疫致病，导致眼表病变加重，TG和脑干中的病毒负荷增加。我们的数据表明，临床菌株的遗传差异导致的受体偏差可能决定疾病的严重程度和治疗结果。
Herpes simplex virus-1 (HSV-1) infection leads to varying pathologies including the development of ocular lesions, stromal keratitis and encephalitis. While the role for host immunity in disease progression is well understood, the contribution of genetic variances in generating preferential viral entry receptor usage and resulting immunopathogenesis in humans are not known. Ocular cultures were obtained from patients presenting distinct pathologies of herpes simplex keratitis (HSK). Next-generation sequencing and subsequent analysis characterized genetic variances among the strains and estimated evolutionary divergence. Murine model of ocular infection was used to assess phenotypic contributions of strain variances on damage to the ocular surface and propagation of innate immunity. Flow cytometry of eye tissue identified differential recruitment of immune cell populations, cytokine array probed for programming of local immune response in the draining lymph node and histology was used to assess inflammation of the trigeminal ganglion (TG). Ex-vivo corneal cultures and in-vitro studies elucidated the role of genetic variances in altering host-pathogen interactions, leading to divergent host responses. Phylogenetic analysis of the clinical isolates suggests evolutionary divergence among currently circulating HSV-1 strains. Mutations causing alterations in functional host interactions were identified, particularly in viral entry glycoproteins which generated a receptor bias to herpesvirus entry mediator, an immune modulator involved in immunopathogenic diseases like HSK, leading to exacerbated ocular surface pathologies and heightened viral burden in the TG and brainstem. Our data suggests receptor bias resulting from genetic variances in clinical strains may dictate disease severity and treatment outcome.
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单纯疱疹病毒1型糖蛋白GC的补体相互作用结构域的体内作用。
影响因子：
15.3
作者：
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通讯作者：
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影响因子：
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作者：
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影响因子：
4.8
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通讯作者：
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影响因子：
3.7
作者：
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通讯作者：
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影响因子：
5.4
作者：
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通讯作者：
Rixon, FJ