Koujah Lulia, Allaham Mowafak, Patil Chandrashekhar D, Ames Joshua M, Suryawanshi Rahul K, Yadavalli Tejabhiram, Agelidis Alex, Mun Christine, Surenkhuu Bayasgalan, Jain Sandeep, Shukla Deepak
Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, IL, 60612, USA; Department of Microbiology and Immunology, University of Illinois at Chicago, Chicago, IL, 60612, USA.
Department of Mathematics, Statistics and Computer Science, University of Illinois at Chicago, Chicago, IL, 60612, USA.
Ocul Surf. 2021 Jul;21:238-249. doi: 10.1016/j.jtos.2021.03.005. Epub 2021 Mar 22.
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.
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、基质性角膜炎和脑炎的发生。虽然宿主免疫在疾病进展中的作用已得到充分了解，但基因变异在人类中产生优先的病毒进入受体使用以及由此导致的免疫发病机制方面的作用尚不清楚。
从表现出单纯疱疹性角膜炎（HSK）不同病理特征的患者中获取眼部培养物。下一代测序及后续分析对菌株间的基因变异进行了表征，并估计了进化分歧。使用眼部感染的小鼠模型评估菌株变异对眼表损伤和先天免疫传播的表型贡献。对眼组织进行流式细胞术分析，以确定免疫细胞群体的差异募集，通过细胞因子阵列检测引流淋巴结中局部免疫反应的编程情况，并利用组织学评估三叉神经节（TG）的炎症。体外角膜培养和体外研究阐明了基因变异在改变宿主-病原体相互作用从而导致不同宿主反应方面的作用。
对临床分离株的系统发育分析表明，目前流行的HSV-1菌株之间存在进化分歧。鉴定出了导致功能性宿主相互作用改变的突变，特别是在病毒进入糖蛋白中，这些突变产生了对疱疹病毒进入介质的受体偏向性，疱疹病毒进入介质是一种参与HSK等免疫致病疾病的免疫调节剂，导致眼表病理加重以及TG和脑干中的病毒载量增加。
我们的数据表明，临床菌株中的基因变异导致的受体偏向性可能决定疾病的严重程度和治疗结果。
