牛病毒性腹泻病毒持续感染胎儿脾脏的表观基因组和蛋白质组变化：对发育中免疫系统、骨骼、大脑和心脏的影响。

Epigenomic and Proteomic Changes in Fetal Spleens Persistently Infected with Bovine Viral Diarrhea Virus: Repercussions for the Developing Immune System, Bone, Brain, and Heart.

机构信息

Animal Reproduction and Biotechnology Laboratory, Department of Biomedical Sciences, Colorado State University, Fort Collins, CO 80523, USA.

Australian Infections Diseases Research Centre, The University of Queensland, St. Lucia, QLD 4072, Australia.

出版信息

Viruses. 2022 Feb 28;14(3):506. doi: 10.3390/v14030506.

DOI:10.3390/v14030506

PMID:35336913

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8949278/

Abstract

Bovine viral diarrhea virus (BVDV) infection during early gestation results in persistently infected (PI) immunotolerant calves that are the primary reservoirs of the virus. Pathologies observed in PI cattle include congenital defects of the brain, heart, and bone as well as marked functional defects in their immune system. It was hypothesized that fetal BVDV infection alters T cell activation and signaling genes by epigenetic mechanisms. To test this, PI and control fetal splenic tissues were collected on day 245 of gestation, 170 days post maternal infection. DNA was isolated for reduced representation bisulfite sequencing, protein was isolated for proteomics, both were analyzed with appropriate bioinformatic methods. Within set parameters, 1951 hypermethylated and 691 hypomethylated DNA regions were identified in PI compared to control fetuses. Pathways associated with immune system, neural, cardiac, and bone development were associated with heavily methylated DNA. The proteomic analysis revealed 12 differentially expressed proteins in PI vs. control animals. Upregulated proteins were associated with protein processing, whereas downregulated proteins were associated with lymphocyte migration and development in PI compared to control fetal spleens. The epigenetic changes in DNA may explain the immune dysfunctions, abnormal bone formation, and brain and heart defects observed in PI animals.

摘要

牛病毒性腹泻病毒（BVDV）在妊娠早期感染会导致持续感染（PI）的免疫耐受小牛，这些小牛是病毒的主要储主。在 PI 牛中观察到的病理学包括脑、心脏和骨骼的先天性缺陷，以及免疫系统的明显功能缺陷。据推测，胎儿 BVDV 感染通过表观遗传机制改变 T 细胞激活和信号基因。为了验证这一点，在母体感染后第 245 天即妊娠 170 天收集 PI 和对照胎儿脾脏组织。用于还原代表性亚硫酸氢盐测序的 DNA 被分离，用于蛋白质组学的蛋白质被分离，两者都用适当的生物信息学方法进行分析。在设定的参数范围内，与对照胎儿相比，PI 胎儿中鉴定出 1951 个高甲基化和 691 个低甲基化 DNA 区域。与免疫系统、神经、心脏和骨骼发育相关的途径与高度甲基化的 DNA 相关。蛋白质组学分析显示，PI 与对照动物相比有 12 种差异表达的蛋白质。与对照胎儿脾脏相比，PI 中上调的蛋白质与蛋白质加工有关，而下调的蛋白质与淋巴细胞迁移和发育有关。DNA 中的表观遗传变化可能解释了 PI 动物中观察到的免疫功能障碍、异常骨形成以及脑和心脏缺陷。