Determinants of host susceptibility to murine respiratory syncytial virus (RSV) disease identify a role for the innate immunity scavenger receptor MARCO gene in human infants
Determinants of host susceptibility to murine respiratory syncytial virus (RSV) disease identify a role for the innate immunity scavenger receptor MARCO gene in human infants
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DOI：
10.1016/j.ebiom.2016.08.011
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发表时间：
2016-09-01
期刊：
影响因子：
11.1
通讯作者：
Kleeberger, Steven R.
中科院分区：
文献类型：
--
作者：
High, Monica;Cho, Hye-Youn;Kleeberger, Steven R.
背景：呼吸道合胞病毒（RSV）是全球导致婴儿下呼吸道感染的主要原因。近30%的受感染婴儿发展为包括细支气管炎在内的严重疾病，但易感机制尚不清楚。方法：我们用30个自交系小鼠感染RSV，测量感染后1天和5天肺部疾病参数的变化，并将其用于全基因组关联（GWA）研究，以确定数量性状位点（QTL）和易感基因候选基因。结果：GWA鉴定出RSV疾病表型的qtl，先天免疫清道夫受体Marco为候选易感基因；靶向删除Marco会加重小鼠RSV疾病。我们鉴定了一个人类MARCO启动子SNP，该SNP导致基因表达缺失，增加了体外细胞对RSV感染的反应，并与两个独立RSV感染儿童的疾病严重程度风险增加相关。解释：遗传动物模型和体外人类研究的翻译整合确定了MARCO在人类RSV疾病严重程度中的作用。由于没有RSV疫苗被批准用于临床使用，基因研究对诊断有严重RSV疾病风险的个体和疾病预防策略（例如RSV抗体）具有重要意义。Elsevier B.V.出版
Background: Respiratory syncytial virus (RSV) is the global leading cause of lower respiratory tract infection in infants. Nearly 30% of all infected infants develop severe disease including bronchiolitis, but susceptibility mechanisms remain unclear.Methods: We infected a panel of 30 inbred strains of mice with RSV and measured changes in lung disease parameters 1 and 5 days post-infection and they were used in genome-wide association (GWA) studies to identify quantitative trait loci (QTL) and susceptibility gene candidates.Findings: GWA identified QTLs for RSV disease phenotypes, and the innate immunity scavenger receptor Marco was a candidate susceptibility gene; targeted deletion of Marco worsened murine RSV disease. We characterized a human MARCO promoter SNP that caused loss of gene expression, increased in vitro cellular response to RSV infection, and associated with increased risk of disease severity in two independent populations of children infected with RSV.Interpretation: Translational integration of a genetic animal model and in vitro human studies identified a role for MARCO in human RSV disease severity. Because no RSV vaccines are approved for clinical use, genetic studies have implications for diagnosing individuals who are at risk for severe RSV disease, and disease prevention strategies (e.g. RSV antibodies). Published by Elsevier B.V.