Genetic Basis for Sensitivity of Neonates to Retroviruses

新生儿对逆转录病毒敏感性的遗传基础

• 批准号: 9195081
• 负责人: Tatyana V Golovkina
• 金额: $ 19.75万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-12-15 至 2017-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9195081
• 关键词: Adult; Affect; Age; Agreement; Alleles; Animals; Antibodies; Antibody Response; Antigen Presentation; Bacterial Artificial Chromosomes; Bioinformatics; Birth; Breast Feeding; Candidate Disease Gene; Chromosomes, Human, Pair 15; Chromosomes, Human, Pair 17; Databases; Dimerization; Genes; Genetic; Genomics; Goals; HIV; Histocompatibility; Human; I/LnJ Mouse; Immune response; Immune system; Impairment; Inbred C57BL Mice; Inbred Mouse; Infection; Infection Control; Leptin; Life; Link; MHC Class II Genes; Maps; Mediating; Mothers; Mouse Mammary Tumor Virus; Murine leukemia virus; Mus; Names; Neonatal; Newborn Infant; Penetrance; Peptides; Predisposition; Privatization; Recombinants; Resistance; Retroviridae; Risk; T-Lymphocyte; Time; Transgenic Organisms; Vaccination; Vaccines; Virus; congenic; dimer; experience; genome wide association study; human disease; leukemia virus; mouse model; mutant; neonate; neutralizing antibody; pathogen; positional cloning; public health relevance; resistance gene; response; tool

 DESCRIPTION (provided by applicant) Rare humans demonstrate resistance to retroviral infections. Although GWAS studies point at genetic loci that are behind the resistance, pinpointing resistance genes in humans is too complicated, and so far has not led to any clear results. At the same time, inbred mice offer a great alternative for mapping mammalian genes responsible for resistance and susceptibility to retroviruses. Our group has described a locus named 'virus infectivity controller 1' (vic1) in mice from the I/LnJ strain. The vic1 locus contains a recessive retrovirus resistance-conferring gene mapped to Chromosome 17. vic1 confers resistance to two distinct retroviruses: MuLV and a Mouse Mammary Tumor Virus (MMTV). Using congenic and bacterial artificial chromosome (BAC) transgenic and computational approaches we fine-mapped the vic1 locus to a 32Kb region and identified a non- classical major histocompatibility class II (MHC class II) gene, H2-Ob (Ob) as the gene encoding for Vic1. The evolutionarily conserved Ob encodes the Oβ molecule, a part of a heterodimer with Oα, which together compose the DO molecule. It is thought that DO interacts with the DMDM dimer, modifying its ability to edit the loading of antigenic peptides onto classical MHC class II molecules in endocytic compartments. The precise function of DO is unclear, but it appears to affect the repertoire of antigenic peptides presented to T cells. This is in agreement with our finding that the I/LnJ Ob allele promotes a broad-spectrum Ab response in infected mice correlating with very low levels of Ob protein in I/LnJ mice. We have shown that this is due to a reduced inhibitory effect of O on antigen presentation. When the I/LnJ Ob allele was moved to several virus-susceptible backgrounds, such as C3H/HeN, B6 and BALB/cJ, it conferred the ability to produce virus-neutralizing Abs to these mice. However, the effect had high penetrance only if these animals were infected as adults. In contrast, I/LnJ mice produce virus-neutralizing Abs irrespective of their age at infectin and even when infected as newborns. We have found that the ability to respond to the virus as neonates was linked to a single dominant locus (vic2) mapped to a 30 Mb region of Chromosome 15. vic2 is a modifier of Ob and inheritance of both Ob and vic2 of the I/LnJ origin confers the ability to produce anti-virus Abs to neonatal mice from all susceptible strains. Retroviruses infect adults, but are also passed from mothers to newborns during birth and through breastfeeding. It is commonly accepted that the immune system of a newborn is undeveloped, increasing the risk of infection and impairing responses to many vaccines. However, I/LnJ mice generate virus-neutralizing immune response independently of the age at which they were exposed to the pathogen. Thus, it is fundamentally important to unravel the mechanism of Vic2 function in order to understand the unknown features of the neonate immune system and to reach the goal of high efficacy of early-life vaccination.

 描述（由申请人提供） 罕见的人类表现出对逆转录病毒感染的抵抗力。尽管全基因组关联分析（GWAS）研究指出了耐药性背后的基因位点，但精确定位人类的耐药基因过于复杂，迄今为止还没有得出任何明确的结果。与此同时，近交小鼠为绘制负责逆转录病毒抗性和易感性的哺乳动物基因图谱提供了一个很好的选择。我们的小组在小鼠中描述了一个名为“病毒感染控制器 1”(vic1) 的位点 来自 I/LnJ 菌株。 vic1 基因座包含映射到 17 号染色体的隐性逆转录病毒抗性基因。vic1 赋予对两种不同逆转录病毒的抗性：MuLV 和小鼠乳腺肿瘤病毒 (MMTV)。使用同源和细菌人工染色体 (BAC) 转基因和计算方法，我们将 vic1 基因座精细定位到 32Kb 区域，并鉴定出一个非经典主要组织相容性 II 类 (MHC II 类) 基因 H2-Ob (Ob) 作为 Vic1 的编码基因。 进化上保守的 Ob 编码 Oβ 分子，它是与 Oα 异二聚体的一部分，它们一起组成了 DO 分子。据认为，DO 与 DMDM 二聚体相互作用，改变其在内吞区室中编辑抗原肽加载到经典 MHC II 类分子上的能力。 DO 的确切功能尚不清楚，但它似乎会影响呈递给 T 细胞的抗原肽库。这与我们的发现一致，即 I/LnJ Ob 等位基因促进受感染小鼠的广谱 Ab 反应，与 I/LnJ 小鼠中极低水平的 Ob 蛋白相关。我们已经证明这是由于 O 对抗原呈递的抑制作用降低。 当 I/LnJ Ob 等位基因被转移到几个病毒敏感背景，如 C3H/HeN、B6 和 BALB/cJ 时，它赋予这些小鼠产生病毒中和抗体的能力。然而，只有当这些动物成年后被感染时，这种效应才具有高外显率。相比之下，I/LnJ 小鼠无论感染时的年龄如何，甚至在新生儿时被感染，都会产生病毒中和抗体。我们发现，新生儿对病毒的反应能力与映射到 15 号染色体 30 Mb 区域的单个显性位点 (vic2) 有关。vic2 是 Ob 的修饰因子，I/LnJ 起源的 Ob 和 vic2 的遗传赋予所有易感品系的新生小鼠产生抗病毒抗体的能力。 逆转录病毒会感染成年人，但也会在出生时和通过母乳喂养从母亲传给新生儿。人们普遍认为新生儿的免疫系统尚未发育，这增加了感染的风险并削弱了对许多疫苗的反应。然而，I/LnJ 小鼠产生病毒中和免疫反应，与暴露于病原体的年龄无关。因此，阐明Vic2的功能机制对于了解新生儿免疫系统的未知特征并达到生命早期高效疫苗接种的目标至关重要。