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）研究指出了抵抗力背后的基因位点，但精确定位人类的抵抗基因过于复杂，而且迄今为止还没有得出任何明确的结果。我们的研究小组在小鼠体内描述了一个名为“病毒感染性控制器 1”（vic1）的基因座。 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 使用同源和细菌人工染色体 (BAC) 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)。 ）转基因和计算方法，我们将 vic1 基因座精细映射到 32Kb 区域，并确定了一个非经典的主要组织相容性 II 类(MHC II 类) 基因，H2-Ob (Ob) 作为编码 Vic1 的基因 进化上保守的 Ob 编码 Oβ 分子，Oβ 分子是与 Oα 的异二聚体的一部分，它们一起组成 DO 分子。 DO 的确切功能尚不清楚，但与 DMDM 二聚体一起，改变其编辑抗原肽加载到内吞区室中经典 MHC II 类分子上的能力。它似乎影响呈递给 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 中极低水平的 Ob 蛋白相关。我们已经证明，这是由于当 I/LnJ Ob 等位基因转移到几种病毒易感背景时，O 对抗原呈递的抑制作用降低。 C3H/HeN、B6 和 BALB/cJ 赋予这些小鼠产生病毒中和抗体的能力，但只有在这些动物成年后被感染时，该效果才具有高外显率。相反，I/LnJ 小鼠产生病毒。无论感染时的年龄如何，甚至在新生儿时感染，我们都发现中和抗体的能力与映射的单个显性位点（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，但逆转录病毒感染成年小鼠。人们普遍认为，新生儿的免疫系统尚未发育成熟，从而增加了感染风险并削弱了对许多疫苗的反应。 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，为了了解新生儿免疫系统的未知特征并了解 Vic2 的功能机制，至关重要。达到生命早期疫苗接种高效的目标。