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GWAS的研究指出了耐药性背后的遗传位点，但在人类中精确定位耐药性基因太复杂了，到目前为止还没有得出任何明确的结果。与此同时，近交系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提供了一个很好的选择。我们的研究小组已经在小鼠中描述了一个名为"病毒感染性控制器1"（vic 1）的位点。 来自I/LnJ菌株。vic1基因座含有一个隐性逆转录病毒抗性赋予基因，定位于17号染色体。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，并鉴定了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O β分子，O β分子是与O α异源二聚体的一部分，它们共同组成DO分子。据认为，DO与DM β DM β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，但它似乎影响呈递给T细胞的抗原肽的库。这与我们的发现一致，即I/LnJ Ob等位基因在感染小鼠中促进广谱Ab应答，与I/LnJ小鼠中Ob蛋白水平非常低相关。我们已经表明，这是由于O-β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种病毒易感背景，如C3H/HeN，B6和BALB/cJ，它赋予这些小鼠产生病毒中和抗体的能力。然而，只有当这些动物在成年时被感染时，这种效果才有高的感染率。相比之下，I/LnJ小鼠产生病毒中和抗体，无论其感染时的年龄如何，甚至在新生儿感染时。我们发现，新生儿对病毒的反应能力与定位于15号染色体30 Mb区域的单个显性基因座（vic2）有关。vic2是Ob的修饰物，I/LnJ来源的Ob和vic2的遗传赋予了从所有易感品系向新生小鼠产生抗病毒Ab的能力。 逆转录病毒感染成年人，但也在分娩期间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，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应答，与它们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，并达到早期疫苗接种的高效率的目标，解开Vic2功能的机制是至关重要的。