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) 很少有人类对逆转录病毒感染表现出抵抗力。尽管Gwas的研究指出了抗药性背后的遗传基因，但精确定位人类的抗药性基因太复杂了，到目前为止还没有产生任何明确的结果。与此同时，近亲交配的小鼠为定位哺乳动物对逆转录病毒的抗性和易感性基因提供了一个很好的选择。我们的研究小组在小鼠中描述了一个名为病毒感染性控制器1(Vic1)的基因座 来自I/LnJ菌株。Vic1基因座含有一个隐性逆转录病毒抗性基因，位于17号染色体上。vic1基因对两种截然不同的逆转录病毒：小鼠乳癌病毒和小鼠乳腺肿瘤病毒(MMTV)具有抗性。利用同源基因和细菌人工染色体(BAC)转基因和计算方法，我们将vic1基因定位到一个32kb的区域，并确定了一个非经典的主要组织相容性II类(MHC Class II)基因H2-Ob(Ob)为Vic1的编码基因。进化保守的Ob编码Oβ分子，Oα分子是与O DNA杂二聚体的一部分，共同组成DO分子。DO被认为与DMDM二聚体相互作用，改变其编辑抗原肽的能力，将抗原肽装载到经典的MHC II类分子的胞内隔室。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等位基因促进感染小鼠的广谱抗体反应，与I/LnJ小鼠中非常低的Ob蛋白水平相关。我们已经证明这是由于O对抗原提呈的抑制作用减弱所致。当将I/LnJ Ob等位基因移至C3H/HEN、B6和BALB/CJ等几个病毒易感背景时，可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后被感染时，这种效果才会有很高的外显性。相比之下，I/LnJ小鼠产生病毒中和抗体，无论它们感染时的年龄如何，甚至在新生儿感染时也是如此。我们已经发现，新生儿对病毒的应答能力与定位于15号染色体30Mb区域的单个显性基因座(Vic2)有关。vic2是Ob的修饰性基因，I/LnJ起源的Ob和vic2的遗传赋予了从所有敏感株向新生小鼠产生抗病毒抗体的能力。逆转录病毒感染成人，但也会在分娩期间和母乳喂养期间从母亲传播给新生儿。人们普遍认为，新生儿的免疫系统不发达，增加了感染的风险，并损害了对许多疫苗的反应。然而，I/LnJ小鼠产生的病毒中和免疫反应与它们接触病原体的年龄无关。因此，为了了解新生儿免疫系统的未知特征，达到高效早期免疫接种的目的，了解Vic2的功能机制是非常重要的。