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） 罕见的人表现出对逆转录病毒感染的抗性。尽管GWAS的研究指向遗传基因座的抗药性，但人类中的抗药性基因过于复杂，到目前为止，尚未导致任何明确的结果。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提供了一个很好的替代方法。我们的小组描述了小鼠中名为“病毒感染控制器1”（VIC1）的基因座 来自I/LNJ菌株。 VIC1基因座包含一个隐性逆转录病毒抗性的基因，该基因映射到染色体17。VIC1赋予对两个不同逆转录病毒的耐药性：MULV和小鼠乳腺肿瘤病毒（MMTV）。使用先天性和细菌性人造染色体（BAC）转基因和计算方法，我们将VIC1基因座定为32KB区域，并鉴定出非经典的主要组织相容性II类（MHC II类）基因（MHC II类）基因，H2-OB（ob）作为VIC1的基因编码。进化构成的OB编码Oβ分子，Oβ分子是与Oα的异二聚体的一部分，它们共同组成了DO分子。人们认为确实与DMDM二聚体相互作用，从而修改了其在内吞室中经典MHC II类分子上编辑抗原宠物的负载的能力。 DO的精确函数尚不清楚，但它似乎会影响呈现在T细胞的抗原性胡椒的曲目。这与我们的发现一致，即I/LNJ OB等位基因在感染的小鼠中促进了与I/LNJ小鼠中非常低的OB蛋白相关的感染小鼠的广谱AB反应。我们已经表明，这是由于O对抗原表现的抑制作用降低所致。当I/LNJ OB等位基因被转移到几种具有病毒的背景时，例如C3H/HEN，B6和BALB/CJ时，它赋予了对这些小鼠产生病毒中和ABS的能力。但是，只有当这些动物被感染成人时，这种影响才具有很高的渗透率。相比之下，I/LNJ小鼠在感染年龄以及被感染为新生儿时都会产生病毒中和ABS。我们发现，由于新生儿的反应能力与映射到30 MB染色体15染色体区域的单个主要基因座（VIC2）有关。VIC2是OB的修改器，并且I/LNJ起源的OB和VIC2的遗传都带来了产生来自所有不良效应的抗病毒ABS的能力。逆转录病毒感染的成年人，但在出生期间和通过母乳喂养期间也从母亲转移到新生儿。人们普遍认为，新生儿的免疫系统未开发，增加了感染的风险和对许多疫苗的反应。但是，I/LNJ小鼠独立于暴露于病原体的年龄独立于病毒中和免疫反应。这是从根本上重要的是要了解VIC2功能的机制，以了解新生儿免疫系统的未知特征并实现高效率的早期疫苗接种效率。