A neonatal mouse model to study retrovirus-specific humoral responses

研究逆转录病毒特异性体液反应的新生小鼠模型

• 批准号: 10241945
• 负责人: Tatyana V Golovkina
• 金额: $ 46.32万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-24 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10241945
• 关键词: Adult; Affect; Age; Alleles; Animals; Antibodies; Antibody Response; Antigen Presentation; Bacterial Artificial Chromosomes; Bioinformatics; Birth; Breast Feeding; Candidate Disease Gene; Cells; Chromosome 15; Chromosome 17; Code; DNA Markers; Evolution; Exposure to; Genes; Genetic; Goals; HIV; Haplotypes; Hepatitis B; Hepatitis C virus; Homologous Gene; Human; I/LnJ Mouse; Immune response; Immune system; Immunity; Impairment; Inbred C57BL Mice; Inbred Mouse; Infection; Infection Control; Knock-out; Link; MHC Class II Genes; Major Histocompatibility Complex; Maps; Mediating; Molecular; Mothers; Mouse Mammary Tumor Virus; Murine leukemia virus; Mus; Mutate; Names; Natural Resistance; Neonatal; Newborn Infant; Pathway interactions; Penetrance; Peptides; Phenotype; Predisposition; Production; Resistance; Resolution; Retroviridae; Role; Spleen; Transgenic Mice; Vaccines; Virus; gain of function; gene function; genome wide association study; genomic locus; human disease; infection risk; mouse model; neonatal mice; neonate; neutralizing antibody; pathogen; positional cloning; resistance gene; response; trait; virus identification

Project Summary Only rare humans are naturally resistant to retroviral infections. Although genome wide association studies can identify genetic loci associated with the resistance, finding particular resistance genes within gene- rich loci has proven to be a great challenge. On the other hand, inbred mice offer a great alternative for mapping mammalian genes responsible for resistance and susceptibility to retroviruses. We have described a recessive locus named ‘virus infectivity controller 1’ (vic1), which is responsible for production of retrovirus- neutralizing antibodies (Ab) in mice from the I/LnJ strain (2). vic1 mediates a neutralizing Ab response against two different murine retroviruses (6, 2, 8). Thus, vic1 represents a mechanism of broad resistance against retroviruses. Using positional cloning and computational approaches we identified H2-Ob (Ob) as the gene coding for Vic1 (1). Ob encodes the beta subunit which together with alpha subunit, encoded by Oa, forms evolutionally conserved the non-classical Major Histocompatibility Complex class II-like molecule H2-O (HLA- DO in humans), a negative regulator of antigen presentation. The precise function of H2-O/HLA-DO is still debated, but it appears to be related to its ability to modify the MHC-II peptide repertoire by inhibiting another MHC-II-like molecule, H-2M (HLA-DM in humans) (9). The role of non-functional Ob in retroviral resistance was confirmed by moving the I/LnJ allele of Ob to several virus-susceptible backgrounds, such as C3H/HeN, B6, and BALB/cJ, and by producing a knock-out allele of the gene in B6 mice. All these animals produced retrovirus-neutralizing Abs. However, the effect only had high penetrance if these animals were infected as adults. In contrast, I/LnJ mice produced retrovirus- neutralizing Abs irrespective of their age at infection, even when they were infected as newborns. The finding prompted us to search for the genetic basis of resistance of I/LnJ neonates. The trait was successfully linked to a single dominant 4.1 Mb region of Chromosome 15, virus infectivity controller 2 (vic2). Vic2 function was only apparent in the absence of functional Ob. The inheritance of both non-functional Ob and vic2i conferred the ability to produce anti-virus Abs to neonatal mice from all susceptible strains. Many viruses, including retroviruses, infect adults, but are also passed from mothers to newborns during birth and breastfeeding. It is commonly accepted that the immune system of a newborn is underdeveloped, increasing the risk of infection and impairing responses to many vaccines. However, I/LnJ mice generate a virus-neutralizing immune response independent of the age at which they were exposed to the pathogen. Thus, it is fundamentally important to unravel the mechanism of Vic2’s function in order to understand the unknown features of the neonate immune system and to acquire the ability of stimulating productive pathogen-specific immunity in neonates. Identification of vic2 and the delineation of the pathway that it controls are the goals of this proposal.

项目摘要 只有罕见的人类对逆转录病毒感染具有天然抵抗力。尽管全基因组关联 研究可以确定与抗性相关的遗传位点，在基因内找到特定的抗性基因。 事实证明，丰富的基因座是一个巨大的挑战。另一方面，近亲交配的老鼠提供了一个很好的选择 绘制哺乳动物对逆转录病毒的抗性和易感性基因图谱。我们已经描述了一种 隐性基因座‘病毒感染性控制基因1’(Vic1)，负责逆转录病毒的产生。 来自I/LnJ株(2)的小鼠中和抗体。VIC1介导中和抗体反应 两种不同的小鼠逆转录病毒(6、2、8)。因此，vic1代表了一种广泛抵抗 逆转录病毒。利用位置克隆和计算方法，我们确定了H2-Ob(Ob)为该基因 为Vic1(1)编码。Ob编码β亚基，该β亚基与由Oa编码的α亚基一起形成 进化上保守的非经典主要组织相容性复合体II类分子H2-O(HLA- 在人类中也是如此)，它是抗原提呈的负调节因子。H2-O/人类白细胞抗原-DO的精确功能仍然是 有争议，但似乎与它通过抑制另一个MHC-II多肽来修改MHC-II多肽的能力有关 类MHC-II分子，H-2m(人类的人类白细胞抗原-DM)(9)。 通过将Ob的I/LnJ等位基因转移到 几种病毒易感背景，如C3H/HEN、B6和BALB/CJ，并通过产生敲除 该基因在B6小鼠中的等位基因。所有这些动物都产生了逆转录病毒中和抗体。然而，其效果仅限于 如果这些动物在成年后被感染，就会有很高的外显率。相比之下，I/LnJ小鼠产生了逆转录病毒- 中和抗体，无论他们感染时的年龄，即使他们是在新生儿感染的时候。这一发现 提示我们寻找I/LnJ新生儿耐药的遗传基础。该性状已成功链接 病毒感染性控制基因2(Vic2)位于15号染色体4.1Mb的单一显性区域。VIC2函数是 只有在没有功能性Ob的情况下才是明显的。非功能性Ob和vic2i的遗传 从所有敏感品系产生抗病毒抗体给新生小鼠的能力。 许多病毒，包括逆转录病毒，会感染成人，但也会从母亲传给新生儿 在分娩和哺乳期间。人们普遍认为新生儿的免疫系统是 不发达，增加了感染的风险，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，与它们接触的年龄无关 病原体。因此，从根本上讲，解开维吾尔人S的作用机制是至关重要的 了解新生儿免疫系统的未知特征，获得刺激能力 新生儿的产生性病原体特异性免疫。VIC2基因的鉴定及其途径的描述 它控制的是这项提案的目标。