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 只有罕见的人天然对逆转录病毒感染具有抗性。虽然基因组范围的关联 研究可以鉴定与抗性相关的遗传局部，发现基因内的特定抗性基因 Rich Loci已被证明是一个巨大的挑战。另一方面，近交小鼠为 绘制负责抗逆转录病毒抗性和易感性的哺乳动物基因。我们已经描述了一个 隐性基因座为“病毒感染控制器1”（VIC1），该基因座负责产生逆转录病毒 - 来自I/LNJ菌株的小鼠中和抗体（AB）（2）。 VIC1介导了针对中和的AB反应 两种不同的鼠逆转录病毒（6、2、8）。这是VIC1代表了一种广泛抵抗的机制 逆转录病毒。使用位置克隆和计算方法，我们将H2-OB（OB）确定为基因 编码VIC1（1）。 OB编码由OA编码的Alpha亚基一起编码的Beta亚基 进化上配置了非古典主要组织相容性复合物II类样分子H2-O（HLA-- 在人类中做），一种抗原表现的负调节剂。 H2-O/HLA-DO的精确函数仍然 辩论，但它似乎与它通过抑制另一种修改MHC-II肽库的能力有关 MHC-II样分子，H-2M（人类中的HLA-DM）（9）。 通过将OB的I/LNJ等位基因移至 几种具有病毒的背景，例如C3H/HEN，B6和BALB/CJ，并通过产生敲除 B6小鼠基因的等位基因。所有这些动物都会产生逆转录病毒中和ABS。但是，只有效果 如果这些动物被感染为成年人，则具有很高的渗透率。相反，I/LNJ小鼠产生了逆转录病毒 - 中和ABS不论其感染年龄如何，即使它们被感染为新生儿。发现 促使我们寻找I/LNJ新生儿抗性的遗传基础。特征成功链接了 至单个显性染色体15的4.1 MB区域，病毒感染控制器2（VIC2）。 VIC2函数是 仅在没有功能性OB的情况下才明显。赋予了非功能性OB和VIC2I的继承 从所有易感性菌株中产生抗病毒ABS的抗病毒ABS的能力。 许多病毒，包括逆转录病毒，感染了成年人，但也从母亲传给了新生儿 出生和母乳喂养期间。通常认为，新生儿的免疫系统是 欠发达，增加了感染的风险和对许多疫苗的反应。但是，我/lnj 小鼠会产生一种与病毒中和免疫响应，与暴露于年龄的年龄无关 病原体。这是从根本上重要的是要阐明VIC2功能的机制以便 了解新生儿免疫系统的未知特征，并获得刺激的能力 新生儿的生产性病原体特异性免疫。 VIC2的识别和途径的描述 它的控制是该提议的目标。