Genetic-epigenetic and aging interactions at COVID- 19 host response loci in Down syndrome and mouse models

唐氏综合症和小鼠模型中 COVID-19 宿主反应位点的遗传-表观遗传和衰老相互作用

• 批准号: 10221384
• 负责人: Benjamin Tycko
• 金额: $ 69.68万
• 依托单位: HACKENSACK UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-13 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10221384
• 关键词: 2019-nCoV; 3p21; 9q34; ABO blood group system; Acute; Adult; Affect; Age; Aging; Alleles; Animal Model; Biological; Biological Markers; Biological Models; CCR9 gene; COVID-19; COVID-19 pandemic; CRISPR/Cas technology; CXCR6 gene; Cells; Cessation of life; Chromosome 21; Chromosome Band; Clinical; DNA; DNA Methylation; Data; Death Rate; Dependence; Disease; Down Syndrome; Drug Targeting; Elderly; Elements; Engineering; Epigenetic Process; Exposure to; FYCO1 gene; Folic Acid; Funding; Gene Expression; General Population; Genes; Genetic; Genetic Engineering; Genomics; Homing; Human; Hyperactive behavior; Immune; Immune response; Immune system; Individual; Infection; Inflammatory; Interferon Receptor; Interferons; Interleukin-6; Investigation; Lead; Link; Maps; Measures; Mediating; Methylation; Methyltransferase; Modeling; Mus; Pathogenesis; Pathway interactions; Pattern; Population Genetics; Public Health; Regulatory Element; Research; Research Personnel; Role; S-Adenosylmethionine; S100 Family Gene; S100 Proteins; Sampling; Severities; Severity of illness; Signal Transduction; Single Nucleotide Polymorphism; Syndrome; TMPRSS2 gene; Testing; Virus; Work; XCR1 gene; age related; body system; case control; cell type; cohort; cytokine; design; genetic variant; genome wide association study; health management; improved; lung injury; member; methylation pattern; mouse Ts65Dn; mouse model; novel coronavirus; receptor; response; viral RNA

The importance of the COVID-19 pandemic, with >3M cases and >130K deaths in the USA alone, cannot be overstated. This highly contagious and too often lethal infection with SARS-CoV-2 has both severe acute effects and longer-term adverse sequelae, and disease severity and death rates are strikingly higher in elderly individuals. Pathogenesis and host responses to COVID-19 are still very much under investigation, but initial hypotheses include roles for host cytokines, including pro-inflammatory IL-6 and Type I and III interferons (IFNs), and S100-family proteins. Importantly, a group of IFN pathway genes are triplicated in people with Down syndrome (DS; trisomy 21), and other COVID-19 relevant genes, including S100B and TMPRSS2 are also on chromosome 21. In addition, investigators seeking drug targets have pointed out the dependence of the virus on the methyl donor (folate pathway; S-adenosylmethionine; SAM) status of host cells, and a group of genes in this pathway are triplicated in DS. From research on COVID-19 in the general population, the genetic background of the infected host is known to be important, with a Genome Wide Association Study (GWAS) revealing significant associations with single nucleotide polymorphism rs11385942 in chromosome band 3p21 and rs657152 at 9q34. At locus 3p21, the association signal spans the genes SLC6A20, LZTFL1, CCR9, FYCO1, CXCR6 and XCR1, and it is not yet clear which is the most important gene, and which is the critical genetic variant. How the presence of the extra chromosome 21 in DS might affect this important locus is a critical issue, and we have preliminary data pointing to differences in DNA methylation in this region in DS vs. control individuals. Importantly, an accurate mouse model of COVID-19 in the DS genetic background is needed but has not yet been developed. Given these challenges, here we propose to localize COVID-19 related host genomic sequences that are epigenetically regulated and altered in immune cell types from DS vs euploid individuals, to use allele-specific methylation mapping to pinpoint key regulatory elements in the 3p21 COVID-19 GWAS region, and ask whether these elements are epigenetically altered in DS. We will engineer CRISPR/Cas9-mediated deletions in the differentially methylated sequences and measure the effects on methylation patterns and regional gene expression. Building upon the progress of genetic engineering, we will develop an experimentally tractable mouse model to ask whether COVID-19 infections are more severe in a genetic background that accurately mimics human DS. In both the mouse model and our human biosamples from DS and controls, we will quantitate the age-dependence of methylation of COVID-19 host response genes. These fundamental studies, to be carried out in one year, will lay a crucial groundwork for subsequent work using biosamples from DS individuals who have been exposed to SARS-CoV-2, cohorts that are being organized by our colleagues under separate funding.

Covid-19大流行的重要性，仅在美国就有> 3M的病例和> 130k死亡，不能是 夸大了。这种高度传染性且经常用SARS-COV-2致命感染都具有严重的急性 老年人的影响和长期不良后遗症以及疾病的严重程度和死亡率明显更高 个人。发病机理和对Covid-19的宿主反应仍在研究中，但初始 假设包括宿主细胞因子的角色，包括促炎性IL-6和I型和III干扰素 （IFN）和S100家族蛋白。重要的是，一组IFN途径基因在患有 唐氏综合症（DS；三体术21）和其他共同基因，包括S100B和TMPRSS2 同样在21号染色体上。此外，寻求药物目标的研究人员指出了 甲基供体（叶酸途径; S-腺苷甲氨酸; SAM）状态的病毒的状态，一组 该途径中的基因在DS中进行了三次。从一般人群中的Covid-19的研究，遗传 众所周知，受感染宿主的背景很重要，其中一项基因组广泛的关联研究（GWAS）很重要 揭示了与染色体条带3P21中的单核苷酸多态性RS11385942的显着关联 和RS657152，第9季度。在基因座3p21，关联信号跨越基因SLC6A20，LZTFL1，CCR9， FYCO1，CXCR6和XCR1，目前尚不清楚哪个是最重要的基因，哪个是关键的基因 遗传变异。 DS中额外染色体21的存在如何影响这个重要的基因座是一个 关键问题，我们有初步数据指出DS VS中该区域DNA甲基化的差异。 控制个人。重要的是，在DS遗传背景中的Covid-19的精确小鼠模型是 需要但尚未开发。鉴于这些挑战，我们在这里建议将Covid-19本地定位 相关的宿主基因组序列，受到DS VS的免疫细胞类型的表观遗传调节和改变 多倍体个体，使用等位基因特异性甲基化映射来查明3p21中的关键调节元素 COVID-19 GWAS区域，并询问这些元素是否在DS中表观遗传变化。我们将设计 CRISPR/CAS9介导的缺失在差异甲基化序列中，并测量对 甲基化模式和区域基因表达。基于基因工程的进步，我们将 开发实验可牵引的小鼠模型，询问在A中的Covid-19感染是否更严重 准确模拟人类DS的遗传背景。在小鼠模型和我们的人类生物样本中 从DS和对照组中，我们将量化COVID-19宿主反应的甲基化的年龄依赖性 基因。这些基本研究将在一年内进行，将为随后的关键基础奠定 使用暴露于SARS-COV-2的DS个人的生物样本，正在 由我们的同事在单独的资金下组织。