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Immune Correlates and Mechanisms of Perinatal Cytomegalovirus Infection and Later Life ALL Development

围产期巨细胞病毒感染和以后生活中 ALL 发展的免疫相关性和机制

基本信息

批准号：
9809304
负责人：
Kyle M Walsh
金额：
$ 24.51万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-01 至 2021-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9809304
关键词：
Acute Lymphocytic Leukemia Adult Affect African Archives Binding Biological Assay Birth Blood Blood Banks Blood donor Blood specimen Bone Marrow Brain C-reactive protein Child Childhood Childhood Leukemia Clinical Cluster Analysis Cytomegalovirus Cytomegalovirus Infections Cytosine Data Development Diagnosis Early Diagnosis Early Intervention Elderly Epidemiologist Epigenetic Process Etiology Exhibits Fetal Development Frequencies Future Genes Genetic Genetic Polymorphism Genetic Transcription Genome Genotype Goals Health Hematopoiesis Human Human Herpesvirus 4 Human Papillomavirus IL17 gene IL18 gene IL6 gene IL8 gene Immune Immune Evasion Immune system Immunity Immunologic Factors Immunologic Monitoring Immunologics Infant Infection Inflammatory Interleukin-10 Lead Life Link Liver Malignant Childhood Neoplasm Malignant Neoplasms Measures Mediating Medical Methylation Methyltransferase Molecular Mothers Neonatal Newborn Infant Oncogenic Viruses Patients Perinatal Plasma Primary Prevention Public Health Research Risk Risk Factors Role Sampling Seroprevalences Specimen Spottings Supervision Susceptibility Gene T-Cell Activation Testing Time Umbilical Cord Blood United States Vaccines Variant Viral cancer risk case control central tolerance chemoradiation congenital cytomegalovirus congenital infection cytokine epigenome experience fetal genetic variant human DNA immunoregulation inflammatory marker leukemia leukemogenesis modifiable risk molecular subtypes neonatal infection neonate oncology pathogenic virus prenatal screening seropositive success virome

项目摘要

ABSTRACT Acute lymphoblastic leukemia (ALL), the most common malignancy of childhood, has a suspected prenatal origin in a majority of cases. Although nearly 90% of ALL patients survive into adulthood, treatment has devastating long-term health effects and primary prevention remains the quintessential goal of oncology research. Children who develop ALL exhibit alterations in inflammatory cytokine levels at birth and experience more medically diagnosed early-life infections, suggesting that early-life infections may be a modifiable etiologic agent. We recently demonstrated that pretreatment bone marrow specimens from children with ALL had prevalent cytomegalovirus (CMV) infection. Screening of archived newborn blood samples from 268 children who went on to develop ALL and 270 cancer-free control children demonstrated that ALL patients were nearly 4-times more likely to have detectable CMV in their blood at birth (OR=3.71, P=0.0016), suggesting that congenital CMV infection is an ALL risk factor. CMV is the most common congenital infection worldwide, affecting 1 in 150 infants. CMV infection prior to birth likely has a significant impact on the developing immune system, including T cell activation and central tolerance. CMV has the largest genome of any human viral pathogen and harbors many immune-evasion genes, indicating that CMV modulates the host immune system to escape immunosurveillance. The mechanisms underlying this CMV-induced immune modulation are poorly understood; however, other oncogenic viruses can induce widespread methylation changes to the host epigenome. Virally-induced epigenetic changes may alter the transcriptional landscape of the developing immune system and negatively impact both lineage commitment during hematopoiesis and host immunosurveillance, thereby augmenting ALL risk. Thus, defining the interaction between congenital CMV infection and dysregulation of leukemia-associated genes in early life is an important step toward establishing the mechanistic link between congenital CMV infection and ALL risk, a potentially vaccine-preventable cancer risk factor. We hypothesize that congenital CMV infection induces epigenetic and immunologic changes in the developing fetus that contribute to risk of developing ALL during childhood. Using a matched case-control sample of CMV-infected, CMV-exposed, and CMV-unexposed cord blood donors from the Carolinas Cord Blood Bank, we will identify the epigenetic and immunologic consequences of congenital CMV infection. We will then determine if CMV infection-associated epigenetic and immunologic changes are recapitulated in newborn blood spots from children who went on to develop ALL. Finally, we will determine whether known ALL susceptibility variants modify risk of congenital CMV infection by comparing the frequency of these variants in CMV-infected cord blood donors to uninfected controls. These studies will elucidate the role of congenital CMV infection on later cancer risk and help to identify modifiable early-life factors that can reduce the public health burden associated with the most common cancer of childhood.

抽象的急性淋巴细胞白血病 (ALL) 是儿童期最常见的恶性肿瘤，疑似产前起源在大多数情况下。尽管近 90% 的 ALL 患者能活到成年，但治疗效果却是毁灭性的长期健康影响和初级预防仍然是肿瘤学研究的典型目标。孩子们患有 ALL 的人出生时炎症细胞因子水平会发生变化，并且会经历更多的医学经历诊断出生命早期感染，表明生命早期感染可能是一种可改变的病因。我们最近证明，来自 ALL 儿童的预处理骨髓标本中普遍存在巨细胞病毒（CMV）感染。对 268 名儿童的存档新生儿血液样本进行筛查罹患 ALL 和 270 名无癌症对照儿童的结果表明，ALL 患者的患病率几乎是正常儿童的 4 倍出生时血液中可能检测到 CMV（OR=3.71，P=0.0016），这表明先天性 CMV 感染是 ALL 的危险因素。 CMV 是全世界最常见的先天性感染，每 150 名婴儿中就有 1 人受到感染。出生前巨细胞病毒感染可能对发育中的免疫系统（包括 T 细胞）产生重大影响激活和中枢耐受。 CMV 拥有所有人类病毒病原体中最大的基因组，并含有许多免疫逃避基因，表明 CMV 调节宿主免疫系统以逃避免疫监视。人们对这种 CMV 诱导的免疫调节机制知之甚少。然而，其他致癌病毒可诱导宿主表观基因组发生广泛的甲基化变化。病毒诱导的表观遗传变化可能会改变发育中免疫系统的转录景观，并产生负面影响影响造血过程中的谱系承诺和宿主免疫监视，从而增强 ALL 风险。因此，确定先天性 CMV 感染与白血病相关细胞因子失调之间的相互作用生命早期的基因是建立先天性巨细胞病毒感染之间机制联系的重要一步 ALL 风险，一种潜在的疫苗可预防的癌症风险因素。我们推测先天性 CMV 感染诱导发育中胎儿的表观遗传和免疫学变化，从而增加患 ALL 的风险童年时期。使用 CMV 感染、CMV 暴露和 CMV 未暴露的匹配病例对照样本来自卡罗莱纳州脐带血库的脐带血捐赠者，我们将鉴定表观遗传和免疫学先天性 CMV 感染的后果。然后我们将确定 CMV 感染是否与表观遗传和继发于 ALL 的儿童的新生儿血斑中再现了免疫学变化。最后，我们将确定已知的 ALL 易感性变异是否会改变先天性 CMV 感染的风险比较感染 CMV 的脐带血捐献者与未感染的对照者中这些变异的频率。这些研究将阐明先天性巨细胞病毒感染对后期癌症风险的影响，并有助于确定可改变的方法可以减轻与儿童最常见癌症相关的公共卫生负担的早期因素。