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）是最常见的儿童时期恶性肿瘤，可疑起源在大多数情况下。尽管将近90％的患者在成年期生存，但治疗具有毁灭性长期健康影响和初级预防仍然是肿瘤学研究的典型目标。孩子们他们出生时炎症性细胞因子水平的所有发生变化被诊断出的早期感染，表明早期感染可能是一种可修改的病因剂。我们最近证明，来自所有儿童的预处理骨髓标本都普遍存在巨细胞病毒（CMV）感染。从268名儿童中筛选存档的新生儿样本为了开发所有和270名无癌对照的儿童，所有患者都近4倍出生时血液中可能有可检测的CMV（OR = 3.71，p = 0.0016），表明先天性CMV 感染是全风险因素。 CMV是全球最常见的先天性感染，影响150名婴儿中的1人。出生前CMV感染可能对发展中的免疫系统有重大影响，包括T细胞激活和中央公差。 CMV具有任何人类病毒病原体中最大的基因组，并且拥有许多免疫异常基因，表明CMV调节宿主免疫系统以逃避免疫监视。该CMV诱导的免疫调节的基础机制知之甚少。但是，其他致癌病毒可以诱导宿主表观基因组的广泛甲基化变化。病毒引起的表观遗传变化可能会改变发育中的免疫系统的转录格局，并负面影响造血期间的谱系承诺和宿主免疫监视，从而增加所有风险。因此，定义先天性CMV感染与白血病相关的失调之间的相互作用早期生命中的基因是建立先天性CMV感染之间机械联系的重要一步以及所有风险，这是一种潜在的可预防疫苗的癌症危险因素。我们假设先天性CMV感染在发育中的胎儿引起表观遗传和免疫学变化，这有助于发展所有人的风险在童年时期。使用匹配的CMV感染，CMV暴露和CMV未暴露的病例对照样本卡罗来纳州脐带血库的脐带血供体，我们将确定表观遗传和免疫学先天性CMV感染的后果。然后，我们将确定与CMV感染相关的表观遗传学和从继续发展所有人的儿童的新生儿斑点中概括了免疫学变化。最后，我们将确定是否知道所有敏感性变体是否通过将CMV感染的脐带供血者中这些变体的频率与未感染的对照进行比较。这些研究将阐明先天性CMV感染对以后的癌症风险的作用，并有助于识别可修改可以减轻与最常见的儿童癌症相关的公共卫生负担的早期生活因素。