MOLECULAR EPIDEMIOLOGY OF PRIMARY CMV INFECTION

描述(申请人提供)：Ravit Boger博士是约翰霍普金斯大学儿科感染科的助理教授。近年来，她与她的导师海沃德博士和帕斯博士合作研究CMV毒株的变异。通过这个K08奖项，她将进行转化研究，以确定健康成年人中CMV原发感染的分子流行病学，并获得分子流行病学和病毒学方面的专业知识，基因组测序、实时聚合酶链式反应和负责任的研究指导方面的高级技能。分子技术已经在种群中检测到大量的CMV毒株。传统上认为原发人类巨细胞病毒感染是由单一毒株引起的，而分离出多个毒株被认为是再次感染的证据。而特定人群(移植受者、艾滋病患者、日托儿童等)随着时间的推移，可能会再次感染多种CMV毒株，以前没有研究确定健康受试者最初的CMV感染是否涉及多种毒株。在此之前，我们从巨细胞病毒引起的胎儿死亡的组织中鉴定了多种CMV毒株，然而从CMV感染的活体婴儿的培养分离株中只鉴定出一种毒株。目前尚不清楚这种差异是否具有临床意义，或者与组织直接测序有关，而不是在培养中选择优先菌株后进行测序。这项应用的目的是在参加随机双盲GB疫苗试验并在随访期间血清转换的健康女性队列中表征CMV原发感染期间的菌株异质性。Boger博士将从原始体液和培养分离株的系列样本中分析高可变CMV基因，这些样本是在CMV初次感染期间和6-24个月后从这些人身上获得的。她还将确定疫苗诱导的免疫是否会随着时间的推移影响菌株的获得，以及特定的基因类型是否与各种体液中的病毒载量有关。这项研究将有助于理解菌株多样性在多大程度上可以作为再感染的证据，以及自然感染CMV如何导致对病毒的广泛免疫力。这项工作与公众健康有关，因为株系变异可能导致某些感染的毒力增加，而且株系变异现象可能会影响旨在预防先天性CMV感染的有效疫苗的开发。

DESCRIPTION (provided by applicant): Dr. Ravit Boger is an assistant professor, division of pediatric infectious diseases at Johns Hopkins. In recent years, she worked with her mentors Dr. Hayward and Dr. Pass on CMV strain variation. Through this K08 award, she will conduct translational research to determine the molecular epidemiology of primary CMV infection in healthy adults, and gain expertise in molecular epidemiology and virology, advanced skills in genome sequencing, real-time PCR, and the responsible conduct of research. Molecular techniques have detected numerous CMV strains in the population. Primary human CMV infection is traditionally believed to be caused by a single strain, and isolation of multiple strains has been considered proof of re-infection. While specific populations (transplant recipients, AIDS patients, children in day care, etc.) may over time be re-infected with multiple CMV strains, no previous studies have determined whether initial CMV infection in healthy subjects involves multiple strains. Previously, we identified multiple CMV strains from tissues of CMV-induced fetal demise, yet only a single strain was identified from cultured isolates of CMV-infected live infants. It is unclear whether this difference has clinical significance or is related to direct sequencing from tissue as opposed to sequencing after selection of preferential isolates in culture. This application aims to characterize strain heterogeneity during primary CMV infection in a cohort of healthy women who participated in a randomized double-blind gB vaccine trial and who seroconverted during follow up. Dr. Boger will analyze hypervariable CMV genes from serial samples of original body fluids and cultured isolates that have been obtained from these individuals during primary CMV infection and 6-24 months afterwards. She will also determine whether vaccine-induced immunity affects the acquisition of strains over time, and whether specific genotypes are associated with viral load in various body fluids. This study will help understand the extent to which strain diversity can be used as evidence of re-infection and how natural CMV infection leads to broad immunity to the virus. This work is relevant to public health since strain variation may be responsible for increased virulence of some infections and because the phenomenon of strain variation may impact on the development of effective vaccine aimed at prevention of congenital CMV infection.