Advancing the health and well-being of animals and people


Principal Investigator: Brian Rudd

Department of Microbiology & Immunology
Email: bdr54@cornell.edu; Phone: 607-253-4418
Sponsor: Weill Cornell Medical College (WCMC)
Grant Number: UL1TR000457/93.350
Title: Using T-cell Repertoire as a Biomarker for Congenital HCMV Disease
Project Amount: $39,965
Project Period: 06/01/13-05/31/14

DESCRIPTION (Provided by Applicant): Human cytomegalovirus (HCMV) infection is the most common congenital viral infection in the U.S., occurring in up to 2.2% of all live births. The ability of the immune system to mediate protection against HCMV infection is closely correlated with its maturation status. However, the correlates of immune protection against HCMV are currently not known. As CD8+ T cells are required to control HCMV, our primary focus is to identify key developmental-related differences among fetal, neonatal and adult CD8+ T cells. One of the major developmental-related differences between different aged CD8+ T cells relates to the diversity of the T-cell repertoire. This is important, since the likelihood of having a T-cell that recognizes a particular viral peptide on the surface of infected cells increases with the diversity of the repertoire, and the repertoire becomes progressively more diverse throughout the gestational period. Our central hypothesis is that infection with HCMV in early stages of development ‘locks-in’ a less diverse CD8+ TCR repertoire comprised of structurally distinct TCRs, which are impaired at providing immune defense. We will test our hypothesis by pursuing the following specific aims: Aim 1: Identify the unique TCR features found in fetal, neonatal and adult CD8+ T cells prior to infection with HCMV. Here, we will deep sequence millions of CD8+ TCRs from healthy pre-term infants, term-infants and adults to uncover distinctive features in TCRs produced during various stages of development that can later be used to estimate the time of HCMV infection. Aim 2: Determine how timing of HCMV infection alters the repertoire and functionality of HCMV-specific CD8+ T cells. In this aim, we will sequence HCMV-specific TCRs from newborns and correlate TCR usage with immune functionality. We will also compare the repertoire of fetal HCMV-specific T cells with adults. These studies will provide critical insight into why individuals in early life respond poorly to HCMV as well as whether TCR repertoire could be a useful diagnostic for the outcome and treatment of congenital HCMV. Results obtained will provide the necessary framework for developing diagnostics and therapeutics for the treatment of HCMV in early life.