Sunday, May 18, 2025
5/18/2025
Adaptive Immune Responses to Congenital and Postnatal Cytomegalovirus Infection - ABSTRACT Congenital cytomegalovirus (cCMV) infection is the most common congenital viral infection in the U.S, affecting 1 in 200 liveborn infants annually, and can cause permanent neurodevelopmental and hearing impairment. In contrast, postnatal CMV infection in full-term infants causes no clinical illness or neurologic sequelae. The immunologic differences underlying the clinical manifestations induced by cCMV but not postnatal infection are undefined. Our group recently found that cCMV infected infants expressed a spectrum of CD8+ T cell responses, ranging from naïve-like T cells (TN) resembling those of CMV uninfected newborns, to highly differentiated cells with features of T cell exhaustion (TEX). By comparison, the CD8+ T cells of postnatally infected infants were differentiated and lacked TEX characteristics. Importantly, cCMV-induced developmental delay was associated with the TN-like phenotype, whereas progressive SNHL was associated with persistent TEX-like cells, underscoring the clinical relevance of understanding these T cell responses to cCM infection. This project will test the central hypothesis that cCMV infection impairs the infant’s T cell response to CMV, impeding effective viral control and increasing risk for neurologic injury. We will compare CD4+ and CD8+ T cell responses to CMV between a large enrolled cohort of cCMV infected infants and a group with early postnatal CMV infection acquired through breastfeeding. Aim 1 will identify pathways inhibiting Th1 cell responses after cCMV infection by assessing several possible causes for the lack of neonatal Th1 responses during cCMV infection: (1) Th1 cell differentiation occurs, but cytokine-secreting function is limited by inhibitory signals; (2) Th2/Treg cells develop preferentially, inhibiting Th1 cell differentiation; (3) TLR signaling by dendritic cells is inhibited by cCMV infection, reducing cytokine and proliferative signals to CD4+ cells. Comparisons between cCMV and postnatally infected infants will identify key differences in the CD4+ T cell responses and their upstream regulators. Aim 2 will identify differences in CD8+ T cell responses induced by congenital and postnatal infection and the T cell characteristics associated with cCMV-induced neurodevelopmental impairment. In this Aim, the surface receptor and transcriptional profiles of antigen-specific CD8+ T cells will be compared between cCMV and postnatally infected infants to discern distinctive features generated during cCMV infection in the absence of CD4+ T cell help. Anti-PD-1 antibodies will be used in-vitro to test if function can be restored to CD8+ TEX cells induced by cCMV infection. The CD4+ and CD8+ T cell parameters associated with cCMV-induced neurodevelopmental impairment will be identified. Together, these studies will advance our fundamental understanding of human T cell responses to a congenital viral infection and their potential impact upon neurologic outcomes. This knowledge may inform development of new therapeutic approaches to reinvigorate T cells and improve neurodevelopmental outcomes among cCMV infected infants.
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