Cytomegalovirus (CMV) is the most common congenital infection and the leading cause of birth defects in children in the United States. While the urgent need for a vaccine against congenital CMV is widely recognized, the underlying mechanisms responsible for the poor generation and inadequate maintenance of immunity remain undefined, thus compromising our ability to create effective methods for prevention and treatment. The goal of this proposal is to use a murine model of congenital CMV to identify both the mechanisms and consequences of failing to control CMV in early life. Since immune control of CMV is largely dependent upon CD8+ T cells, we have focused our studies on understanding why CD8+ T cells in early life fail to control congenital CMV infection. Based on our published studies and new preliminary data, we hypothesize that neonatal CD8+ T cells have an inherent propensity to become functionally exhausted during CMV infection, leading to prolonged viral shedding and the altered development of the CD8+ T cell compartment. In the first aim, we will determine why neonatal CD8+ T cells fail to control CMV during the acute stage of infection and attempt to revive immune functionality by blocking inhibitory receptors. In the second aim, we will examine why CD8+ T cells made after infection fail to control ongoing viral replication during the latent stage of infection and attempt to limit viral shedding by increasing numbers of nave T cells with IL-7 therapy. Knowledge from these studies is expected to pave the way for the development of vital preventative and therapeutic strategies against congenital CMV disease.
Many persistent viral infections are transmitted early in life and are responsible for long-term morbidity and mortality. At the conclusion of these studies, we expect to have a better understanding of the mechanisms limiting immune protection, while also offering insight into safe and effective strategies to boost immunity during critical stages of early development.
| Venturi, Vanessa; Nzingha, Kito; Amos, Timothy G et al. (2016) The Neonatal CD8+ T Cell Repertoire Rapidly Diversifies during Persistent Viral Infection. J Immunol 196:1604-16 |
| Wang, Jocelyn; Wissink, Erin M; Watson, Neva B et al. (2016) Fetal and adult progenitors give rise to unique populations of CD8+ T cells. Blood 128:3073-3082 |
| Reynaldi, Arnold; Smith, Norah L; Schlub, Timothy E et al. (2016) Modeling the dynamics of neonatal CD8+ T-cell responses. Immunol Cell Biol 94:838-848 |
| Wissink, Erin M; Smith, Norah L; Spektor, Roman et al. (2015) MicroRNAs and Their Targets Are Differentially Regulated in Adult and Neonatal Mouse CD8+ T Cells. Genetics 201:1017-30 |
| Smith, Norah L; Wissink, Erin M; Grimson, Andrew et al. (2015) miR-150 Regulates Differentiation and Cytolytic Effector Function in CD8+ T cells. Sci Rep 5:16399 |
| Smith, Norah L; Wissink, Erin; Wang, Jocelyn et al. (2014) Rapid proliferation and differentiation impairs the development of memory CD8+ T cells in early life. J Immunol 193:177-84 |
