Cardiovascular disease affects a large proportion of individuals, responsible for one-third of deaths in the US. Gammaherpesvirus infections can contribute to the development of these diseases. As 95% of the adult population is infected with a gammaherpesvirus, there is a significant risk of infection compounding with other predisposing factors which will lead to the development of cardiovascular disease. Studying factors which control gammaherpesvirus infection is essential to understanding how infection can serve as a risk factor. Our lab has discovered that the cytokine interleukin 1 (IL-1) facilitates chronic gammaherpesvirus infection. IL-1 is associated with cardiovascular disease as elevated levels have been found in atherosclerotic lesions and damaged heart tissue. This novel, pro-viral role of IL-1 indicates that the contribution of this cytokine to cardiovascular disease is multifaceted.The proposed studies will utilize the rodent gammaherpesvirus, MHV68 to define the role of IL-1 in gammaherpesvirus infection. Mice deficient in the IL-1 receptor will be utilized to investigate how parameters of MHV68 infection are reliant on IL-1 signaling and how cell populations change and respond to IL-1 signaling during infection. Experiments will explore the hypothesis that IL-1 signaling facilitates gammaherpesvirus infection by promoting infected B cell differentiation and viral reactivation. In Specific Aim 1, we will determine the extent to which IL-1 signaling promotes gammaherpesvirus reactivation. Germinal center B cells and plasma cells will be the focus of this aim as these are the predominantly infected cell populations. In this aim we will also utilize a cell line infected with the human gammaherpesvirus, EBV, to directly asses the role of IL-1 in the human virus infection. In Specific Aim 2, we will determine the extent to which T cell-intrinsic IL-1 signaling facilitates MHV68 infection. Experiments will focus on the effects of IL-1 on T follicular helper (Tfh) cell proliferation as they support the germinal center B cell population, enabling gammaherpesviruses to establish infection.With the completion of these studies, we will understand how IL-1 signaling supports gammaherpesvirus infection. We can then identify how to target IL-1 in order to control gammaherpesvirus infection and reduce the risk of developing the associated cardiovascular diseases.
|Program type||Predoctoral Fellowship|
|Effective start/end date||01/01/2020 → 12/31/2021|