Mechanisms of plasmacytoid dendritic cells exhaustion and the impact on viral infection in sickle cell anemia mice.

Abstract

Sickle Cell Anemia (SCA) is a genetic disorder caused by a mutation in the beta globin chain, leading to the production of hemoglobin S. This event causes red blood cells to sickle during deoxygenation, increasing hemolysis and reducing cell lifespan. Hemolysis occurs both in the spleen and intravascularly, releasing damage-associated molecular patterns (DAMPs) that trigger inflammation and oxidative stress. As a result, there is endothelium and leucocyte activation, with elevation on adhesion molecules, contributing to vaso-occlusive crises and chronic inflammation, which leads to complications such as acute chest syndrome and stroke. Recent studies have identified an abnormal type I interferon (IFN-I) signature in SCA patients, although the source of IFN-I and the mechanisms of its stimulation are still unclear. Plasmacytoid dendritic cells (pDCs) are known for their high IFN-I production capability and our preliminary data show that they are stimulated on SCA to produce IFN-a and consequently showed an exhausted phenotype with impaired ability to respond to a secondary stimulus.This project aims to explore whether pDC exhaustion is associated with metabolic changes and its consequences to viral infections in sickle cell anemia mice. The study will use model mice of SCA to differentiate and isolate pDCs, analyze their metabolism and conduct viral infection experiments with murine hepatitis virus (MHV) to evaluate the impact of pDC exhaustion on infection outcomes. The research, spanning 8 months, will be guided by Professor Elina Zuniga at the University of California, San Diego.