Ebola virus (EBOV) is a global public health threat, as demonstrated in the 2013-2016 EBOV epidemic in West Africa, which led to more than 11,000 deaths. The second largest outbreak which started in the Democratic Republic of the Congo in 2018 is not
yet completely contained even in the context of a swift response demonstrating the need for more effective medical countermeasures against EBOV. This project aims to contribute to the development of advanced medical countermeasures against EBOV.
EBOV infections are characterized by strong interferon antagonism that results in the lack of maturation of infected dendritic cells, which in turn leads to a deficient stimulation of T cells, eventually resulting in T-cell apoptosis and lymphopenia. In addition, the sole EBOV envelope glycoprotein (GP) interacts with TLR4 on T cells, resulting in abortive infection and massive secretion of cytokines contributing to hyperinflammation. This paradoxical immune dysregulation is the major contributor to pathogenesis observed in EBOV disease, and thus we consider that understanding the mechanisms of immune dysregulation will lead to understanding pathogenesis. The central hypothesis of the proposed program is that EBOV infection leads to cell-type specific alterations at every level of gene expression that result in a dysregulated immune response characterized by “immune paralysis” and, paradoxically, hyperinflammation. To test the hypothesis, three research Projects (RPs) are proposed: RP1 focuses on pathogenic mechanisms at the transcriptional level, RP2 focuses on posttranscriptional events, and RP3 focuses on posttranslational modifications.