Thorough investigation of dysregulated immune responses to Ebola virus (EBOV) requires an integrated approach that addresses regulation of gene transcription by epigenetic and non-epigenetic mechanisms, posttranscriptional mechanisms of gene regulation and posttranslational protein modifications. Attempts to investigate the lack of function or altered function of certain host proteins during EBOV infection by focusing on only some of these mechanisms would not be productive and would provide an incomplete picture of gene expression in response to EBOV infection. As such, this Program Project proposal comprises an integrated approach that will combine both epigenetic and nonepigenetic transcriptional mechanisms (Project 1, Dr. Alexander Bukreyev, Project Lead, UTMB), posttranscriptional mechanisms (Project 2, Dr. Mariano Garcia-Blanco, Project Lead, University of Virginia) and posttranslational protein modifications (Project 3, Dr. Ricardo Rajsbaum, Project Lead, Rutgers University) caused by EBOV infection. All three Research Projects require the BSL-4 Core (Core B, Dr. Alexander Bukreyev, Core Lead, UTMB), which will be responsible for performing infections of human immune and non-immune cells, as well as mice and nonhuman primates, and also will perform the initial steps of experiments that involve infectious virus. Analysis of infected immune cells will be performed by the Proteogenomics Core (Core C, Dr. Andrew Routh, Core Lead, UTMB); the results will be analyzed using bioinformatics and modeling approaches (Core D, Dr. Ivan Marazzi, Core Lead, University of California - Irvine) to investigate the nature of dysregulated immune response to EBOV. An Administrative Core (Core A, Dr. Alexander Bukreyev, Core Lead) will function as the critical coordinating component of the P01. The combined approach that we propose will provide the most detailed view of the host immune response to EBOV infection yet described.