Molecular Mechanisms of the Dysregulated Immune Response to Ebola Virus

OVERALL: PROJECT SUMMARY/ABSTRACT
The central hypothesis of the proposed P01 Program is that Ebola virus infection leads to cell-type specific
transcriptional, posttranscriptional, and posttranslational alterations that create aberrant counterproductive
responses of immune cells, leading to a dysregulated immune response, which paradoxically produces “immune
paralysis” and hyperinflammation. To address the hypothesis, three Research Projects are proposed. Research
Project 1 focuses on pathogenic mechanisms at the transcriptional level, while Research Project 2 focuses on
posttranscriptional events, and Research Project 3 focuses on posttranslational modifications, each contributing
to the dysregulated immune response to Ebola virus. The dysregulated immune response is responsible for most
of the pathogenesis observed in Ebola virus disease.
All projects require the BSL-4 Core (Core B), which will be responsible for performing infections of human
immune and nonimmune cells, nonhuman primates, and the initial steps of experiments that involve infectious
virus. Importantly, Core B will provide each of the research projects samples from the same experimental
samples insuring that data from each project can be compared directly—this is a unique feature of this P01
Program. The Proteogenomics Core (Core C) will be responsible for massive parallel sequencing and mass
spectrometry-based studies. The Bioinformatics and Modeling Core (Core D) is critical for generating tools
employed in the experimental designs, including statistical help for OMICS experiments, analyzing OMICS data
and integrating OMICS data into networks that model the behavior of various cell populations infected with
EBOV. The work done in Core D will synthesize a model to explain how transcriptional, posttranscriptional, and
posttranslational responses of individual cell populations lead to immune dysregulation. The comprehensive
picture painted by this collaborative effort will revolutionize our understanding of the immunopathogenesis of
severe acute viral infections (e.g., immune imbalance seen in COVID-19). The Administrative Core (Core A)
will be responsible for strategic planning, continual evaluation, and communication and coordination of activities
among the various components of the project according to a detailed management plan.
The expected outcomes will contribute substantially to our knowledge of the fundamental mechanisms of the
immunopathogenesis of EBOV infections toward the development of effective countermeasures. The expected
outcomes will include (1) detailed knowledge of transcriptional mechanisms leading to the dysregulated immune
response to EBOV, (2) elucidation of the role of posttranscriptional mechanisms in the dysregulated immune
response to EBOV, (3) elucidation of the role of posttranslational mechanisms in the dysregulated immune
response to EBOV, and (4) experimental validation of the identified pathogenic mechanisms and their targeting.
The proposed tightly coordinated and comprehensive analysis has not been done before for any virus.

Grant Number: 5P01AI150585-05
NIH Institute/Center: NIH
Principal Investigator: Alexander Bukreyev