Therapeutics of Ebola hemorrhagic fever: whole-genome transcriptional analysis of successful disease mitigation.

Abstract

The mechanisms of Ebola (EBOV) pathogenesis are only partially understood, but the dysregulation of normal host immune responses (including destruction of lymphocytes, increases in circulating cytokine levels, and development of coagulation abnormalities) is thought to play a major role. Accumulating evidence suggests that much of the observed pathology is not the direct result of virus-induced structural damage but rather is due to the release of soluble immune mediators from EBOV-infected cells. It is therefore essential to understand how the candidate therapeutic may be interrupting the disease process and/or targeting the infectious agent. To identify genetic signatures that are correlates of protection, we used a DNA microarray-based approach to compare the host genome-wide responses of EBOV-infected nonhuman primates (NHPs) responding to candidate therapeutics. We observed that, although the overall circulating immune response was similar in the presence and absence of coagulation inhibitors, surviving NHPs clustered together. Noticeable differences in coagulation-associated genes appeared to correlate with survival, which revealed a subset of distinctly differentially expressed genes, including chemokine ligand 8 (CCL8/MCP-2), that may provide possible targets for early-stage diagnostics or future therapeutics. These analyses will assist us in understanding the pathogenic mechanisms of EBOV infection and in identifying improved therapeutic strategies.

• Authors: Judy Y Yen, Sara Garamszegi, Joan B Geisbert, Kathleen H Rubins, Thomas W Geisbert, Anna Honko, Yu Xia, John H Connor, Lisa E Hensley
• Journal: The Journal of infectious diseases (J Infect Dis) Vol. 204 Suppl 3 Pg. S1043-52 (Nov 2011) ISSN: 1537-6613 [Electronic] United States
• PMID: 21987740 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Blood Coagulation Factor Inhibitors

Topics

• Animals
• Blood Coagulation (genetics)
• Blood Coagulation Factor Inhibitors (genetics, metabolism)
• Ebolavirus (immunology)
• Gene Expression Profiling
• Gene Expression Regulation, Viral
• Genetic Predisposition to Disease
• Genome
• Hemorrhagic Fever, Ebola (genetics, immunology, therapy)
• Lymphocyte Activation (genetics)
• Macaca mulatta
• Multigene Family
• Oligonucleotide Array Sequence Analysis
• Transcription, Genetic