Functional genomics reveals the induction of inflammatory response and metalloproteinase gene expression during lethal Ebola virus infection

Cristian Cilloniz, Hideki Ebihara, Chester Ni, Gabriele Neumann, Marcus J. Korth, Sara M. Kelly, Yoshihiro Kawaoka, Heinz Feldmann, Michael G. Katze

Research output: Contribution to journalArticle

27 Scopus citations

Abstract

Ebola virus is the etiologic agent of a lethal hemorrhagic fever in humans and nonhuman primates with mortality rates of up to 90%. Previous studies with Zaire Ebola virus (ZEBOV), mouse-adapted virus (MAZEBOV), and mutant viruses (ZEBOV-NP ma, ZEBOV-VP24 ma, and ZEBOV-NP/VP24 ma) allowed us to identify the mutations in viral protein 24 (VP24) and nucleoprotein (NP) responsible for acquisition of high virulence in mice. To elucidate specific molecular signatures associated with lethality, we compared global gene expression profiles in spleen samples from mice infected with these viruses and performed an extensive functional analysis. Our analysis showed that the lethal viruses (MA-ZEBOV and ZEBOV-NP/VP24 ma) elicited a strong expression of genes 72 h after infection. In addition, we found that although the host transcriptional response to ZEBOV-VP24 ma was nearly the same as that to ZEBOV-NP/VP24 ma, the contribution of a mutation in the NP gene was required for a lethal phenotype. Further analysis indicated that one of the most relevant biological functions differentially regulated by the lethal viruses was the inflammatory response, as was the induction of specific metalloproteinases, which were present in our newly identify functional network that was associated with Ebola virus lethality. Our results suggest that this dysregulated proinflammatory response increased the severity of disease. Consequently, the newly discovered molecular signature could be used as the starting point for the development of new drugs and therapeutics. To our knowledge, this is the first study that clearly defines unique molecular signatures associated with Ebola virus lethality.

Original languageEnglish (US)
Pages (from-to)9060-9068
Number of pages9
JournalJournal of virology
Volume85
Issue number17
DOIs
StatePublished - Sep 1 2011

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ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Insect Science
  • Virology

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