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Pre-symptomatic diagnosis of Ebola virus infection

ABSTRACT: Normalized Gene expression data used for meta-analysis from studies: GSE31747, GSE8317, GSE24943, GSE24125. We studied the changes in macaque and human peripheral blood cell gene expression after infection with Ebola Zaire virus (EBZ) to identify host responses that occur before the emergence of symptoms. We integrated data from in vivo and in vitro infection studies of macaque or human peripheral blood. We identified mRNAs that were differentially expressed at early, middle, and late times after infection. The EBZ early genes showing increased or decreased expression were then compared to literature-derived host responses to malaria, rhinovirus and influenza virus which identified the patterns unique to each pathogen. From the group of EBZ-specific genes, we next predicted those that encoded secreted or membrane-associated proteins. Pairs of these host response mRNAs or proteins could become candidates for differential diagnosis of an early EBZ infection, before the emergence of conventional symptoms. Four key immune response pathways that were activated early showed profoundly decreased expression at late times.

ORGANISM(S): Homo sapiens Macaca fascicularis Macaca mulatta

PROVIDER: GSE83331 | GEO | 2016/06/14

SECONDARY ACCESSION(S): PRJNA325626

REPOSITORIES: GEO

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Project description:Zaire ebolavirus (ZEBOV) is among the deadliest known human pathogens, causing severe hemorrhagic fever with high case fatality rates ranging from 70-90%. The lack of effective vaccines or treatment available for ZEBOV renders this pathogen as a significant global biodefense threat, as evidenced by the current, highly lethal outbreak of a novel ZEBOV variant in western Africa. Existing mouse models of lethal ZEBOV infection do not reproduce hallmark symptoms of Ebola hemorrhagic fever (EHF) including prolonged blood coagulation, acute hepatitis, disseminated intravascular coagulation (DIC), and death from hemorrhagic shock, thus restricting pathogenesis studies to non-human primates (NHP). This has prevented rapid evaluation of countermeasures in outbreak scenarios, and impeded a comprehensive understanding of how host responses to infection contribute to severe EHF disease. Here we demonstrate that mice from the Collaborative Cross (CC), a panel of reproducible, recombinant inbred animals that span the genetic breadth of three murine subspecies, are susceptible to a spectrum of disease phenotypes following ZEBOV infection. In contrast to C57Bl6/J mice, which develop lethal disease without symptoms of EHF, CC recombinant inbred intercrossed (CC-RIX) lines develop either complete resistance to lethal disease or severe EHF characterized by prolonged coagulation times and 100% mortality. Disease resistance and survival is not dependent on viral tropism, as both resistant and EHF-susceptible lines show similar inflammation and cytopathic effect in target organs. Transcriptomics reveal potential mechanisms for both induction of severe hemorrhage in EHF mediated by IL-6 and vascular activation, and resistance to lethal infection by induction of lymphocyte differentiation and cellular adhesion. These data demonstrate that host responses specific to unique genetic backgrounds determine susceptibility to hemorrhagic syndrome independent of virus replication. The CC represents a novel mouse model for studying EHF pathogenesis, and we anticipate that it will be applied immediately to developing and evaluating therapeutic countermeasures. Microarrays were performed on liver and spleen samples from mice collected at days 1, 3, and 5 post-infection with mouse adapted Zaire ebolavirus or from time-matched mock-infected animals.

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Pre-symptomatic diagnosis of Ebola virus infection

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