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A conserved transcriptional response to intranasal Ebola virus exposure in nonhuman primates before onset of fever

ABSTRACT: Ebola Virus Disease (EVD), caused by the Ebola virus (EBOV), recently made headlines as it cause a large outbreak in West Africa killing more than 11,000 individuals. One aspect of an outbreak of this scale is understanding disease transmission and differences in the host response to infection. In animal models for disease, particularly non-human primate models of disease, a large infectious dose of 1000PFU through intramuscular injection results if a fairly uniformly lethal disease were the animals die after 6-9 days. However, this is not representative of actual transmission routes of infection as humans tend to have variable exposures through cuts and mucosal surfaces and have variable times to death. To determine if a low dose infection through a mucosal surface results in a different host response to infection, we infected 12 cynomologus macaques with 100PFU of EBOV-Makona (EBOV-Mak). To follow the host response to infection, we utilized RNA-Sequencing and a newly developed NanoString codeset to monitor changes in RNA transcripts. We found that despite different onset of disease and some animals presenting with delayed time to death, there was a highly conserved and predictable host response to infection. When animals were aligned based on onset of fever, the first clinical sign of severe disease, the host response to infection was able to be modeled showing a predictable pattern of gene expression with ISG appearing as early as 4 days before fever onset. Together, this shows that lethal EVD has a uniform and predictable response to infection and that expression of a subst of genes is present before the onset of fever.

ORGANISM(S): Macaca fascicularis

PROVIDER: GSE103825 | GEO | 2018/04/12

REPOSITORIES: GEO

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Project description:Ebola (EBOV) virus causes severe and often lethal hemorrhagic fever in humans and nonhuman primates (NHP), and has been classified as a Category A bioweapon agent. There are currently no approved preventive vaccines or postexposure treatments for EBOV hemorrhagic fever. The mechanisms of EBOV pathogenesis are only partially understood, but the dysregulation of normal host immune responses (including destruction of lymphocytes, increases in levels of circulating proinflammatory cytokines, 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. Identification of effective treatment strategies may greatly benefit based on identification of molecular features of the host response to infection and treatment. In order to identify these gene signatures related to correlates of protection, we used a DNA microarray-based approach to compare the host genome-wide responses of EBOV-infected NHP responding to candidate therapeutics. With this approach, we have identified genes that appear to correlate with survival, including chemokine ligand 8 (CCL8/MCP-2), and revealed a subset of distinctly differently expressed genes that may provide possible targets for future diagnostics or therapeutics. These analyses will assist us in understanding the pathogenic mechanisms of EBOV infection as well as identify improved therapeutic strategies. Transcriptional analysis of global gene expression changes in Zaire Ebola Virus (ZEBOV)-infected rhesus macaques that were treated with either recombinant nematode anticoagulant protein c2 (rNAPc2) or recombinant human activated protein C (rhAPC). Animals were infected with 1000pfu ZEBOV, then subsequently treated with rNAPc2 or rhAPC. Four animals were left untreated for controls. Blood samples were taken at specified days post-infection and PBMCs were isolated from the samples and inactivated in TRIzol reagent. Total RNA was isolated from the samples, then linearly amplified and hybridized to a whole genome long-oligonucleotide microarray in a two color comparative format with a commercially available human reference RNA from Stratagene as a consistent control in dataset comparisons.

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A conserved transcriptional response to intranasal Ebola virus exposure in nonhuman primates before onset of fever

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