Comparative Transcriptomics in Ebola Makona-Infected Ferrets, Nonhuman Primates, and Humans

Abstract

The domestic ferret is a uniformly lethal model of infection for 3 species of Ebolavirus known to be pathogenic in humans. Reagents to systematically analyze the ferret host response to infection are lacking; however, the recent publication of a draft ferret genome has opened the potential for transcriptional analysis of ferret models of disease. In this work, we present comparative analysis of longitudinally sampled blood taken from ferrets and nonhuman primates infected with lethal doses of the Makona variant of Zaire ebolavirus. Strong induction of proinflammatory and prothrombotic signaling programs were present in both ferrets and nonhuman primates, and both transcriptomes were similar to previously published datasets of fatal cases of human Ebola virus infection.

Asymptomatic Infection of Marburg Virus Reservoir Bats Is Explained by a Strategy of Immunoprotective Disease Tolerance

“…14 Specifically, we show significant induction of a cluster of canonical antiviral genes (including DDX58 [RIG-I], IFIT1, IRF7, ISG15, and OAS3) typical of viral infection in mammals, but strikingly, almost no significant changes in expression of traditional markers of adaptive immunity or inflammation, including the cytokines and chemokines IFNg, CCL8, FAS, and IL6, normally associated with MARV pathogenesis in primates. 8,25,[27][28][29][30][31] Our findings identify putative virulence-determining differences between reservoir and spillover host, as well as immunoprotective commonalities likely shared between ERBs and bat reservoir hosts of other emerging zoonotic pathogens (e.g., SARS, Ebola), which could be exploitable for human therapeutic development.…”

“…The clearest response trend was a common cluster of 26 DEGs (D2-D5) that accounted for the most strongly upregulated genes (denoted by asterisks in Fig . 25,28,29,31,38 Some were significantly but transiently downregulated in spleen on D8 (CD163, RIG-I, ISG15, USP18), most after strong initial induction ( Figure 5C). Indeed, all but one of the three highest-induced genes across tissue/ cell types were cluster DEGs, except late (D14) upregulation of IL8 in skin, which was the study's strongest induced gene.…”

A Two-Antibody Pan-Ebolavirus Cocktail Confers Broad Therapeutic Protection in Ferrets and Nonhuman Primates

“…We determined MPB134 AF ’s protective efficacy against the wild-type Makona variant of EBOV (EBOV/Makona) (Mire et al, 2015), SUDV variant Gulu (SUDV/Gulu) and BDBV variant But-811250 (BDBV/But-811250) in the recently established ferret model, which does not require any viral adaptation and recapitulates key hallmarks of human EVD (Cross et al, 2016; Cross et al, 2018; Kozak et al, 2016). Ferrets challenged intranasally with a lethal dose of EBOV/Makona received two 15-mg doses of MBP134 AF three days apart, with the treatment initiated on either day 2 (ferrets 1–4) or day 3 (ferrets 5–8) post infection (p.i.)…”

Previremic Identification of Ebola or Marburg Virus Infection Using Integrated Host-Transcriptome and Viral Genome Detection

“…Several reports have identified rapidly upregulated mRNAs in blood and peripheral blood mononuclear cells (PBMCs) in response to EBOV infection (17)(18)(19)(20)(21). We sought mRNAs that were consistently upregulated at early time points postexposure in existing data sets of NHPs infected with EBOV Kikwit (19), EBOV Makona C07 (20), EBOV Makona SL 3864.1 (17), or EBOV Makona C05 (24,25). These studies represented various strains and isolates, routes of exposure, and variations in whether PBMCs or whole blood was used for sequencing.…”