Abstract
Zaire Ebolavirus (ZEBOV) continues to pose a significant threat to human health as highlighted by the recent epidemic that originated in West Africa and the ongoing outbreak in the Democratic Republic of the Congo. Although the ZEBOV variant responsible for this epidemic (Makona) shares significant genetic similarity with previously identified variants (Kikwit and Mayinga), recent reports suggest slower disease progression in nonhuman primates. However, the pathogenesis caused by the new variant is not fully understood. We present the first comprehensive approach in understanding ZEBOV-Makona pathogenesis in cynomolgus macaques by measuring changes in immune cell frequencies, plasma levels of immune mediators, and differentially expressed genes (DEGs) within whole blood (WB) and peripheral blood mononuclear cells (PBMC). Our combined approach revealed a link between: 1) increased interferon-stimulated gene expression, IFNα levels, and activated plasmacytoid dendritic cells; 2) higher proinflammatory gene expression, cytokine and chemokine levels, and non-classical monocytes; 3) gene signature of leukocyte activation and increased granulocytes; and 4) decreased expression of lymphocyte related genes and lymphopenia. In addition, our data strongly indicate delayed disease progression as well as limited overlap (~30%) in host transcriptome changes following ZEBOV-Makona infection compared to ZEBOV-Kikwit. These observations provide novel insight into the molecular mechanisms of ZEBOV-Makona pathogenesis.
Highlights
Zaire Ebolavirus (ZEBOV) continues to pose a significant threat to human health as highlighted by the recent epidemic that originated in West Africa and the ongoing outbreak in the Democratic Republic of the Congo
ZEBOV infection in humans is characterized by hemorrhage, lymphopenia, high levels of circulating pro-inflammatory mediators, liver failure, and disseminated intravascular coagulation, which culminate in death due to hypovolemic shock and multi-organ failure[2,3,4]
We detected a significant increase in transcripts from all open reading frame (ORF) and intergenic region (IGR) 5-6 days post infection (DPI)
Summary
Zaire Ebolavirus (ZEBOV) continues to pose a significant threat to human health as highlighted by the recent epidemic that originated in West Africa and the ongoing outbreak in the Democratic Republic of the Congo. Our data strongly indicate delayed disease progression as well as limited overlap (~30%) in host transcriptome changes following ZEBOV-Makona infection compared to ZEBOV-Kikwit. These observations provide novel insight into the molecular mechanisms of ZEBOV-Makona pathogenesis. Little is known about the progression of disease caused by this newly identified variant To address this gap in knowledge, we conducted a longitudinal study to characterize the host immune response to ZEBOV-Makona infection in NHP using a multipronged approach that combined immunological assays and generation sequencing in both whole blood (WB) and peripheral blood mononuclear cells (PBMC). Our data show delayed appearance of clinical symptoms as well as overlapping but distinct host transcriptome changes during ZEBOV-Makona infection compared to ZEBOV-Kikwit in ZEBOV-Makona-infected animals thereby providing novel insight into ZEBOV-Makona pathogenesis
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