Transcriptomic Analysis Reveals Host miRNAs Correlated with Immune Gene Dysregulation during Fatal Disease Progression in the Ebola Virus Cynomolgus Macaque Disease Model.

Christopher P Stefan,Korey L Delp,Joshua D Shamblin,Catherine E Arnold,Louis A Altamura,Christina E Douglas,Elizabeth E Zumbrun,Heather L Esham,Amanda S Graham,Justine M Zelko,Holly A Bloomfield,Timothy D Minogue,Keersten M Ricks,Cheryl L Taylor-Howell,Suzanne E Wollen,Candace D Blancett,Charles J Shoemaker,Scott P Olschner,Thomas R Sprague

doi:10.3390/microorganisms9030665

Christopher P Stefan, Korey L Delp + Show 17 more

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https://doi.org/10.3390/microorganisms9030665

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Abstract

Ebola virus is a continuing threat to human populations, causing a virulent hemorrhagic fever disease characterized by dysregulation of both the innate and adaptive host immune responses. Severe cases are distinguished by an early, elevated pro-inflammatory response followed by a pronounced lymphopenia with B and T cells unable to mount an effective anti-viral response. The precise mechanisms underlying the dysregulation of the host immune system are poorly understood. In recent years, focus on host-derived miRNAs showed these molecules to play an important role in the host gene regulation arsenal. Here, we describe an investigation of RNA biomarkers in the fatal Ebola virus disease (EVD) cynomolgus macaque model. We monitored both host mRNA and miRNA responses in whole blood longitudinally over the disease course in these non-human primates (NHPs). Analysis of the interactions between these classes of RNAs revealed several miRNA markers significantly correlated with downregulation of genes; specifically, the analysis revealed those involved in dysregulated immune pathways associated with EVD. In particular, we noted strong interactions between the miRNAs hsa-miR-122-5p and hsa-miR-125b-5p with immunological genes regulating both B and T-cell activation. This promising set of biomarkers will be useful in future studies of severe EVD pathogenesis in both NHPs and humans and may serve as potential prognostic targets.

Highlights

Ebola virus is a member of the negative single strand RNA virus family Filoviridae, noted for causing a virulent hemorrhagic fever in humans and non-human primates (NHPs) termed Ebola virus disease (EVD)
Intramuscular challenge of eight NHPs with a 100 plaque forming units (PFU) target dose (152.5 actual dose) of Ebola-Kikwit with one sham infected (MEM + 2% Heat Inactivated Fetal Calf Serum (HI-FCS) diluent), showed that all infected NHPs developed clinical signs starting at 5 days post-infection (DPI)
Infected NHPs progressed to a severe disease state and reached endpoint euthanasia criteria between 6–8 DPI (Figure 1a,b)

Summary

Introduction

Ebola virus is a member of the negative single strand RNA virus family Filoviridae, noted for causing a virulent hemorrhagic fever in humans and non-human primates (NHPs) termed Ebola virus disease (EVD). The genus Ebolavirus includes five species with case fatality rates up to 90%. Zaire Ebolavirus (EBOV) is the most common species in human. Microorganisms 2021, 9, 665 outbreaks and has claimed the most lives to date. Natural outbreaks of filoviruses in humans have occurred in numerous countries in Central and Western Africa since its discovery in 1976, with the 2013–2016 EBOV outbreak in West Africa being the largest to date. Characteristic EVD symptoms include fever, myalgia, headache, and gastrointestinal symptoms with patients potentially developing a maculopapular rash [1,2]. Diagnosis of EVD is critical for implementation of effective clinical interventions as well as limiting disease spread

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