Abstract
Early detection of Ebola virus (EBOV) infection is essential to halting transmission and adjudicating appropriate treatment. However, current methods rely on viral identification, and this approach can misdiagnose presymptomatic and asymptomatic individuals. In contrast, disease-driven alterations in the host transcriptome can be exploited for pathogen-specific diagnostic biomarkers. Here, we present for the first time EBOV-induced changes in circulating miRNA populations of nonhuman primates (NHPs) and humans. We retrospectively profiled longitudinally-collected plasma samples from rhesus macaques challenged via intramuscular and aerosol routes and found 36 miRNAs differentially present in both groups. Comparison of miRNA abundances to viral loads uncovered 15 highly correlated miRNAs common to EBOV-infected NHPs and humans. As proof of principle, we developed an eight-miRNA classifier that correctly categorized infection status in 64/74 (86%) human and NHP samples. The classifier identified acute infections in 27/29 (93.1%) samples and in 6/12 (50%) presymptomatic NHPs. These findings showed applicability of NHP-derived miRNAs to a human cohort, and with additional research the resulting classifiers could impact the current capability to diagnose presymptomatic and asymptomatic EBOV infections.
Highlights
Rapid and accurate diagnosis of highly transmissible, lethal illnesses such as Ebola virus disease (EVD) is critical to restricting pathogen spread and to applying appropriate therapeutic strategies
Circulating virus was detectable in one animal at day 3 and in all nonhuman primates (NHPs) starting on day 6; viral titers ranged from 103–106 plaque-forming units (PFU)/mL through death/euthanasia (Fig. 1A)
Documented cases of symptomless Ebola virus (EBOV) infection showed no detectable levels of circulating virus in over a third of the cases[43]
Summary
Rapid and accurate diagnosis of highly transmissible, lethal illnesses such as Ebola virus disease (EVD) is critical to restricting pathogen spread and to applying appropriate therapeutic strategies. Current diagnostics rely on identifying Ebola virus (EBOV) in blood samples by targeting viral antigens using enzyme immunoassays or by amplifying specific viral sequences through quantitative reverse transcriptase polymerase chain reaction (RT-PCR)[11], with PCR results available 1–2 days earlier than corollary immunoassays These tests may be unreliable until 3–4 days after symptom onset[12,13]. MiRNAs are readily accessible for interrogation due to release into circulation through active secretion or cell death (apoptosis, necrosis)[23] In this context and in terms of diagnostic relevance, miRNAs are remarkably robust and survive nuclease degradation, with previous studies documenting detection in various bodily fluids such as blood (serum, plasma), cerebrospinal fluid, breast milk, urine, and saliva[24]. Inhibitors of three of these sequences could prevent GP-induced cytotoxicity in vitro, underscoring the potential therapeutic benefits from this line of inquiry
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