Chromatin Memories: Epigenetic Reprogramming, and the Immunological Aftermath of Ebola Virus Infection and Long-Term Sequelae in Survivors

Abstract

Background: About half of the people who survive Ebola virus infection suffer life-changing multiorgan damage after recovering from acute infection. These conditions (or syndrome) are called "Post-Ebola Syndrome" (PES), and they bear similarities to the ongoing manifestations of COVID-19 (commonly referred to as "long COVID"). Current theory posits that epigenomic mechanisms (i.e., alterations to DNA methylation, chromatin modification and regulation of expression by non-coding RNA) are potential mediators of biological alterations that have occurred during the initial phase of disease and continue after acute recovery.

Objective: To examine the potential role of epigenetic scarring as a key mechanism contributing to PES through the review of DNA methylation changes, histone modification patterns, alteration in expression of non-coding RNA and evidence of persistent viral transcription in immune-privileged sites.

Methods: We searched for literature on this topic from the following databases: PubMed, Scopus, Web of Science, Embase, WHO IRIS, and the Lancet Ebola archives (2014-2025). All studies published in one of these databases were searched based upon established guidelines for systematic review (PRISMA 2020) and 65 studies identified through systematic screening that produced a total of 3892 individual search results were included in the final analysis of evidence. Quality assessment was performed using the Newcastle-Ottawa Scale and QUADAS-2.

Results: Persistent DNA hypermethylation of promoters for the interferon pathway (IFNB1, TLR3, OAS1) in individuals remained for up to 24 months after discharge from hospital. Evidence for H3K27me3 chromatin expansion at interferon loci, and loss of H3K4me3 at IRF7 enhancers, was observed in peripheral blood mononuclear cells from survivors. Upregulation of miR-29a/b was correlated with the presence of fibrous tissue and collagen deposition. The presence of viral-specific RNA (VP35, VP30) was detected in cerebrospinal fluid, aqueous humor or semen up to several years after patients had recovered from infection. Evidence from epigenetic clock analyses suggested that the biological age of survivors was 4.2 years greater than that of non-infected controls.

Conclusion: Survivors of Ebola virus infection show evidence of persistent epigenetic reprogramming of immune cells that correlate with clinical manifestations of PES. Preliminary findings suggest that use of HDAC inhibitors and BET bromodomain inhibitors could be used to reverse these epigenetic changes. There is an urgent need for standardised longitudinal epigenomic monitoring of survivors from Ebola virus infection.