Ebola Research Articles

Mechanism of Viral Immune Evasion

This article explores how viruses evade the host’s immune system through various mechanisms. Initially, the article introduces the innate immune system as the first line of defense against pathogens, activating an immune response by recognizing pathogen-associated molecular patterns (PAMPs). However, viruses such as HIV-1, Ebola virus (EBOV), and members of the Herpesviridae family have developed complex strategies to circumvent these defense mechanisms.HIV-1 evades the immune system by integrating into the host genome to form latent infections, exhibiting high genetic variability, and through cell-to-cell transmission. Ebola virus suppresses the function of pattern recognition receptors (PRRs), such as RIG-I and MDA5, and interferes with signaling pathways through its VP35 and VP24 proteins, thereby inhibiting the production of interferons (IFNs). Members of the Herpesviridae family evade the host’s innate immune response by interfering with PRRs, degrading immune factors, inducing post-translational modifications (PTMs), utilizing molecular sink strategies, and inhibiting the production of type I interferons and pro-inflammatory cytokines.The article emphasizes that a deep understanding of these viral immune evasion mechanisms is crucial for the development of effective antiviral therapies and vaccines.

Discovery of Nanosota-EB1 and -EB2 as Novel Nanobody Inhibitors Against Ebola Virus Infection.

The Ebola filovirus (EBOV) poses a serious threat to global health and national security. Nanobodies, a type of single-domain antibody, have demonstrated promising therapeutic potential. We identified two anti-EBOV nanobodies, Nanosota-EB1 and Nanosota-EB2, which specifically target the EBOV glycoprotein (GP). Cryo-EM and biochemical data revealed that Nanosota-EB1 binds to the glycan cap of GP1, preventing its protease cleavage, while Nanosota-EB2 binds to critical membrane-fusion elements in GP2, stabilizing it in the pre-fusion state. Nanosota-EB2 is a potent neutralizer of EBOV infection in vitro and offers excellent protection in a mouse model of EBOV challenge, while Nanosota-EB1 provides moderate neutralization and protection. Nanosota-EB1 and Nanosota-EB2 are the first nanobodies shown to inhibit authentic EBOV. Combined with our newly developed structure-guided in vitro evolution approach, they lay the foundation for nanobody-based therapies against EBOV and other viruses within the ebolavirus genus.

Public health system in post-pandemic Sierra Leone: a scoping review

BackgroundSince the outbreak of the novel SARS-CoV-2 that caused COVID-19 in 2019, the government of Sierra Leone implemented immediate preventive measures to stop the disease from entering the country. On March 24, 2020, the country declared a state of emergency in response to the emerging global COVID-19 pandemic, even though no confirmed cases had been reported at that time. However, Sierra Leone recorded its first COVID-19 case later in March 2020. While there have been few scoping reviews to date, these primarily focuses on experiences from Western countries or expatriates. The main purpose of this scoping review is to document the various COVID-19 pandemic preparedness measures undertaken by the Sierra Leone health system, assess the impacts of the pandemic on health systems, and document the various responses of health systems implemented across different settings from a home-based perspective.MethodsWe searched peer-reviewed papers and articles under review or submitted for publication in Sierra Leone and the COVID-19 pandemic found in the Web of Science, Scopus, Pubmed, Google Scholar, MedRxiv, and Research Square databases. In addition, we examined gray literature, including Sierra Leone government reports and academic unpublished works on Sierra Leone’s COVID-19 situation. Both quantitative and qualitative studies were analyzed, focusing on the Sierra Leone health system or on the essential health services provided by the Sierra Leone health system during the COVID-19 pandemic.ResultsFew (48.7%) studies were multi-country studies (i.e., involving different countries and Sierra Leone). The majority (83.7%) were original articles published either in peer-reviewed journals or were deposited in preprint repositories; 10.9% were editorials, commentaries, or news reports; 1 (2.7%) was a working paper; and 1 (2.7%) was personal correspondence.ConclusionSierra Leone’s health system was partially prepared for the COVID-19 pandemic, largely due to its previous experience in managing the Ebola virus disease outbreaks from 2013 to 2016. However, the pandemic had significant impact on other health services. Although the country’s response to the pandemic was swift, it fell below average in addressing the scale of the challenges posed by the crisis.

Ebola Outbreak Response in the DRC with rVSV-ZEBOV-GP Ring Vaccination

BackgroundAt the beginning of the 2018–2020 outbreak of Ebola virus disease (EVD) in eastern Democratic Republic of Congo (DRC), no vaccine had been licensed. However, cluster-randomized evidence from Guinea in 2015 had indicated that ring vaccination around new cases (targeting contacts and contacts-of-contacts) with the use of single-dose live-replicating rVSV-ZEBOV-GP vaccine reduced EVD rates starting 10 days after vaccination. Thus, ring vaccination was added to the standard control measures for that outbreak.MethodsIn this study, we evaluated the incidence of EVD within the first 9 days after vaccination (when little protection was expected from case isolation or ring vaccination), during days 10 to 29, and at later time periods. We established 1853 rings around new cases or clusters within 21 days after symptom onset in the index case and offered vaccination to the ring members. Vaccinees were monitored for EVD onset until the end of the outbreak in mid-2020.ResultsFrom August 8, 2018, to January 14, 2020, we vaccinated 265,183 participants. Of these vaccinees, 102,515 were monitored on days 0, 3, and 21 for safety. Among the contacts and contacts-of-contacts, 434 cases of EVD (0.2 per ring) were diagnosed, almost all within 0 to 9 days (380 cases) or 10 to 29 days (32 cases) after vaccination. An additional 22 cases were diagnosed after day 29 during an average of 170 more days of follow-up. The sooner that control measures (including ring vaccination) began after EVD onset in the index case, the sooner EVD rates fell among contacts. In each subgroup, EVD rates fell suddenly around day 10. Among the contacts and contacts-of-contacts who were still disease-free at day 10, the EVD onset rate during days 10 to 29 was 0.16 per 1000 (in 32 of 194,019 participants). This rate was much lower than the rate of 4.64 per 1000 (in 21 of 4528 participants) that had been seen among similarly defined ring members in Guinea, in whom standard control measures had been promptly initiated but vaccination was delayed until 21 days after ring formation (rate ratio, 0.04; 95% confidence interval, 0.02 to 0.06). No safety concerns with the vaccine were identified.ConclusionsNonrandomized evidence regarding standard EVD control measures plus ring vaccination in eastern DRC reinforces the earlier randomized evidence from Guinea of vaccine efficacy against EVD onset 10 or more days after vaccination.

Marburg virus reaches Rwanda: how close are we to a vaccine solution?

Marburg virus disease (MVD) is a highly virulent and often fatal disease caused by the Marburg virus, a member of the Filoviridae family, closely related to the Ebola virus. Historically, outbreaks have been sporadic but lethal across various African countries, with high case fatality rates (CFRs). In 2023, significant outbreaks occurred in Tanzania and Equatorial Guinea, with CFRs of 62.5% and 75%, respectively. In 2024, Rwanda faced its first outbreak, starting on September 27, 2024. By November 8, 2024, Rwanda had conducted 7,408 tests, confirming 66 cases, 15 of which were fatal, and 51 recoveries. Although no approved vaccine currently exists for MVD, global health authorities are prioritizing the development of effective vaccines. Drawing on insights from the rapid COVID-19 vaccine development, several promising candidates are under exploration, with the cAd3-MARV showing notable potential. This paper examines the current MVD outbreak in Rwanda and the progress toward developing a long-term vaccine solution.

A Randomized, Blinded, Vehicle-Controlled Dose-Ranging Study to Evaluate and Characterize Remdesivir Efficacy Against Ebola Virus in Rhesus Macaques.

Ebola virus (EBOV) causes severe disease in humans, with mortality as high as 90%. The small-molecule antiviral drug remdesivir (RDV) has demonstrated a survival benefit in EBOV-exposed rhesus macaques. Here, we characterize the efficacy of multiple intravenous RDV dosing regimens on survival of rhesus macaques 42 days after intramuscular EBOV exposure. Thirty rhesus macaques underwent surgical implantation of telemetry devices for the fine-scale monitoring of body temperature and activity, as well as central venous catheters, to enable treatment administration and blood collection. Treatment, consisting of a loading dose of RDV followed by once-daily maintenance doses for 11 days, was initiated 4 days after virus exposure when all animals were exhibiting disease signs consistent with incipient EBOV disease as well as quantifiable levels of EBOV RNA in plasma. In the RDV treatment groups receiving loading/maintenance doses of 5/2.5 mg/kg, 10/5 mg/kg, and 20/10 mg/kg, a total of 6 of 8 (75%), 7 of 8 (87.5%), and 5 of 7 (71.4%) animals survived, respectively. In the vehicle control group, one of seven animals (14.3%) survived. The improved survival rate compared to the control group was statistically significant only for the 10/5 mg/kg RDV treatment group. This treatment regimen also resulted in a significantly lower systemic viral load compared to the vehicle control after a single RDV treatment. All three RDV regimens produced a significantly lower systemic viral load after two treatments. For most animals, RDV treatment, regardless of dose, resulted in the amelioration of many of the clinical-pathological changes associated with EBOV disease in this model.

Systematic Review and Meta-Analysis of Female Reproductive Health Following Ebola Virus Disease.

The viral hemorrhagic fevers Lassa fever (LF) and Ebola virus disease (EVD) have been documented to cause long-term health problems in survivors. Limited studies have noted the presence of adverse reproductive health outcomes, including menstrual irregularities and pregnancy loss, after recovery from infection. The objective of this systematic review and meta-analysis is to summarize existing knowledge surrounding reproductive health in female survivors of LF and EVD. Literature was gathered from PubMed, Embase, Ovid Medline, Cumulative Index of Nursing and Allied Health (CINAHL) Complete, Web of Science, and Global Health databases and subsequently reviewed in Covidence. Included studies described at least one reproductive health outcome in women after recovery from EVD or LF. Thirteen studies were identified in the systematic review, all of which only discussed reproductive health in EVD survivors. No studies of reproductive health among survivors of LF were identified. The included studies were conducted in Guinea, Sierra Leone, and Liberia, and they reported irregular menstruation, pregnancy loss, decreased libido, pelvic inflammatory disease, sexual dysfunction, female reproductive odor, and genital problems/infections among survivors. In a meta-analysis of nine studies, 14.0% of female EVD survivors experienced any adverse reproductive health outcome. However, there was significant heterogeneity among the included studies. This study highlights the health problems faced by female EVD survivors and underscores the need for more research surrounding the effects of viral hemorrhagic fevers on women's health.

Guardians at the Gate: Optimization of Small Molecule Entry Inhibitors of Ebola and Marburg Viruses.

Ebola and Marburg (EBOV and MARV) filoviral infections lead to fatal hemorrhagic fevers and have caused over 30 outbreaks in the last 50 years. Currently, there are no FDA-approved small molecule therapeutics for effectively treating filoviral diseases. To address this unmet medical need, we have conducted a systematic structural optimization of an early lead compound, N-(4-(4-methylpiperidin-1-yl)-3-(trifluoromethyl)phenyl)-4-(morpholinomethyl)benzamide (1), borne from our previously reported hit-to-lead effort. This secondary round of structure-activity relationship (SAR) involved the design and synthesis of several deconstructed and reconstructed analogs of compound 1, which were then tested against pseudotyped EBOV and MARV. The antiviral activities of the most promising leads were further validated in infectious assays. The optimized analogs exhibited desirable antiviral activity against different ebolaviruses and reduced off-target activity. Additionally, they also possessed druglike properties, that make them ideal candidates for in vivo efficacy studies as part of our ongoing drug discovery campaign against EBOV and MARV.

Stigma among ebola disease survivors in Mubende and Kassanda districts, Central Uganda, 2022.

Ebola disease survivors often experience stigma in multiple forms, including felt (perceived) stigma, enacted (action-based) stigma, and institutional stigma. On September 20, 2022, Uganda declared a Sudan Virus Disease (species orthoebolavirus sudanense) outbreak after a patient with confirmed Sudan virus (SUDV) infection was identified in Mubende District. The outbreak led to 142 confirmed and 22 probable cases over the next two months. We examined the types of stigma experienced by survivors and their household members and its effect on their well-being. We conducted a qualitative study during January 2023 in Mubende and Kassanda Districts. We conducted in-depth and key informant interviews with ten SUDV disease survivors, ten household members of SUDV disease survivors, and ten key informants (district officials and health workers in the affected communities). Interviews were recorded, translated, transcribed, and analyzed thematically. Survivors reported experiencing isolation and rejection by community members and loss of work. They reported being denied purchases at shops or having their money collected in a basket and disinfected (enacted stigma), which led to self-isolation (felt stigma). Educational institutions denied admission to some students from affected homes, while parents of children in some affected families stopped sending children to school due to verbal abuse from students and teachers (structural stigma). Prolonged SUDV disease symptoms and additional attention to survivors from responders (including home visits by health workers, public distribution of support items, and conspicuous transport from home to the survivor's clinic) were perceived as aggravating both felt and enacted stigma. Even after the outbreak had been declared over, survivors felt that they were still considered a threat to the community. Survivors experienced mainly enacted stigma which was aggravated by the outbreak response and control activities such as additional attention to survivors from responders. Strengthening community engagement to counteract stigma, rethinking response activities that aggravate stigma, integrated response interventions by partners, private distribution of support items, and increasing awareness and sensitization could reduce stigma among the Ebola disease survivors in future responses.

Embedding treatment in stronger care systems.

A key lesson from the west Africa (2014-16) Ebola disease epidemic was that outbreak responses fail when they respond to patients through a narrow clinical lens without considering the broader community and social context of care. Here, in the second of two Series papers on the modern landscape of Ebola disease, we review progress made in the last decade to improve patient-centred care. Although the biosafety imperatives of treating Ebola disease remain, recent advances show how to mitigate these so that patients are cared for in a safe and dignified manner that encourages early treatment-seeking behaviour and provides support after the return of patients to their communities. We review advances in diagnostics, including faster Ebola disease detection via real-time RT-PCR, and consider design improvements in Ebola disease treatment units that enhance patient safety and dignity. We also review advances in care provision, such as the integration of palliative care and mobile communication into routine care, and address how greater access to research is possible through harmonised clinical trials. Finally, we discuss how strengthened community engagement and psychosocial programmes are addressing stigma and providing holistic support for survivors.

Identification and Potential Functions of Ebola Virus-Encoded MicroRNAs in EBOV-Infected Human ARPE Cells

Ebola virus (EBOV) causes Ebola virus disease (EVD), a severe and often fatal hemorrhagic fever. Although much research has focused on host miRNA expression during EBOV infection, it has been discovered that EBOV itself also produces miRNAs. However, further studies are needed to fully comprehend the role of these EBOV-encoded miRNAs in infection and disease development. This study aimed to identify known and novel EBOV-encoded miRNAs and their potential functions in the pathogenic mechanisms of EBOV. We reanalyzed previously available small RNASeq data to identify the miRNAs and predict their cellular targets and functions. We identified four EBOV-encoded miRNAs—EBOV-mir-M1 (4390–4414), EBOV-mir-M4, EBOV-mir-M2 (8288–8309), and EBOV-mir-M3 (9885–9906)—expressed specifically in Ebola-infected human adult retinal pigment epithelial (ARPE) cells. EBOV-mir-M1 (4390–4414) was expressed up to 19 times more than the other three miRNAs. The identified miRNAs were predicted to target genes associated with pathways such as calcium signaling, MAPK signaling, type I interferon signaling, and cytokine-mediated signaling, which play critical roles in Ebola infection and pathogenesis. This study contributes to our understanding of the role of EBOV-encoded miRNAs in infection and pathogenesis by demonstrating the expression of these miRNAs in human ARPE cells, providing insights into the mechanisms underlying EBOV pathogenesis.

Ebola disease: bridging scientific discoveries and clinical application.

The west Africa Ebola disease epidemic (2014-16) marked a historic change of course for patient care during emerging infectious disease outbreaks. The epidemic response was a failure in many ways-a slow, cumbersome, and disjointed effort by a global architecture that was not fit for purpose for a rapidly spreading outbreak. In the most affected countries, health-care workers and other responders felt helpless-dealing with an overwhelming number of patients but with few, if any, tools at their disposal to provide high-quality care. These inadequacies, however, led to attention and innovation. The decade since then has seen remarkable achievements in clinical care for Ebola disease, including the approval of the first vaccines and treatments. In this paper, the first in a two-part Series, we reflect on this progress and provide expert summary of the modern landscape of Ebola disease, highlighting the priorities and ongoing activities aimed at further improving patient survival and wellbeing in the years ahead.

Seroprevalence of Antibodies to Filoviruses with Outbreak Potential in Sub-Saharan Africa: A Systematic Review to Inform Vaccine Development and Deployment.

Background/Objectives: Orthoebolaviruses and orthomarburgviruses are filoviruses that can cause viral hemorrhagic fever and significant morbidity and mortality in humans. The evaluation and deployment of vaccines to prevent and control Ebola and Marburg outbreaks must be informed by an understanding of the transmission and natural history of the causative infections, but little is known about the burden of asymptomatic infection or undiagnosed disease. This systematic review of the published literature examined the seroprevalence of antibodies to orthoebolaviruses and orthomarburgviruses in sub-Saharan Africa. Methods: The review protocol was registered on PROSPERO (ID: CRD42023415358) and previously published. Eighty-seven articles describing 85 studies were included, of which seventy-six measured antibodies to orthoebolaviruses and forty-one measured antibodies to orthomarburgviruses. Results: The results highlight three central findings that may have implications for vaccine development and deployment. First, substantial antibody seropositivity to Ebola virus (EBOV) and Sudan virus (SUDV) was observed in populations from outbreak-affected areas (≤33% seroprevalence among general populations; ≤41% seroprevalence among healthcare workers and close contacts of disease cases). Second, antibody seropositivity to EBOV, SUDV, and Marburg virus (MARV) was observed among populations from areas without reported outbreaks, with seroprevalence ranging from <1 to 21%. Third, in Central and East Africa, MARV antibody seroprevalence was substantially lower than EBOV or SUDV antibody seroprevalence, even in outbreak-affected areas and in populations at a moderate or high risk of infection (with MARV seroprevalence mostly ranging from 0 to 3%). Conclusions: Whilst gaps remain in our understanding of the significance of antibody seropositivity in some settings and contexts, these findings may be important in considering target indications for novel filovirus vaccines, in defining study designs and strategies for demonstrating vaccine efficacy or effectiveness, and in planning and evaluating vaccine deployment strategies to prevent and control outbreaks.

Ebolavirus evolution and emergence are associated with land use change

AbstractAnthropogenic land use change facilitates disease emergence by altering the interface between humans and pathogen reservoirs and is hypothesized to drive pathogen evolution. Here, we show a positive association between land use change and the evolution and dispersal of Zaire ebolavirus (EBOV) and Sudan ebolavirus (SUDV). We update the phylogeographies of EBOV and SUDV, which reveal that the most recent common ancestor of EBOV was circulating around 1960 in the forests of what is now the northwestern Democratic Republic of the Congo, while the most recent common ancestor of SUDV was circulating around 1958 in the southern Sudanese savanna. Both landscapes underwent significant anthropogenic fragmentation between 1940 and 1960, associated with specific colonial “schemes,” which substantially altered local human settlement patterns and the surrounding vegetation to support intensive cash crop agriculture. Since these disturbances, landscape fragmentation was spatiotemporally associated with the divergence and dispersal of new variants of both viruses into new ecoregions of Africa. These variants segregated geographically along ecoregion boundaries, resembling a pattern observable for other bat‐borne viruses. The amino acid changes which characterized each variant disproportionately involved glycosylation‐sensitive amino acids in the surface glycoprotein domain responsible for immune evasion and attachment to host cells, suggesting adaptation to new hosts amidst changing landscapes. Our results show that land use change not only increases the risk of spillover, but also impacts the evolution of viruses themselves.

HIPSTR: highest independent posterior subtree reconstruction in TreeAnnotator X.

In Bayesian phylogenetic and phylodynamic studies it is common to summarise the posterior distribution of trees with a time-calibrated consensus phylogeny. While the maximum clade credibility (MCC) tree is often used for this purpose, we here show that a novel consensus tree method - the highest independent posterior subtree reconstruction, or HIPSTR - contains consistently higher supported clades over MCC. We also provide faster computational routines for estimating both consensus trees in an updated version of TreeAnnotator X, an open-source software program that summarizes the information from a sample of trees and returns many helpful statistics such as individual clade credibilities contained in the consensus tree. HIPSTR and MCC reconstructions on two Ebola virus and two SARS-CoV-2 data sets show that HIPSTR yields consensus trees that consistently contain clades with higher support compared to MCC trees. The MCC trees regularly fail to include several clades with very high posterior probability (≥ 0.95) as well as a large number of clades with moderate to high posterior probability (≥ 0.50), whereas HIPSTR achieves near-perfect performance in this respect. HIPSTR also exhibits favorable computational performance over MCC in TreeAnnotator X. Comparison to the recently developed CCD0-MAP algorithm yielded mixed results, and requires more in-depth exploration in follow-up studies. TreeAnnotator X - which is part of the BEAST X (v10.5.0) software package - is available at https://github.com/beast-dev/beast-mcmc/releases .

Viral interactions with host factors (TIM-1, TAM -receptors, Glut-1) are related to the disruption of glucose and ascorbate transport and homeostasis, causing the haemorrhagic manifestations of viral haemorrhagic fevers.

The haemorrhagic features of viral haemorrhagic fevers may be caused by common patterns of metabolic disturbances of the glucose and ascorbate homeostasis. Haemorrhages and vasculature disfunctions are a clinical feature not only of viral haemorrhagic fevers, but also in scurvy, diabetes and thrombotic microangiopathic haemolytic anaemia. Interestingly, the expression of glucose and ascorbate transporter Glut-1 on the erythrocyte membrane is associated with the inability to synthesize ascorbate and is restricted to that very species that are susceptible to filoviruses (primates, humans and fruit bats). Glut-1 may play a pivotal role in haemorrhagic fever pathogenesis. TIM-1 and TAM receptors have been recognized to enhance entry of Ebola, Lassa and Dengue viruses and viral interferences with TIM-1 could disturb its function, disturbing the expression of Glut-1. In those species not able to synthesize ascorbate and expressing Glut-1 on erythrocytes virus could interact with Glut-1 or other functionally related protein, and the influx of glucose into the cells would be severely impaired. As a consequence, transient hyperglycemia and a marked oxidative stress coupled with the high levels of glucose in plasma would be established, and then promote the activation of NF–κB transcription, exacerbating a pro-inflammatory response mediated by cytokines and chemokines: The inability to synthesize ascorbate is an Achilles Heel when trying to counteract the oxidative stress.

The Maturation of the International Health Crisis Response: The Polish Typhus Epidemic of 1916-1923 Compared to the African Ebola Virus Disease Epidemic of 2013-2016: Part I, the Polish Epidemic.

Poland suffered an epidemic of louse-borne typhus from 1916-1923, with 400,000 cases and more than 130,000 deaths. The causative factors were depressed economic conditions and a refugee crisis that engulfed Poland after World War I. The recognition of the epidemic in 1919 stimulated the creation of the League of Red Cross Societies (LRCS). However, the LCRS had limited resources, and the Poles requested help from other governments and the League of Nations (LoN). The United States sent the American-Polish Relief Expedition to conduct delousing. However, the Polish-Soviet War of 1920 disrupted typhus control and exacerbated the refugee situation. The LoN belatedly organized an underfunded Epidemic Commission. The LCRS sent a research team that did groundbreaking work on the pathology of typhus. Into 1921, the epidemic continued, driven by refugees from typhus-stricken Russia. By 1924, typhus cases were finally approaching pre-World War I levels. Multiple factors lead to the amelioration of the epidemic. The repatriation of prisoners of war and displaced civilians had concluded by 1923. Also, there had been a steady influx of sanitary, food, economic, and medical aid from various organizations into Poland since 1919. Administratively, within Poland, the anti-typhus campaign was also conducted more effectively by the Extraordinary Epidemic Commissariat.

Psychosocial Impacts of COVID-19 and 2014-16 Ebola Virus Disease Outbreaks on Australian - based West Africans: A Narrative Summary of Systematic Reviews

Psychosocial Impacts of COVID-19 and 2014-16 Ebola Virus Disease Outbreaks on Australian - based West Africans: A Narrative Summary of Systematic Reviews

On modified Mittag–Leffler coupled hybrid fractional system constrained by Dhage hybrid fixed point in Banach algebra

This research investigates the dynamics of nonlinear coupled hybrid systems using a modified Mittag–Leffler fractional derivative. The primary objective is to establish criteria for the existence and uniqueness of solutions through the implementation of Dhage’s hybrid fixed-point theorem. The study further analyzes the stability of the proposed model. To demonstrate the practical application of this framework, we utilize a modified Mittag–Leffler operator to model the transmission of the Ebola virus, known for its complex and diverse dynamics. The analysis is conducted using a combination of theoretical and numerical methods, including transforming the system of equations into an equivalent integral form, applying the fixed-point theorem, and developing a numerical scheme based on Lagrange’s interpolation for simulating the Ebola virus model. This study aims to enhance our understanding of Ebola virus dynamics and provide valuable insights for developing effective control strategies.

Inhibitors of dihydroorotate dehydrogenase synergize with the broad antiviral activity of 4′-fluorouridine

RNA viruses present a constant threat to human health, often with limited options for vaccination or therapy. Notable examples include influenza viruses and coronaviruses, which have pandemic potential. Filo- and henipaviruses cause more limited outbreaks, but with high case fatality rates. All RNA viruses rely on the activity of a virus-encoded RNA-dependent RNA polymerase (RdRp). An antiviral nucleoside analogue, 4'-Fluorouridine (4'-FlU), targets RdRp and diminishes the replication of several RNA viruses, including influenza A virus and SARS-CoV-2, through incorporation into nascent viral RNA and delayed chain termination. However, the effective concentration of 4'-FlU varied among different viruses, raising the need to fortify its efficacy. Here we show that inhibitors of dihydroorotate dehydrogenase (DHODH), an enzyme essential for pyrimidine biosynthesis, can synergistically enhance the antiviral effect of 4'-FlU against influenza A viruses, SARS-CoV-2, henipaviruses, and Ebola virus. Even 4'-FlU-resistant mutant influenza A virus was re-sensitized towards 4'-FlU by DHODH inhibition. The addition of uridine rescued influenza A virus replication, strongly suggesting uridine depletion as a mechanism of this synergy. 4'-FlU was also highly effective against SARS-CoV-2 in a hamster model of COVID. We propose that the impairment of endogenous uridine synthesis by DHODH inhibition enhances the incorporation of 4'-FlU into viral RNAs. This strategy may be broadly applicable to enhance the efficacy of pyrimidine nucleoside analogues for antiviral therapy.