Search Results (77)

The family Arenaviridae encompasses zoonotic, rodent-borne pathogens (e.g., Lassa, Machupo, and Junín viruses) that cause severe viral hemorrhagic fevers with high case fatality rates. The current therapeutic landscape is severely limited, underscoring the urgent need for novel antiviral strategies. A promising approach involves combining directly acting antivirals with host-targeted antivirals. A compelling host-targeted antiviral target is the aryl hydrocarbon receptor (AHR). This ubiquitous ligand-activated transcription factor is a recognized pro-viral host factor across multiple viral families. Building on prior work with Junín and Tacaribe viruses, we investigated whether the AHR inhibitor CH223191 could enhance the virus-directed antiviral activity of favipiravir against these viruses. First, we evaluated the toxicity and antiviral potential of CH223191 against a lethal Junín virus infection in male and female hTfR1 mice. After demonstrating substantial protection, we conducted preliminary assays to study the antiviral effects of combining CH223191 and favipiravir on Tacaribe virus (TCRV) infections in the Vero cell culture model. We observed synergistic interaction with all four models (ZIP, Loewe, Bliss, and HSA). We next determined the sub-optimal dose of favipiravir and conducted an antiviral combination study in the male and female AG129 mouse model infected with TCRV. The combination effectively protected mice from a lethal TCRV infection and showed cooperative effects, reducing weight loss and viral loads. Overall, these results show that the AHR is a promising pharmacological target for the development of novel antivirals. Furthermore, we discovered a cooperative interaction between the activities of favipiravir and CH223191. Full article

Mammarenaviruses (MaAv) cause persistent infection in their natural rodent hosts across the world and, via zoonotic events, can cause severe disease in humans. Thus, the MaAv Lassa virus (LASV) in Western Africa and the Junin virus (JUNV) in the Argentinean Pampas cause hemorrhagic fever diseases with significant case fatality rates in their endemic regions. In addition, the globally distributed MaAv lymphocytic choriomeningitis virus (LCMV) is an underrecognized human pathogen of clinical significance capable of causing devastating infections in neonates and immunocompromised individuals. Despite their impact on human health, there are currently no FDA-approved vaccines or specific antiviral treatments for MaAv infections. Existing anti-MaAv therapies are limited to the off-label use of ribavirin, whose efficacy remains controversial; hence, the development of novel therapeutics to combat human pathogenic MaAv is vital. We employed a high-throughput cell-based infection assay to screen the Pandemic Response Box, a collection of 400 diverse compounds with established antimicrobial activity, for MaAv inhibitors. We identified Ro-24-7429, an antagonist of the HIV-1 Tat protein and RUNX family transcription factor 1 inhibitor; WO 2006118607 A2, a dihydroorotate dehydrogenase inhibitor; and verdinexor, a novel selective inhibitor of nuclear export (SINE) targeting the XPO1/CRM1, as potent anti-MaAv compounds. Consistent with their distinct validated targets, verdinexor and WO 2006118607 A2 exhibited very strong synergistic antiviral activity when used in combination therapy. Our findings pave the way for the development of verdinexor as a potent host-directed antiviral against MaAv, which could be integrated into the development of combination therapy with direct- or host-acting antivirals to combat human pathogenic MaAv. Full article

Lassa fever (LF), a severe hemorrhagic disease endemic to West Africa, is primarily transmitted by rodents of the genus Mastomys, particularly Mastomys natalensis, which serve as the main reservoirs of Lassa virus (LASV). There have been reports of high prevalence of LF in Nigeria, and outbreaks tend to be recurrent yet geographically restricted, implying that additional ecological or epidemiological factors influence the distribution of the disease beyond the mere presence of M. natalensis. However, national-scale data on LASV prevalence in rodent populations remain scarce. To address this gap, a targeted small mammal survey was conducted over a four-month period (May to August 2024) in Otukpo Local Government Area (LGA) of Benue State, north-central Nigeria. Rodents and other small mammals were trapped across three purposively selected wards identified as high-risk areas based on prior reports of occurrence of such small mammals in the areas and the informal settlements in which the selected wards were located in in Otukpo LGA. Analysis of the samples revealed no statistically significant variation in LASV prevalence among the study sites, indicating a relatively uniform, low-level exposure risk across the LGA and region. However, a marginally significant difference in LASV detection between plasma and serum samples suggests that sample type and storage conditions may influence serological sensitivity. These findings highlight the importance of refining diagnostic protocols, broadening surveillance to include additional rodent hosts, and integrating ecological data with public health strategies to improve early warning systems and strengthen Lassa fever control efforts. Full article

Sin Nombre virus (SNV) is the main causative agent of hantavirus cardiopulmonary syndrome (HCPS) in North America. SNV is transmitted via environmental biological aerosols (bioaerosols) produced by infected deer mice (Peromyscus maniculatus). It is similar to other viruses that have environmental transmission routes rather than a person-to-person transmission route, such as avian influenza (e.g., H5N1) and Lassa fever. Despite the lack of person-to-person transmission, these viruses cause a significant public health and economic burden. However, due to the lack of targeted pharmaceutical preventatives and therapeutics, the recommended approach to prevent SNV infections is to avoid locations that have a combination of low foot traffic, receive minimal natural sunlight, and where P. maniculatus may be found nesting. Consequently, gaining insight into the SNV bioaerosol decay profile is fundamental to the prevention of SNV infections. The Biological Aerosol Reaction Chamber (Bio-ARC) is a flow-through system designed to rapidly expose bioaerosols to environmental conditions (ozone, simulated solar radiation (SSR), humidity, and other gas phase species at stable temperatures) and determine the sensitivity of those particles to simulated ambient conditions. Using this system, we examined the bioaerosol stability of SNV. The virus was found to be susceptible to both simulated solar radiation and ozone under the tested conditions. Comparisons of decay between the virus aerosolized in residual media and in a mouse bedding matrix showed similar results. This study indicates that SNV aerosol particles are susceptible to inactivation by solar radiation and ozone, both of which could be implemented as effective control measures to prevent disease in locations where SNV is endemic. Full article

Lassa fever, a viral hemorrhagic illness that first came into the limelight as a clinical entity in 1969 when it was discovered in Northern Nigeria, is now found in other West African countries such as Sierra Leone, Liberia, Guinea, Togo, and the Benin Republic. Over the years, the disease, which is primarily transmitted from contact with infected mastomys rodents to humans, has the capability of secondary human-to-human transmission with significant morbidity and mortality, especially in healthcare settings. The disease is typically characterized by seasonal outbreaks, which peak during the dry season months of December to March. Lassa fever significantly impacts public health and the socioeconomic life of people in affected communities. In Nigeria, the Integrated Disease Surveillance and Response Strategy (IDSR), along with other medical countermeasures, have been employed to curtail the impact of the disease in endemic regions of Nigeria and other West Africa countries. The one-health approach to combat the disease is a promising strategy. This, along with the hope of a safe and effective vaccine, is a ray of hope on the horizon for public health authorities in Nigeria and other West African countries that the battle against Lassa fever might indeed end sooner than later. Full article

(1) Background: Mopeia–Lassa reassortant ML29 virus is an investigational, reassortant virus vaccine for the prevention of Lassa fever caused by Lassa virus (LASV). (2) Methods: The vaccine virus ML29-SF was prepared in Vero cells using a serum-free culture medium under Good Manufacturing Practice. A 2-week repeat dose toxicity study was performed in guinea pigs under Good Laboratory Practice (GLP) regulations to assess the local and systemic toxicological effects. (3) Results: Following an intramuscular (IM) or subcutaneous (SC) injection of 10⁴ PFU of ML29-SF LASV vaccine at the start of the study, with a second dose 15 days later, no toxicological response attributable to the vaccine was observed. Vaccine-related effects were not observed in any in-life or post-mortem parameter evaluated, including clinical observations, injection site observations, body temperature, body weight, food consumption, ophthalmology, immunology, hematology, clinical chemistry, gross anatomical pathology, organ weights, and histopathology. An immunogenic response, as measured by the elicitation of IgG antibodies against major LASV immunogens, nucleocapsid and glycoprotein precursor, was observed in all vaccine-treated animals prior to the booster dose (Study Day 15) which endured through the end of the study (Study Day 42). There was no evidence of viral shedding in any vaccinated animal. (4) Conclusions: Overall, this single-dose vaccine was locally and systemically well tolerated even after a two-dose repeat administration, confirming the high level of safety of ML29-SF vaccination and supporting the future evaluation of this LASV vaccine, including in clinical trials. Full article

The spread of Lassa virus in West Africa is reliant on the abundance and distribution of its rodent host reservoirs. While the impact of environmental change on viral spread has been studied for many zoonotic viruses, there is still a limited understanding of how seasonal impacts, land-use conversion, and biodiversity loss influence the expansion of Lassa virus among reservoirs. This systematic review synthesizes existing research on the association between environmental variables and Lassa virus circulation in West Africa to inform future research, public health interventions, and One Health policy. We searched international and African scientific databases using a set of pre-defined search terms to obtain publications reporting on Lassa virus in West Africa between 1969 and 2023. A total of 9465 articles were retrieved from this search and 70 studies met inclusion criteria for this review. Through systematic data extraction, we identified seasonal precipitation, land-use change, and host expansion as key environmental drivers of Lassa virus in reservoir hosts; however, we also highlight notable gaps in knowledge that limit our current understanding of these complex relationships. This review underscores the need for interdisciplinary research and strategies to mitigate the impacts of environmental change on Lassa virus transmission and protect vulnerable populations in West Africa. Full article

Lassa fever (LF), a viral hemorrhagic fever disease with a case fatality rate that can be over 20% among hospitalized LF patients, is endemic to many West African countries. Currently, no vaccines or therapies are specifically licensed to prevent or treat LF, hence the significance of developing therapeutics against the mammarenavirus Lassa virus (LASV), the causative agent of LF. We used in silico docking approaches to investigate the binding affinities of 2015 existing drugs to LASV proteins known to play critical roles in the formation and activity of the virus ribonucleoprotein complex (vRNP) responsible for directing replication and transcription of the viral genome. Validation of docking protocols were achieved with reference inhibitors of the respective targets. Our in silico docking screen identified five drugs (dexamethasone, tadalafil, mefloquine, ergocalciferol, and flunarizine) with strong predicted binding affinity to LASV proteins involved in the formation of the vRNP. We used cell-based functional assays to evaluate the antiviral activity of the five selected drugs. We found that flunarizine, a calcium-entry blocker, inhibited the vRNP activity of LASV and LCMV and virus surface glycoprotein fusion activity required for mammarenavirus cell entry. Consistently with these findings, flunarizine significantly reduced peak titers of LCMV in a multi-step growth kinetics assay in human A549 cells. Flunarizine is being used in several countries worldwide to treat vertigo and migraine, supporting the interest in exploring its repurposing as a candidate drug to treat LASV infections. Full article

The mammarenavirus matrix Z protein plays critical roles in virus assembly and cell egress. Meanwhile, heterotrimer complexes of a stable signal peptide (SSP) together with glycoprotein subunits GP1 and GP2, generated via co-and post-translational processing of the surface glycoprotein precursor GPC, form the spikes that decorate the virion surface and mediate virus cell entry via receptor-mediated endocytosis. The Z protein and the SSP undergo N-terminal myristoylation by host cell N-myristoyltransferases (NMT1 and NMT2), and G2A mutations that prevent myristoylation of Z or SSP have been shown to affect the Z-mediated virus budding and GP2-mediated fusion activity that is required to complete the virus cell entry process. In the present work, we present evidence that the validated on-target specific pan-NMT inhibitor DDD85646 exerts a potent antiviral activity against the prototypic mammarenavirus lymphocytic choriomeningitis virus (LCMV) that correlates with reduced Z budding activity and GP2-mediated fusion activity as well as with proteasome-mediated degradation of the Z protein. The potent anti-mammarenaviral activity of DDD85646 was also observed with the hemorrhagic-fever-causing Junin (JUNV) and Lassa (LASV) mammarenaviruses. Our results support the exploration of NMT inhibition as a broad-spectrum antiviral against human pathogenic mammarenaviruses. Full article

Lassa Fever is a deadly viral haemorrhagic disease, causing annually several hundreds of deaths in West Africa. This zoonotic disease is primarily transmitted to humans by rodents of the genus Mastomys, even though other rodents reportedly carry the Lassa virus, while secondary interhuman transmission accounts for approximately 20% of cases. Although this disease has been endemic in rural zones of Nigeria, Sierra Leone, Liberfia, and Guinea for hundreds of years, it is also characterised by epidemic outbreaks in the dry season, responsible for heavy death tolls. No licensed vaccine or satisfying treatment is currently available. Disease management is hindered by the incomplete knowledge of the epidemiology and distribution of the disease, resulting from an inadequate health and surveillance system. Additional scientific constraints such as the genetic diversity of the virus and the lack of understanding of the mechanisms of immune protection complexify the development of a vaccine. The intricate socio-economic context in the affected regions, and the lack of monetary incentive for drug development, allow the disease to persist in some of West Africa’s poorest communities. The increase in the number of reported cases and in the fatality rate, the expansion of the endemic area, as well as the threat Lassa Fever represents internationally should urge the global community to work on the disease control and prevention. The disease control requires collaborative research for medical countermeasures and tailored public health policies. Lassa Fever, created by the interconnection between animals, humans, and ecosystems, and embedded in an intricate social context, should be addressed with a ‘One Health’ approach. This article provides an overview of Lassa Fever, focusing on Nigeria, and discusses the perspectives for the control of disease. Full article

There are currently no prophylactic vaccines licensed to protect against Lassa fever caused by Lassa virus (LASV) infection. The Emergent BioSolutions (EBS) vaccine candidate, EBS-LASV, is being developed for the prevention of Lassa fever. EBS-LASV is a live-attenuated recombinant Vesicular Stomatitis Virus (rVSV)-vectored vaccine encoding the surface glycoprotein complex (GPC) from LASV and has two attenuating vector modifications: a gene shuffle of the VSV N gene and a deletion of the VSV G gene. Preclinical studies were performed to evaluate EBS-LASV’s neurovirulence potential following intracranial (IC) injection and to determine the biodistribution and vector replication following intramuscular (IM) inoculation in mice. In addition, the potential EBS-LASV toxicity was assessed using repeated-dose IM EBS-LASV administration to rabbits. All mice receiving the IC injection of EBS-LASV survived, while mice administered the unattenuated control vector did not. The vaccine was only detected in the muscle at the injection site, draining lymph nodes, and the spleen over the first week following IM EBS-LASV injection in mice, with no detectable plasma viremia. No toxicity was observed in rabbits receiving a three-dose regimen of EBS-LASV. These studies demonstrate that EBS-LASV is safe when administered to animals and supported a first-in-human dose-escalation, safety, and immunogenicity clinical study. Full article

Lymphocytic choriomeningitis virus (LCMV) and Lassa virus (LASV) share many genetic and biological features including subtle differences between pathogenic and apathogenic strains. Despite remarkable genetic similarity, the viscerotropic WE strain of LCMV causes a fatal LASV fever-like hepatitis in non-human primates (NHPs) while the mouse-adapted Armstrong (ARM) strain of LCMV is deeply attenuated in NHPs and can vaccinate against LCMV-WE challenge. Here, we demonstrate that internalization of WE is more sensitive to the depletion of membrane cholesterol than ARM infection while ARM infection is more reliant on endosomal acidification. LCMV-ARM induces robust NF-κB and interferon response factor (IRF) activation while LCMV-WE seems to avoid early innate sensing and failed to induce strong NF-κB and IRF responses in dual-reporter monocyte and epithelial cells. Toll-like receptor 2 (TLR-2) signaling appears to play a critical role in NF-κB activation and the silencing of TLR-2 shuts down IL-6 production in ARM but not in WE-infected cells. Pathogenic LCMV-WE infection is poorly recognized in early endosomes and failed to induce TLR-2/Mal-dependent pro-inflammatory cytokines. Following infection, Interleukin-1 receptor-associated kinase 1 (IRAK-1) expression is diminished in LCMV-ARM- but not LCMV-WE-infected cells, which indicates it is likely involved in the LCMV-ARM NF-κB activation. By confocal microscopy, ARM and WE strains have similar intracellular trafficking although LCMV-ARM infection appears to coincide with greater co-localization of early endosome marker EEA1 with TLR-2. Both strains co-localize with Rab-7, a late endosome marker, but the interaction with LCMV-WE seems to be more prolonged. These findings suggest that LCMV-ARM’s intracellular trafficking pathway may facilitate interaction with innate immune sensors, which promotes the induction of effective innate and adaptive immune responses. Full article

Lassa virus (LASV) is a zoonotic pathogen endemic throughout western Africa and is responsible for a human disease known as Lassa fever (LF). Historically, LASV has been emphasized as one of the greatest public health threats in West Africa, with up to 300,000 cases and 5000 associated deaths per year. This, and the fact that the disease has been reported in travelers, has driven a rapid production of various vaccine candidates. Several of these vaccines are currently in clinical development, despite limitations in understanding the immune response to infection. Alarmingly, the host immune response has been implicated in the induction of sensorineural hearing loss in LF survivors, legitimately raising safety questions about any future vaccines as well as efficacy in preventing potential hearing loss. The objective of this article is to revisit the importance and prevalence of LF in West Africa, with focus on Nigeria, and discuss current therapeutic approaches and ongoing vaccine development. In addition, we aim to emphasize the need for more scientific studies relating to LF-associated hearing loss, and to promote critical discussion about potential risks and benefits of vaccinating the population in endemic regions of West Africa. Full article

Background: Lassa virus (LASV) can cause severe acute systemic infection in humans. No approved antiviral drugs or vaccines are currently available. Antibody-based therapeutics are considered a promising treatment strategy in the management of LASV disease. Methods: We used chimeric Ifnar^−/− C57BL/6 (Ifnar^−/− Bl6) mice, a lethal LASV mouse model, to evaluate the protective efficacy of polyclonal antibodies purified from sera of rabbits hyperimmunized with virus-like particles displaying native-like LASV glycoprotein GP spikes. Results: Polyclonal anti-LASV GP antibodies provided 100% protection against lethal LASV infection in a pre- and post-exposure treatment setting and prevented LASV disease. Treatment also significantly lowered viremia level and virus load in organs. When treatment was initiated at the onset of symptoms, the hyperimmune antibodies provided partial protection and increased the survival rate by 80%. Conclusions: Our findings support the consideration of animal-derived hyperimmune antibodies targeting GP as an effective treatment option for highly pathogenic LASV. Full article

Nigeria experiences annual outbreaks of Lassa fever (LF) with high case numbers. At least three clades of Lassa virus (LASV) have been documented in Nigeria, though recent outbreaks are most often associated with clade II or clade III viruses. Using a recently isolated clade III LASV from a case of LF in Nigeria in 2018, we developed and characterized a guinea pig adapted virus capable of causing lethal disease in commercially available Hartley guinea pigs. Uniform lethality was observed after four passages of the virus and was associated with only two dominant genomic changes. The adapted virus was highly virulent with a median lethal dose of 10 median tissue culture infectious doses. Disease was characterized by several hallmarks of LF in similar models including high fever, thrombocytopenia, coagulation disorders, and increased inflammatory immune mediators. High viral loads were noted in all solid organ specimens analyzed. Histological abnormalities were most striking in the lungs and livers of terminal animals and included interstitial inflammation, edema, and steatosis. Overall, this model represents a convenient small animal model for a clade III Nigeria LASV with which evaluation of specific prophylactic vaccines and medical countermeasures can be conducted. Full article