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Emerging Microbes & Infections Dec 2021Lassa virus (LASV), a Risk Group-4 zoonotic haemorrhagic fever virus, affects sub-Saharan African countries. Lassa fever, caused by LASV, results in thousands of annual...
Lassa virus (LASV), a Risk Group-4 zoonotic haemorrhagic fever virus, affects sub-Saharan African countries. Lassa fever, caused by LASV, results in thousands of annual deaths. Although decades have elapsed since the identification of the Natal multimammate mouse () as a natural reservoir of LASV, little effort has been made to characterize LASV infection in its reservoir. The natural route of infection and transmission of LASV within remains unknown, and the clinical impact of LASV in is mostly undescribed. Herein, using an outbred colony of , we investigate the replication and dissemination dynamics of LASV in this reservoir following various inoculation routes. Inoculation with LASV, regardless of route, resulted in a systemic infection and accumulation of abundant LASV-RNA in many tissues. LASV infection in the Natal multimammate mice was subclinical, however, clinical chemistry values were transiently altered and immune infiltrates were observed histologically in lungs, spleens and livers, indicating a minor disease with coordinated immune responses are elicited, controlling infection. Intranasal infection resulted in unique virus tissue dissemination dynamics and heightened LASV shedding, compared to subcutaneous inoculation. Our study provides important insights into LASV infection in its natural reservoir using a contemporary infection system, demonstrating that specific inoculation routes result in disparate dissemination outcomes, suggesting intranasal inoculation is important in the maintenance of LASV in the natural reservoir, and emphasizes that selection of the appropriate inoculation route is necessary to examine aspects of viral replication, transmission and responses to zoonotic viruses in their natural reservoirs.
Topics: Animals; Disease Reservoirs; Female; Humans; Lassa Fever; Lassa virus; Male; Murinae; Rodent Diseases; Viral Zoonoses; Virus Shedding
PubMed: 34792436
DOI: 10.1080/22221751.2021.2008773 -
Virulence Dec 2023Recent viral hemorrhagic fever (VHF) disease outbreaks caused by Ebola virus (EBOV) and Marburg virus (MARV) in West Africa are unique and alarming. The intents of this...
Recent viral hemorrhagic fever (VHF) disease outbreaks caused by Ebola virus (EBOV) and Marburg virus (MARV) in West Africa are unique and alarming. The intents of this editorial are to highlight what is known about these viruses and the disease outbreaks that they cause in the African continent and elsewhere and to raise awareness of a related virus called Lassa virus (LASV) that causes endemic viral hemorrhagic fever infections and frequent outbreaks in West Africa.
Topics: Humans; Hemorrhagic Fevers, Viral; Lassa virus; Ebolavirus; Africa, Western; Disease Outbreaks; Hemorrhagic Fever, Ebola
PubMed: 36748841
DOI: 10.1080/21505594.2023.2176980 -
The Yale Journal of Biology and Medicine May 1975
Topics: Animals; Arboviruses; Arenaviruses, New World; Chiroptera; Cricetinae; Hemorrhagic Fever, American; Humans; Lassa virus; Lymphocytic Choriomeningitis; Lymphocytic choriomeningitis virus; Mice; RNA Viruses; Rats
PubMed: 168692
DOI: No ID Found -
BMC Infectious Diseases Mar 2024Lassa fever is a hemorrhagic disease caused by Lassa virus (LASV), which has been classified by the World Health Organization as one of the top infectious diseases...
BACKGROUND
Lassa fever is a hemorrhagic disease caused by Lassa virus (LASV), which has been classified by the World Health Organization as one of the top infectious diseases requiring prioritized research. Previous studies have provided insights into the classification and geographic characteristics of LASV lineages. However, the factor of the distribution and evolution characteristics and phylodynamics of the virus was still limited.
METHODS
To enhance comprehensive understanding of LASV, we employed phylogenetic analysis, reassortment and recombination detection, and variation evaluation utilizing publicly available viral genome sequences.
RESULTS
The results showed the estimated the root of time of the most recent common ancestor (TMRCA) for large (L) segment was approximately 634 (95% HPD: [385879]), whereas the TMRCA for small (S) segment was around 1224 (95% HPD: [10301401]). LASV primarily spread from east to west in West Africa through two routes, and in route 2, the virus independently spread to surrounding countries through Liberia, resulting in a wider spread of LASV. From 1969 to 2018, the effective population size experienced two significant increased, indicating the enhanced genetic diversity of LASV. We also found the evolution rate of L segment was faster than S segment, further results showed zinc-binding protein had the fastest evolution rate. Reassortment events were detected in multiple lineages including sub-lineage IIg, while recombination events were observed within lineage V. Significant amino acid changes in the glycoprotein precursor of LASV were identified, demonstrating sequence diversity among lineages in LASV.
CONCLUSION
This study comprehensively elucidated the transmission and evolution of LASV in West Africa, providing detailed insights into reassortment events, recombination events, and amino acid variations.
Topics: Humans; Lassa virus; Phylogeny; Lassa Fever; Amino Acids; Liberia
PubMed: 38486143
DOI: 10.1186/s12879-024-09200-8 -
Journal of Virology Aug 2018(LASV) belongs to the genus (family ) and causes severe hemorrhagic fever in humans. At present, there are no Food and Drug Administration (FDA)-approved drugs or...
(LASV) belongs to the genus (family ) and causes severe hemorrhagic fever in humans. At present, there are no Food and Drug Administration (FDA)-approved drugs or vaccines specific for LASV. Here, high-throughput screening of an FDA-approved drug library was performed against LASV entry by using pseudotype virus bearing LASV envelope glycoprotein (GPC). Two hit compounds, lacidipine and phenothrin, were identified as LASV entry inhibitors in the micromolar range. A mechanistic study revealed that both compounds inhibited LASV entry by blocking low-pH-induced membrane fusion. Accordingly, lacidipine showed virucidal effects on the pseudotype virus of LASV. Adaptive mutant analyses demonstrated that replacement of T40, located in the ectodomain of the stable-signal peptide (SSP), with lysine (K) conferred LASV resistance to lacidipine. Furthermore, lacidipine showed antiviral activity against LASV, the closely related Mopeia virus (MOPV), and the New World arenavirus Guanarito virus (GTOV). Drug-resistant variants indicated that V36M in the ectodomain of the SSP mutant and V436A in the transmembrane domain of the GP2 mutant conferred GTOV resistance to lacidipine, suggesting the interface between SSP and GP2 is the target of lacidipine. This study shows that lacidipine is a candidate for LASV therapy, reinforcing the notion that the SSP-GP2 interface provides an entry-targeted platform for arenavirus inhibitor design. Currently, there is no approved therapy to treat Lassa fever; therefore, repurposing of approved drugs will accelerate the development of a therapeutic stratagem. In this study, we screened an FDA-approved library of drugs and identified two compounds, lacidipine and phenothrin, which inhibited Lassa virus entry by blocking low-pH-induced membrane fusion. Additionally, both compounds extended their inhibition against the entry of Guanarito virus, and the viral targets were identified as the SSP-GP2 interface.
Topics: Antiviral Agents; Arenaviridae; Arenaviruses, New World; DNA Mutational Analysis; Dihydropyridines; Drug Evaluation, Preclinical; Drug Resistance, Viral; High-Throughput Screening Assays; Lassa virus; Pyrethrins; Virus Internalization
PubMed: 29899092
DOI: 10.1128/JVI.00954-18 -
Viruses Mar 2020Ever since it was established that rodents serve as reservoirs of the zoonotic Lassa virus (LASV), scientists have sought to answer the questions: which populations of... (Review)
Review
Ever since it was established that rodents serve as reservoirs of the zoonotic Lassa virus (LASV), scientists have sought to answer the questions: which populations of rodents carry the virus? How do fluctuations in LASV prevalence and rodent abundance influence Lassa fever outbreaks in humans? What does it take for the virus to adopt additional rodent hosts, proliferating what already are devastating cycles of rodent-to-human transmission? In this review, we examine key aspects of research involving the biology of rodents that affect their role as LASV reservoirs, including phylogeography, demography, virus evolution, and host switching. We discuss how this knowledge can help control Lassa fever and suggest further areas for investigation.
Topics: Africa, Western; Animals; Biological Evolution; Disease Outbreaks; Disease Reservoirs; Ecology; Humans; Lassa Fever; Lassa virus; Phylogeography; Prevalence; Rodentia; Viral Zoonoses
PubMed: 32183319
DOI: 10.3390/v12030312 -
Cell Reports May 2022Lassa virus (LASV) is the etiologic agent of Lassa Fever, a hemorrhagic disease that is endemic to West Africa. During LASV infection, LASV glycoprotein (GP) engages...
Lassa virus (LASV) is the etiologic agent of Lassa Fever, a hemorrhagic disease that is endemic to West Africa. During LASV infection, LASV glycoprotein (GP) engages with multiple host receptors for cell entry. Neutralizing antibodies against GP are rare and principally target quaternary epitopes displayed only on the metastable, pre-fusion conformation of GP. Currently, the structural features of the neutralizing GPC-A antibody competition group are understudied. Structures of two GPC-A antibodies presented here demonstrate that they bind the side of the pre-fusion GP trimer, bridging the GP1 and GP2 subunits. Complementary biochemical analyses indicate that antibody 25.10C, which is broadly specific, neutralizes by inhibiting binding of the endosomal receptor LAMP1 and also by blocking membrane fusion. The other GPC-A antibody, 36.1F, which is lineage-specific, prevents LAMP1 association only. These data illuminate a site of vulnerability on LASV GP and will guide efforts to elicit broadly reactive therapeutics and vaccines.
Topics: Antibodies, Neutralizing; Epitopes; Glycoproteins; Humans; Lassa Fever; Lassa virus; Viral Envelope Proteins
PubMed: 35613585
DOI: 10.1016/j.celrep.2022.110841 -
Proceedings of the National Academy of... Jul 2022Completion of the Lassa virus (LASV) life cycle critically depends on the activities of the virally encoded, RNA-dependent RNA polymerase in replication and...
Completion of the Lassa virus (LASV) life cycle critically depends on the activities of the virally encoded, RNA-dependent RNA polymerase in replication and transcription of the viral RNA genome in the cytoplasm of infected cells. The contribution of cellular proteins to these processes remains unclear. Here, we applied proximity proteomics to define the interactome of LASV polymerase in cells under conditions that recreate LASV RNA synthesis. We engineered a LASV polymerase-biotin ligase (TurboID) fusion protein that retained polymerase activity and successfully biotinylated the proximal proteome, which allowed the identification of 42 high-confidence LASV polymerase interactors. We subsequently performed a small interfering RNA (siRNA) screen to identify those interactors that have functional roles in authentic LASV infection. As proof of principle, we characterized eukaryotic peptide chain release factor subunit 3a (eRF3a/GSPT1), which we found to be a proviral factor that physically associates with LASV polymerase. Targeted degradation of GSPT1 by a small-molecule drug candidate, CC-90009, resulted in strong inhibition of LASV infection in cultured cells. Our work demonstrates the feasibility of using proximity proteomics to illuminate and characterize yet-to-be-defined host-pathogen interactome, which can reveal new biology and uncover novel targets for the development of antivirals against highly pathogenic RNA viruses.
Topics: Acetamides; Antiviral Agents; Cell Line, Tumor; Humans; Isoindoles; Lassa Fever; Lassa virus; Peptide Termination Factors; Piperidones; Protein Interaction Maps; Proteolysis; Proteome; Proteomics; RNA-Dependent RNA Polymerase; Viral Proteins
PubMed: 35858434
DOI: 10.1073/pnas.2201208119 -
Journal of Virology Apr 2019Antiviral therapies that impede virus entry are attractive because they act on the first phase of the infectious cycle. Drugs that target pathways common to multiple... (Comparative Study)
Comparative Study
Antiviral therapies that impede virus entry are attractive because they act on the first phase of the infectious cycle. Drugs that target pathways common to multiple viruses are particularly desirable when laboratory-based viral identification may be challenging, e.g., in an outbreak setting. We are interested in identifying drugs that block both Ebola virus (EBOV) and Lassa virus (LASV), two unrelated but highly pathogenic hemorrhagic fever viruses that have caused outbreaks in similar regions in Africa and share features of virus entry: use of cell surface attachment factors, macropinocytosis, endosomal receptors, and low pH to trigger fusion in late endosomes. Toward this goal, we directly compared the potency of eight drugs known to block EBOV entry with their potency as inhibitors of LASV entry. Five drugs (amodiaquine, apilimod, arbidol, niclosamide, and zoniporide) showed roughly equivalent degrees of inhibition of LASV and EBOV glycoprotein (GP)-bearing pseudoviruses; three (clomiphene, sertraline, and toremifene) were more potent against EBOV. We then focused on arbidol, which is licensed abroad as an anti-influenza drug and exhibits activity against a diverse array of clinically relevant viruses. We found that arbidol inhibits infection by authentic LASV, inhibits LASV GP-mediated cell-cell fusion and virus-cell fusion, and, reminiscent of its activity on influenza virus hemagglutinin, stabilizes LASV GP to low-pH exposure. Our findings suggest that arbidol inhibits LASV fusion, which may partly involve blocking conformational changes in LASV GP. We discuss our findings in terms of the potential to develop a drug cocktail that could inhibit both LASV and EBOV. Lassa and Ebola viruses continue to cause severe outbreaks in humans, yet there are only limited therapeutic options to treat the deadly hemorrhagic fever diseases they cause. Because of overlapping geographic occurrences and similarities in mode of entry into cells, we seek a practical drug or drug cocktail that could be used to treat infections by both viruses. Toward this goal, we directly compared eight drugs, approved or in clinical testing, for the ability to block entry mediated by the glycoproteins of both viruses. We identified five drugs with approximately equal potencies against both. Among these, we investigated the modes of action of arbidol, a drug licensed abroad to treat influenza infections. We found, as shown for influenza virus, that arbidol blocks fusion mediated by the Lassa virus glycoprotein. Our findings encourage the development of a combination of approved drugs to treat both Lassa and Ebola virus diseases.
Topics: Animals; Antiviral Agents; COS Cells; Chlorocebus aethiops; Cricetinae; Drug Evaluation, Preclinical; Ebolavirus; HEK293 Cells; Hemorrhagic Fever, Ebola; Humans; Indoles; Lassa Fever; Lassa virus; Vero Cells; Virus Internalization
PubMed: 30700611
DOI: 10.1128/JVI.02185-18 -
Viruses Mar 2020Lassa virus (LASV), which causes considerable morbidity and mortality annually, has a high genetic diversity across West Africa. LASV glycoprotein (GP) expresses this... (Review)
Review
Lassa virus (LASV), which causes considerable morbidity and mortality annually, has a high genetic diversity across West Africa. LASV glycoprotein (GP) expresses this diversity, but most LASV vaccine candidates utilize only the Lineage IV LASV Josiah strain GP antigen as an immunogen and homologous challenge with Lineage IV LASV. In addition to the sequence variation amongst the LASV lineages, these lineages are also distinguished in their presentations. Inter-lineage variations within previously mapped B-cell and T-cell LASV GP epitopes and the breadth of protection in LASV vaccine/challenge studies were examined critically. Multiple alignments of the GP primary sequence of strains from each LASV lineage showed that LASV GP has diverging degrees of amino acid conservation within known epitopes among LASV lineages. Conformational B-cell epitopes spanning different sites in GP subunits were less impacted by LASV diversity. LASV GP diversity should influence the approach used for LASV vaccine design. Expression of LASV GP on viral vectors, especially in its prefusion configuration, has shown potential for protective LASV vaccines that can overcome LASV diversity. Advanced vaccine candidates should demonstrate efficacy against all LASV lineages for evidence of a pan-LASV vaccine.
Topics: Animals; Antigens, Viral; Drug Development; Epitopes; Genetic Variation; Humans; Lassa virus; Phylogeny; Viral Envelope Proteins; Viral Vaccines
PubMed: 32244402
DOI: 10.3390/v12040386