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a single-shot lassa vaccine induces long-term immunity and protects cynomolgus monkeys against heterologous strains.a safe and protective lassa virus vaccine is crucially needed in western africa to stem the recurrent outbreaks of lassa virus infections in nigeria and the emergence of lassa virus in previously unaffected countries, such as benin and togo. major challenges in developing a lassa virus vaccine include the high diversity of circulating strains and their reemergence from 1 year to another. to address each of these challenges, we immunized cynomolgus monkeys with a measles virus vector expressing t ...202134108251
experimental morogoro virus infection in its natural host, mastomys natalensis.natural hosts of most arenaviruses are rodents. the human-pathogenic lassa virus and several non-pathogenic arenaviruses such as morogoro virus (morv) share the same host species, namely mastomys natalensis (m. natalensis). in this study, we investigated the history of infection and virus transmission within the natural host population. to this end, we infected m. natalensis at different ages with morv and measured the health status of the animals, virus load in blood and organs, the development ...202134067011
mastomys natalensis has a cellular immune response profile distinct from laboratory mice.the multimammate mouse (mastomys natalensis; m. natalensis) has been identified as a major reservoir for multiple human pathogens including lassa virus (lasv), leishmania spp., yersinia spp., and borrelia spp. although m. natalensis are related to well-characterized mouse and rat species commonly used in laboratory models, there is an absence of established assays and reagents to study the host immune responses of m. natalensis. as a result, there are major limitations to our understanding of im ...202133922222
epidemiology of lassa fever.lassa fever (lf) is a lethal hemorrhagic disease primarily concentrated in the tropical savannah regions of nigeria and the mano river union countries of sierra leone, liberia, and guinea. endemic hotspots within these countries have had recurrent exposure to lassa virus (lasv) via continual spillover from the host reservoir mastomys natalensis. increased trade and travel throughout the region have spread the virus to previously unexposed countries, including ghana, benin, mali, and côte d'ivoir ...202133861373
establishment of a genetically confirmed breeding colony of mastomys natalensis from wild-caught founders from west africa.mastomys natalensis are a ubiquitous and often dominant rodent across sub-saharan africa. importantly, they are a natural reservoir for microbial pathogens including lassa virus (lasv), the etiological agent of lassa fever in humans. lassa-infected rodents have been documented across west africa and coincide with regions where annual outbreaks occur. zoonotic transmission to humans most often occurs directly from infected rodents. little is known about lasv infection kinetics and transmissibilit ...202133807214
hunting and consumption of rodents by children in the lassa fever endemic area of faranah, guinea.as a consequence of the ebola outbreak, human-animal contact has gained importance for zoonotic transmission surveillance. in faranah (upper guinea), daily life is intertwined with rodents, such as the natal multimammate mouse, mastomys natalensis; a reservoir for lassa virus (lasv). however, this contact is rarely perceived as a health risk by residents, although lassa fever (lf) is known to be endemic to this region. conversely, these observations remain a great concern for global health agend ...202133730025
chadox1-vectored lassa fever vaccine elicits a robust cellular and humoral immune response and protects guinea pigs against lethal lassa virus challenge.lassa virus (lasv) infects hundreds of thousands of individuals each year, highlighting the need for the accelerated development of preventive, diagnostic, and therapeutic interventions. to date, no vaccine has been licensed for lasv. chadox1-lassa-gpc is a chimpanzee adenovirus-vectored vaccine encoding the josiah strain lasv glycoprotein precursor (gpc) gene. in the following study, we show that chadox1-lassa-gpc is immunogenic, inducing robust t-cell and antibody responses in mice. furthermor ...202133654106
lassa virus vaccine candidate ml29 generates truncated viral rnas which contribute to interfering activity and attenuation.defective interfering particles (dips) are naturally occurring products during virus replication in infected cells. dips contain defective viral genomes (dvgs) and interfere with replication and propagation of their corresponding standard viral genomes by competing for viral and cellular resources, as well as promoting innate immune antiviral responses. consequently, for many different viruses, including mammarenaviruses, dips play key roles in the outcome of infection. due to their ability to b ...202133573250
ecology of lassa virus.individuals living in endemic hotspots of lassa fever have recurrent exposure to lassa virus (lasv) via spillover from the primary host reservoir mastomys natalensis. despite m. natalensis being broadly distributed across sub-saharan africa, lassa fever is only found in west africa. in recent years, new lasv reservoirs have been identified. erudition of rodent habitats, reproduction and fecundity, movement patterns, and spatial preferences are essential to institute preventative measures against ...202133564902
hematology and clinical chemistry reference ranges for laboratory-bred natal multimammate mice (mastomys natalensis).laboratory-controlled physiological data for the multimammate rat (mastomys natalensis) are scarce, despite this species being a known reservoir and vector for zoonotic viruses, including the highly pathogenic lassa virus, as well as other arenaviruses and many species of bacteria. for this reason, m. natalensis is an important rodent for the study of host-virus interactions within laboratory settings. herein, we provide basic blood parameters for age- and sex-distributed animals in regards to b ...202133513733
lassa virus circulation in small mammal populations in bo district, sierra leone.lassa fever is a viral hemorrhagic fever caused by the lassa virus lasv, which was first isolated in the rodent mastomys natalensis in 1974 in kenema, sierra leone. as little is known about the abundance and the presence of lasv in rodents living in the bo area, we carried out a small mammal longitudinal population survey. a standardized trapping session was performed in various habitats and seasons in six villages over two years (2014-2016) and samples collected were tested for arenavirus igg a ...202133466234
tetravalent rabies-vectored filovirus and lassa fever vaccine induces long-term immunity in nonhuman primates.the objective of this study is to evaluate the immunogenicity of adjuvanted monovalent rabies virus-based vaccine candidates against ebola virus (filorab1), sudan virus (filorab2), marburg virus (filorab3), lassa virus (lassarab1), and combined trivalent vaccine candidate (filorab1-3) and tetravalent vaccine candidate (filorab1-3 and lassarab) in nonhuman primates.202133421072
systemic viral spreading and defective host responses are associated with fatal lassa fever in macaques.lassa virus (lasv) is endemic in west africa and induces a viral hemorrhagic fever (vhf) with up to 30% lethality among clinical cases. the mechanisms involved in control of lassa fever or, in contrast, the ensuing catastrophic illness and death are poorly understood. we used the cynomolgus monkey model to reproduce the human disease with asymptomatic to mild or fatal disease. after initial replication at the inoculation site, lasv reached the secondary lymphoid organs. lasv did not spread furth ...202133398113
three arenaviruses in three subspecific natal multimammate mouse taxa in tanzania: same host specificity, but different spatial genetic structure?mastomys natalensis is widespread in sub-saharan africa and hosts several arenavirus species, including the pathogenic zoonotic lassa virus in west africa. mitochondrial lineages sub-divide the range of m. natalensis and have been associated with cryptic structure within the species. to test specificity of arenaviruses to hosts carrying these lineages, we screened 1772 m. natalensis in a large area of tanzania where three mitochondrial lineages meet. we detected fifty-two individuals that were p ...202033033629
bayesian estimation of lassa virus epidemiological parameters: implications for spillover prevention using wildlife vaccination.lassa virus is a significant burden on human health throughout its endemic region in west africa, with most human infections the result of spillover from the primary rodent reservoir of the virus, the natal multimammate mouse, m. natalensis. here we develop a bayesian methodology for estimating epidemiological parameters of lassa virus within its rodent reservoir and for generating probabilistic predictions for the efficacy of rodent vaccination programs. our approach uses approximate bayesian c ...202032956349
lassa virus antigen distribution and inflammation in the ear of infected strain 13/n guinea pigs.sudden-onset sensorineuronal hearing loss (snhl) is reported in approximately one-third of survivors of lassa fever (lf) and remains the most prominent cause of lassa virus (lasv)-associated morbidity in convalescence. using a guinea pig model of lf, and incorporating animals from lasv vaccine trials, we investigated viral antigen distribution and histopathology in the ear of infected animals to elucidate the pathogenesis of hearing loss associated with lasv infection. antigen was detected only ...202032898586
adjuvant formulated virus-like particles expressing native-like forms of the lassa virus envelope surface glycoprotein are immunogenic and induce antibodies with broadly neutralizing activity.lassa mammarenavirus (lasv) is a rodent-borne arenavirus endemic to several west african countries. it is the causative agent of human lassa fever, an acute viral hemorrhagic fever disease. to date, no therapeutics or vaccines against lasv have obtained regulatory approval. polyclonal neutralizing antibodies derived from hyperimmunized animals may offer a useful strategy for prophylactic and therapeutic intervention to combat human lasv infections. the lasv envelope surface glycoprotein complex ...202032802410
virulent infection of outbred hartley guinea pigs with recombinant pichinde virus as a surrogate small animal model for human lassa fever.arenaviruses, such as lassa virus (lasv), can cause severe and fatal hemorrhagic fevers (e.g., lassa fever, lf) in humans with no vaccines or therapeutics. research on arenavirus-induced hemorrhagic fevers (ahfs) has been hampered by the highly virulent nature of these viral pathogens, which require high biocontainment laboratory, and the lack of an immune-competent small animal model that can recapitulate ahf disease and pathological features. guinea pig infected with pichinde virus (picv), an ...202032799623
multiple dna viruses identified in multimammate mouse (mastomys natalensis) populations from across regions of sub-saharan africa.the multimammate mouse (mastomys natalensis; m. natalensis) serves as the main reservoir for the zoonotic arenavirus lassa virus (lasv), and this has led to considerable investigation into the distribution of lasv and other related arenaviruses in this host species. in contrast to the situation with arenaviruses, the presence of other viruses in m. natalensis remains largely unexplored. in this study, herpesviruses and polyomaviruses were identified and partially characterized by pcr methods, se ...202032754877
pichinde virus infection of outbred hartley guinea pigs as a surrogate animal model for human lassa fever: histopathological and immunohistochemical analyses.lassa virus (lasv) is a mammarenavirus (arenavirus) that causes zoonotic infection in humans that can lead to fatal hemorrhagic lassa fever (lf) disease. currently, there are no fda-approved vaccines or therapeutics against lasv. development of treatments against lf and other related arenavirus-induced hemorrhagic fevers (ahfs) requires relevant animal models that can recapitulate clinical and pathological features of ahf diseases in humans. laboratory mice are generally resistant to lasv infect ...202032708789
natural history of aerosol induced lassa fever in non‑human primates.lassa virus (lasv), an arenavirus causing lassa fever, is endemic to west africa with up to 300,000 cases and between 5000 and 10,000 deaths per year. rarely seen in the united states, lassa virus is a cdc category a biological agent inasmuch deliberate aerosol exposure can have high mortality rates compared to naturally acquired infection. with the need for an animal model, specific countermeasures remain elusive as there is no fda-approved vaccine. this natural history of aerosolized lassa vir ...202032485952
households as hotspots of lassa fever? assessing the spatial distribution of lassa virus-infected rodents in rural villages of guinea.the natal multimammate mouse (mastomys natalensis) is the reservoir host of lassa virus (lasv), an arenavirus that causes lassa haemorrhagic fever in humans in west africa. while previous studies suggest that spillover risk is focal within rural villages due to the spatial behaviour of the rodents, the level of clustering was never specifically assessed. nevertheless, detailed information on the spatial distribution of infected rodents would be highly valuable to optimize lasv-control campaigns, ...202032459576
population structure of lassa mammarenavirus in west africa.lassa mammarenavirus (lasv) is the etiologic agent of lassa fever. in endemic regions in west africa, lasv genetic diversity tends to cluster by geographic area. seven lasv lineages are recognized, but the role of viral genetic determinants on disease presentation in humans is uncertain. we investigated the geographic structure and distribution of lasv in west africa. we found strong spatial clustering of lasv populations, with two major east-west and north-south diversity gradients. analysis of ...202032294960
structural insight into arenavirus replication machinery.arenaviruses can cause severe haemorrhagic fever and neurological diseases in humans and other animals, exemplified by lassa mammarenavirus, machupo mammarenavirus and lymphocytic choriomeningitis virus, posing great threats to public health1-4. these viruses encode a large multi-domain rna-dependent rna polymerase for transcription and replication of the viral genome5. viral polymerases are one of the leading antiviral therapeutic targets. however, the structure of arenavirus polymerase is not ...202032214249
a lassa virus live-attenuated vaccine candidate based on rearrangement of the intergenic region.lassa virus (lasv) poses a significant public health problem within the regions of lassa fever endemicity in western africa. lasv infects several hundred thousand individuals yearly, and a considerable number of lassa fever cases are associated with high morbidity and lethality. no approved lasv vaccine is available, and current therapy is limited to an off-label usage of ribavirin that is only partially effective and associated with significant side effects. the impact of lassa fever on human h ...202032209677
a lassa fever live-attenuated vaccine based on codon deoptimization of the viral glycoprotein gene.lassa virus (lasv) is endemic in western africa and is estimated to infect hundreds of thousands of individuals annually. a considerable number of these infections result in lassa fever (lf), which is associated with significant morbidity and a case-fatality rate as high as 69% among hospitalized confirmed patients. u.s. food and drug administration-approved lf vaccines are not available. current antiviral treatment is limited to off-label use of a nucleoside analogue, ribavirin, that is only pa ...202032098811
determining ancestry between rodent- and human-derived virus sequences in endemic foci: towards a more integral molecular epidemiology of lassa fever within west africa.lassa fever is a viral hemorrhagic illness responsible for thousands of human deaths in west africa yearly. rodents are known as natural reservoirs of the causative lassa mammarenavirus (lasv) while humans are regarded as incidental, spill-over hosts. analysis of genetic sequences continues to add to our understanding of the evolutionary history, emergence patterns, and the epidemiology of lasv. hitherto, the source of data in such investigations has mainly comprised human clinical samples. pres ...202032046182
quadrivalent vesiculovax vaccine protects nonhuman primates from viral-induced hemorrhagic fever and death.recent occurrences of filoviruses and the arenavirus lassa virus (lasv) in overlapping endemic areas of africa highlight the need for a prophylactic vaccine that would confer protection against all of these viruses that cause lethal hemorrhagic fever (hf). we developed a quadrivalent formulation of vesiculovax that contains recombinant vesicular stomatitis virus (rvsv) vectors expressing filovirus glycoproteins and that also contains a rvsv vector expressing the glycoprotein of a lineage iv stra ...202031820871
vaccines inducing immunity to lassa virus glycoprotein and nucleoprotein protect macaques after a single shot.lassa fever is a major threat in western africa. the large number of people living at risk for this disease calls for the development of a vaccine against lassa virus (lasv). we generated live-attenuated lasv vaccines based on measles virus and mopeia virus platforms and expressing different lasv antigens, with the aim to develop a vaccine able to protect after a single shot. we compared the efficacy of these vaccines against lasv in cynomolgus monkeys. the vaccines were well tolerated and prote ...201931578242
adenoviral vector-based vaccine is fully protective against lethal lassa fever challenge in hartley guinea pigs.lassa virus (lasv), the causative agent of lassa fever (lf), was first identified in 1969. since then, outbreaks in the endemic countries of nigeria, liberia, and sierra leone occur on an annual basis resulting in a case-fatality rate of 15-70% in hospitalized patients. there is currently no licensed vaccine and there are limited animal models to test vaccine efficacy. an estimated 37.7 million people are at risk of contracting lasv; therefore, there is an urgent need for the development of a sa ...201931561999
lethal infection of lassa virus isolated from a human clinical sample in outbred guinea pigs without adaptation.lassa virus (lasv), a member of the family arenaviridae, is the causative agent of lassa fever. lassa virus is endemic in west african countries, such as nigeria, guinea, liberia, and sierra leone, and causes outbreaks annually. lassa fever onset begins with "flu-like" symptoms and may develop into lethal hemorrhagic disease in severe cases. although lassa virus is one of the most alarming pathogens from a public health perspective, there are few licensed vaccines or therapeutics against lassa f ...201931554720
density dependence and persistence of morogoro arenavirus transmission in a fluctuating population of its reservoir host.a key aim in wildlife disease ecology is to understand how host and parasite characteristics influence parasite transmission and persistence. variation in host population density can have strong impacts on transmission and outbreaks, and theory predicts particular transmission-density patterns depending on how parasites are transmitted between individuals. here, we present the results of a study on the dynamics of morogoro arenavirus in a population of multimammate mice (mastomys natalensis). th ...202031545505
animal models for lassa virus infection.in humans, lassa virus infection can result in disease with hemorrhagic manifestations and high fatality rates. there are no approved treatments or vaccines available and the inherent danger of studying lassa virus means it can only be studied in high containment labs (bsl4). under these conditions, mouse models are becoming an important instrument in the study of lassa virus infection, disease and host responses. while guinea pigs and non-human primates are the critical components in assessing ...201931442921
comparative genomic characterization of the multimammate mouse mastomys coucha.mastomys are the most widespread african rodent and carriers of various diseases such as the plague or lassa virus. in addition, mastomys have rapidly gained a large number of mammary glands. here, we generated a genome, variome, and transcriptomes for mastomys coucha. as mastomys diverged at similar times from mouse and rat, we demonstrate their utility as a comparative genomic tool for these commonly used animal models. furthermore, we identified over 500 mastomys accelerated regions, often re ...201931424545
phylogeography of lassa virus in nigeria.lassa virus is genetically diverse with several lineages circulating in west africa. this study aimed at describing the sequence variability of lassa virus across nigeria and inferring its spatiotemporal evolution. we sequenced and isolated 77 lassa virus strains from 16 nigerian states. the final data set, including previous works, comprised metadata and sequences of 219 unique strains sampled between 1969 and 2018 in 22 states. most of this data originated from lassa fever patients diagnosed a ...201931413134
antibody therapy for lassa fever.serum from convalescent lassa fever patients was previously shown to be ineffective as a source of protective antibodies in some early studies. subsequently, monoclonal antibodies (mabs) to the lassa virus (lasv) glycoprotein produced by memory b cells of west african patients who survived lassa fever were identified. development of mabs as potential lassa immunotherapeutics was facilitated by structural studies and mutational analyses that identified protective epitopes on the prefusion form of ...201931401518
lassa virus in pygmy mice, benin, 2016-2017.lassa virus has been identified in 3 pygmy mice, mus baoulei, in central benin. the glycoprotein and nucleoprotein sequences cluster with the togo strain. these mice may be a new reservoir for lassa virus in ghana, togo, and benin.201931365854
a vaccine based on recombinant modified vaccinia ankara containing the nucleoprotein from lassa virus protects against disease progression in a guinea pig model.lassa fever remains the most imported viral haemorrhagic fever in europe and is responsible for 5000 deaths per year throughout western africa. there is no vaccine and treatment is often ineffective. we have developed a vaccine based on modified vaccinia ankara expressing the nucleoprotein from lassa virus (mvalassanp). this study investigated the immunogenicity (in mice) and efficacy (in guinea pigs) of the mvalassanp vaccine as a prime/boost or single vaccination regime. elisa and elispot assa ...201931331770
development and evaluation of a one-step quantitative rt-pcr assay for detection of lassa virus.lassa fever is a severe viral hemorrhagic illness caused by lassa virus. based on estimates, the number of lasv infections ranges from 300,000 to 500,000 cases in endemic areas with a fatality rate of 1%. development of fast and sensitive tools for the control and prevention of lassa virus infection as well as for clinical diagnostics of lassa fever are crucial. here we reported development and evaluation of a one-step quantitative rt-qpcr assay for the lassa virus detection - lasv-fl. this assa ...201931170468
protection from lethal lassa disease can be achieved both before and after virus exposure by administration of single-cycle replicating lassa virus replicon particles.lassa fever is a frequently severe human disease that is endemic to several countries in west africa. to date, no licensed vaccines are available to prevent lassa virus (lasv) infection, even though lassa fever is thought to be an important disease contributing to mortality and both acute and chronic morbidity. we have previously described a vaccine candidate composed of single-cycle lasv replicon particles (vrps) and a stable cell line for their production. here, we refine the genetic compositi ...201931152662
immunogenicity of a protective intradermal dna vaccine against lassa virus in cynomolgus macaques.lassa virus (lasv) is a hemorrhagic fever virus of the arenaviridae family with high rates of mortality and co-morbidities, including chronic seizures and permanent bilateral or unilateral deafness. lasv is endemic in west africa and lassa fever accounts for 10-16% of hospitalizations annually in parts of sierra leone and liberia according to the cdc. an ongoing outbreak in nigeria has resulted in 144 deaths in 568 cases confirmed as lasv as of november 2018, with many more suspected, highlighti ...201931071008
vaccine platforms for the prevention of lassa fever.lassa fever is an acute viral haemorrhagic illness caused by lassa virus (lasv), which is endemic throughout much of west africa. the virus primarily circulates in the mastomys natalensis reservoir and is transmitted to humans through contact with infectious rodents or their secretions; human-to-human transmission is documented as well. with the exception of dengue fever, lasv has the highest human impact of any haemorrhagic fever virus. on-going outbreaks in nigeria have resulted in unprecedent ...201931026485
evaluation of rodent control to fight lassa fever based on field data and mathematical modelling.the natal multimammate mouse (mastomys natalensis) is the reservoir host of lassa virus, an arenavirus that causes lassa haemorrhagic fever in humans in west africa. because no vaccine exists and therapeutic options are limited, preventing infection through rodent control and human behavioural measures is currently considered to be the only option. in order to assess the efficacy of rodent control, we performed a 4-year field experiment in rural upper guinea and developed a mathematical model to ...201931007139
lassa virus targeting of anterior uvea and endothelium of cornea and conjunctiva in eye of guinea pig model.lassa virus (lasv), a hemorrhagic fever virus endemic to west africa, causes conjunctivitis in patients with acute disease. to examine ocular manifestations of lasv, we histologically examined eyes from infected guinea pigs. in fatal disease, lasv immunostaining was most prominent in the anterior uvea, especially in the filtration angle, ciliary body, and iris and in and around vessels in the bulbar conjunctiva and peripheral cornea, where it co-localized with an endothelial marker (platelet end ...201931002065
a recombinant vesicular stomatitis-based lassa fever vaccine elicits rapid and long-term protection from lethal lassa virus infection in guinea pigs.the world health organization has identified lassa virus (lasv) as one of the top five pathogens to cause a severe outbreak in the near future. this study assesses the ability of a leading vaccine candidate, recombinant vesicular stomatitis virus expressing lasv glycoprotein (vsvδg/lasvgpc), and its ability to induce rapid and long-term immunity to lethal guinea pig-adapted lasv (gpa-lasv). outbred guinea pigs were vaccinated with a single dose of vsvδg/lasvgpc followed by a lethal challenge of ...201930774999
lassa virus diversity and feasibility for universal prophylactic vaccine.lassa virus (lasv) is a highly prevalent mammarenavirus in west africa and is maintained in nature in a persistently infected rodent host, mastomys natalensis, which is widely spread in sub-saharan africa. lasv infection of humans can cause lassa fever (lf), a disease associated with high morbidity and significant mortality. recent evidence indicates an lasv expansion outside its traditional endemic areas. in 2017, the world health organization (who) included lasv in top-priority pathogens and r ...201930774934
host-driven phosphorylation appears to regulate the budding activity of the lassa virus matrix protein.lassa mammarenavirus (lasv) is an enveloped rna virus that can cause lassa fever, an acute hemorrhagic fever syndrome associated with significant morbidity and high rates of fatality in endemic regions of western africa. the arenavirus matrix protein z has several functions during the virus life cycle, including coordinating viral assembly, driving the release of new virus particles, regulating viral polymerase activity, and antagonizing the host antiviral response. there is limited knowledge re ...201830544850
persistence of lassa virus associated with severe systemic arteritis in convalescing guinea pigs (cavia porcellus).lassa fever (lf) survivors develop various clinical manifestations including polyserositis, myalgia, epididymitis, and hearing loss weeks to months after recovery from acute infection. we demonstrate a systemic lymphoplasmacytic and histiocytic arteritis and periarteritis in guinea pigs more than 2 months after recovery from acute lassa virus (lasv) infection. lasv was detected in the arterial tunica media smooth muscle cells by immunohistochemistry, in situ hybridization, and transmission elect ...201930517671
rodent control to fight lassa fever: evaluation and lessons learned from a 4-year study in upper guinea.lassa fever is a viral haemorrhagic fever caused by an arenavirus. the disease is endemic in west african countries, including guinea. the rodents mastomys natalensis and mastomys erythroleucus have been identified as lassa virus reservoirs in guinea. in the absence of a vaccine, rodent control and human behavioural changes are the only options to prevent lassa fever in highly endemic areas. we performed a 4 year intervention based on chemical rodent control, utilizing anticoagulant rodenticides ...201830399142
immune-mediated systemic vasculitis as the proposed cause of sudden-onset sensorineural hearing loss following lassa virus exposure in cynomolgus macaques.lassa virus (lasv) causes a severe, often fatal hemorrhagic disease in regions in africa where the disease is endemic, and approximately 30% of patients develop sudden-onset sensorineural hearing loss after recovering from acute disease. the causal mechanism of hearing loss in lasv-infected patients remains elusive. here, we report findings after closely examining the chronic disease experienced by surviving macaques assigned to lasv exposure control groups in two different studies. all nonhuman ...201830377282
non-neutralizing antibodies elicited by recombinant lassa-rabies vaccine are critical for protection against lassa fever.lassa fever (lf), caused by lassa virus (lasv), is a viral hemorrhagic fever for which no approved vaccine or potent antiviral treatment is available. lf is a who priority disease and, together with rabies, a major health burden in west africa. here we present the development and characterization of an inactivated recombinant lasv and rabies vaccine candidate (lassarab) that expresses a codon-optimized lasv glycoprotein (cogpc) and is adjuvanted by a tlr-4 agonist (gla-se). lassarab elicits last ...201830310067
the s genome segment is sufficient to maintain pathogenicity in intra-clade lassa virus reassortants in a guinea pig model.genome reassortment in lassa virus (lasv) has been reported in nature, but phenotypic consequences of this phenomenon are not well described. here we characterize, both in vitro and in vivo, reassortment between 2 lasv strains: the prototypic 1976 josiah strain and a more recently isolated 2015 liberian strain. in vitro analysis showed that although cis- and trans-acting elements of viral rna synthesis were compatible between strains, reassortants demonstrated different levels of viral replicati ...201830050872
widespread arenavirus occurrence and seroprevalence in small mammals, nigeria.lassa fever, killing thousands of people annually, is the most reported viral zoonotic disease in nigeria. recently, different rodent species carrying diverse lineages of the lassa virus (lasv) in addition to a novel mobala-like genetic sequence were detected within the country. here, screening 906 small mammal specimens from 11 localities for igg antibodies and incorporating previous pcr detection data involving the same populations, we further describe arenavirus prevalence across nigeria in r ...201830005641
use of a scalable replicon-particle vaccine to protect against lethal lassa virus infection in the guinea pig model.lassa fever is a viral zoonosis that can be transmitted from person to person, especially in the hospital setting. the disease is endemic to several countries in west africa and can be a major contributor to morbidity and mortality in affected areas. there are no approved vaccines to prevent lassa virus infection. in this work, we present a vaccine candidate that combines the scalability and efficacy benefits of a live vaccine with the safety benefits of single-cycle replication. the system cons ...201829800368
movement patterns of small rodents in lassa fever-endemic villages in guinea.the natal multimammate mouse (mastomys natalensis) is the reservoir host of lassa arenavirus, the etiological agent of lassa fever in humans. because there exists no vaccine for human use, rodent control and adjusting human behavior are currently considered to be the only options for lassa fever control. in order to develop efficient rodent control programs, more information about the host's ecology is needed. in this study, we investigated the spatial behavior of m. natalensis and other small r ...201829572697
dna vaccines elicit durable protective immunity against individual or simultaneous infections with lassa and ebola viruses in guinea pigs.we previously developed optimized dna vaccines against both lassa fever and ebola hemorrhagic fever viruses and demonstrated that they were protective individually in guinea pig and nonhuman primate models. in this study, we vaccinated groups of strain 13 guinea pigs two times, four weeks apart with 50 µg of each dna vaccine or a mock vaccine at discrete sites by intradermal electroporation. five weeks following the second vaccinations, guinea pigs were exposed to lethal doses of lassa virus, eb ...201729135337
a dna vaccine delivered by dermal electroporation fully protects cynomolgus macaques against lassa fever.lassa virus (lasv) is an ambisense rna virus in the arenaviridae family and is the etiological agent of lassa fever, a severe hemorrhagic disease endemic to west and central africa. 1,2 there are no us food and drug administration (fda)-licensed vaccines available to prevent lassa fever. 1,2 in our previous studies, we developed a gene-optimized dna vaccine that encodes the glycoprotein precursor gene of lasv (josiah strain) and demonstrated that 3 vaccinations accompanied by dermal electroporat ...201729045192
understanding the cryptic nature of lassa fever in west africa.lassa fever (lf) is increasingly recognized by global health institutions as an important rodent-borne disease with severe impacts on some of west africa's poorest communities. however, our knowledge of lf ecology, epidemiology and distribution is limited, which presents barriers to both short-term disease forecasting and prediction of long-term impacts of environmental change on lassa virus (lasv) zoonotic transmission dynamics. here, we synthesize current knowledge to show that extrapolations ...201728875769
human-monoclonal-antibody therapy protects nonhuman primates against advanced lassa fever.there are no approved treatments for lassa fever, which is endemic to the same regions of west africa that were recently devastated by ebola. here we show that a combination of human monoclonal antibodies that cross-react with the glycoproteins of all four clades of lassa virus is able to rescue 100% of cynomolgus macaques when treatment is initiated at advanced stages of disease, including up to 8 d after challenge.201728869611
interferon-γ-driven inos: a molecular pathway to terminal shock in arenavirus hemorrhagic fever.arenaviruses such as lassa virus (lasv) cause hemorrhagic fever. terminal shock is associated with a systemic cytokine storm, but the mechanisms are ill defined. here we used hla-a2-expressing mice infected with a monkey-pathogenic strain of lymphocytic choriomeningitis virus (lcmv-we), a close relative of lasv, to investigate the pathophysiology of arenavirus hemorrhagic fever (ahf). ahf manifested as pleural effusions, edematous skin swelling, and serum albumin loss, culminating in hypovolemic ...201728826838
an lasv gpc pseudotyped virus based reporter system enables evaluation of vaccines in mice under non-bsl-4 conditions.lassa virus (lasv) causes a severe hemorrhagic fever endemic throughout western africa. because of the ability to cause lethal disease in humans, limited treatment options, and potential as a bioweapon, the need for vaccines to prevent lasv epidemic is urgent. however, lasv vaccine development has been hindered by the lack of appropriate small animal models for efficacy evaluation independent of biosafety level four (bsl-4) facilities. here we generated an lasv-glycoprotein precursor (gpc)-pseud ...201728797730
evolutionary analysis of old world arenaviruses reveals a major adaptive contribution of the viral polymerase.the old world (ow) arenavirus complex includes several species of rodent-borne viruses, some of which (i.e., lassa virus, lasv and lymphocytic choriomeningitis virus, lcmv) cause human diseases. most lcmv and lasv infections are caused by rodent-to-human transmissions. thus, viral evolution is largely determined by events that occur in the wildlife reservoirs. we used a set of human- and rodent- derived viral sequences to investigate the evolutionary history underlying ow arenavirus speciation, ...201728779541
prevalence of lassa virus among rodents trapped in three south-south states of nigeria.lassa fever has been endemic in nigeria since 1969. the rodent mastomys natalensis has been widely claimed to be the reservoir host of the lassa virus. this study was designed to investigate the dis- tribution of species of rodents in three states (edo, delta and bayelsa) of nigeria and to determine the prevalence of lassa virus amongst trapped rodents in the selected states.201728748835
human antibody pieces together the puzzle of the trimeric lassa virus surface antigen. 201728686227
mutational analysis of lassa virus glycoprotein highlights regions required for alpha-dystroglycan utilization.lassa virus (lasv) is an enveloped rna virus endemic to west africa and responsible for severe cases of hemorrhagic fever. virus entry is mediated by the glycoprotein complex consisting of a stable-signal peptide, a receptor-binding subunit, gp1, and a viral-host membrane fusion subunit, gp2. several cellular receptors can interact with the gp1 subunit and mediate viral entry, including alpha-dystroglycan (αdg) and lysosome-associated membrane protein 1 (lamp1). in order to define the regions wi ...201728679759
prevalence of lassa virus disease (lvd) in nigerian children with fever or fever and convulsions in an endemic area.convulsions with fever in children are a common neurologic emergency in the tropics, and determining the contribution of endemic viral infections can be challenging. in particular, there is a dearth of data on the prevalence and clinical differentiation of lassa virus disease (lvd) in febrile children in endemic areas of nigeria, which has multiple lineages of the virus. the aim of this study was to determine the prevalence and presentation of lvd in febrile children with and without convulsions ...201728671959
[consequences of autopsies for the living : causes of death in the clinical diagnosis "septic and toxic shock"].there is reason to believe that the diagnosis of septic and toxic shock, as indicated on the death certificate, cannot be confirmed as the cause of death without autopsy and subsequent histological analysis. the external examination of the corpse can therefore not represent the sole basis for a reliable statement about the infection status of a corpse, e. g. as a prerequisite for embalming.201728638939
structural basis for antibody-mediated neutralization of lassa virus.the arenavirus lassa causes severe hemorrhagic fever and a significant disease burden in west africa every year. the glycoprotein, gpc, is the sole antigen expressed on the viral surface and the critical target for antibody-mediated neutralization. here we present the crystal structure of the trimeric, prefusion ectodomain of lassa gp bound to a neutralizing antibody from a human survivor at 3.2-angstrom resolution. the antibody extensively anchors two monomers together at the base of the trimer ...201728572385
molecular pathogenesis of viral hemorrhagic fever.the clinical syndrome referred to as viral hemorrhagic fever (vhf) can be caused by several different families of rna viruses, including select members of the arenaviruses, bunyaviruses, filoviruses, and flaviviruses. vhf is characterized by malaise, fever, vascular permeability, decreased plasma volume, coagulation abnormalities, and varying degrees of hemorrhage. study of the filovirus ebola virus has demonstrated a critical role for suppression of innate antiviral defenses in viral pathogenes ...201728555386
lassa virus reverse genetics.the old world (ow) arenavirus lassa (lasv ) is estimated to infect several hundred thousand people yearly in west africa, resulting in high numbers of lassa fever (lf), a viral hemorrhagic fever (hf) disease associated with high morbidity and mortality. to date, no licensed vaccines are available to lasv infections, and anti-lasv drug therapy is limited to an off-label use of ribavirin (rib) that is only partially effective. the development of reverse genetics has provided investigators with a n ...201728508222
differential immune responses to new world and old world mammalian arenaviruses.some new world (nw) and old world (ow) mammalian arenaviruses are emerging, zoonotic viruses that can cause lethal hemorrhagic fever (hf) infections in humans. while these are closely related rna viruses, the infected hosts appear to mount different types of immune responses against them. lassa virus (lasv) infection, for example, results in suppressed immune function in progressive disease stage, whereas patients infected with junín virus (junv) develop overt pro-inflammatory cytokine productio ...201728498311
no measurable adverse effects of lassa, morogoro and gairo arenaviruses on their rodent reservoir host in natural conditions.in order to optimize net transmission success, parasites are hypothesized to evolve towards causing minimal damage to their reservoir host while obtaining high shedding rates. for many parasite species however this paradigm has not been tested, and conflicting results have been found regarding the effect of arenaviruses on their rodent host species. the rodent mastomys natalensis is the natural reservoir host of several arenaviruses, including lassa virus that is known to cause lassa haemorrhagi ...201728449693
mapping of the lassa virus lamp1 binding site reveals unique determinants not shared by other old world arenaviruses.cell entry of many enveloped viruses occurs by engagement with cellular receptors, followed by internalization into endocytic compartments and ph-induced membrane fusion. a previously unnoticed step of receptor switching was found to be critical during cell entry of two devastating human pathogens: ebola and lassa viruses. our recent studies revealed the functional role of receptor switching to lamp1 for triggering membrane fusion by lassa virus and showed the involvement of conserved histidines ...201728448640
temporal progression of lesions in guinea pigs infected with lassa virus.lassa virus (lasv) infection causes an acute, multisystemic viral hemorrhagic fever that annually infects an estimated 100 000 to 300 000 persons in west africa. this pathogenesis study evaluated the temporal progression of disease in guinea pigs following aerosol and subcutaneous inoculation of the josiah strain of lasv as well as the usefulness of strain 13 guinea pigs as an animal model for lassa fever. after experimental infection, guinea pigs ( cavia porcellus; n = 67) were serially sampled ...201728438110
laboratory diagnosis of lassa fever.lassa virus remains an important cause of illness in west africa and among the travelers returning from this region with an acute febrile illness. the symptoms of lassa fever can be nonspecific and mimic those of other endemic infections, especially early in illness, making a clinical diagnosis difficult; therefore, laboratory testing is needed to confirm the diagnosis. an early identification of lassa fever is crucial for maximizing the benefit of available antiviral therapy, as treatment effic ...201728404674
lassa fever: another threat from west africa.lassa fever, a zoonotic viral infection, is endemic in west africa. the disease causes annual wide spread morbidity and mortality in africa, and can be imported by travelers. possible importation of lassa fever and the potential for the use of lassa virus as an agent of bioterrorism mandate clinicians in israel and other countries to be vigilant and familiar with the basic characteristics of this disease. the article reviews the basis of this infection and the clinical management of patients wit ...201628265442
at home with mastomys and rattus: human-rodent interactions and potential for primary transmission of lassa virus in domestic spaces.the multimammate mouse (mastomys natalensis) is the reservoir for lassa virus (lasv). zoonotic transmission occurs when humans are directly or indirectly exposed to fluids of the multimammate mouse, such as urine, saliva, and blood. housing characteristics and domestic organization affect rodent density in and around households and villages, and are likely to be a risk factor for lassa fever in humans where the reservoir exists. we use semi-structured interviews (n = 51), a quantitative survey ( ...201728167603
immunobiology of ebola and lassa virus infections.two of the most important contemporary emerging viruses that affect human health in africa are ebola virus (ebov) and lassa virus (lasv). the 2013-2016 west african outbreak of ebov was responsible for more than 11,000 deaths, primarily in guinea, sierra leone and liberia. lasv is constantly emerging in these and surrounding west african countries, with an estimate of more than 500,000 cases of lassa fever, and approximately 5,000 deaths, annually. both ebov and lasv are zoonotic, and human infe ...201728111475
annual incidence of lassa virus infection in southern mali.previously, we reported a high seroprevalence rate of lassa virus antibodies in inhabitants of three villages in southern mali where infected rodents have been demonstrated. herein, we report a 1-year follow-up study in which we were able to collect a second blood samples from 88.7% of participants of the same cohort. we identified 23 seroconversions for igg antibodies reactive against lassa virus, representing an incidence of 6.3% (95% confidence interval = 3.8-8.8%). seroconversion was frequen ...201728093544
when viruses don't go viral: the importance of host phylogeographic structure in the spatial spread of arenaviruses.many emerging infections are rna virus spillovers from animal reservoirs. reservoir identification is necessary for predicting the geographic extent of infection risk, but rarely are taxonomic levels below the animal species considered as reservoir, and only key circumstances in nature and methodology allow intrinsic virus-host associations to be distinguished from simple geographic (co-)isolation. we sampled and genetically characterized in detail a contact zone of two subtaxa of the rodent mas ...201728076397
25-hydroxycholesterol inhibition of lassa virus infection through aberrant gp1 glycosylation.lassa virus (lasv) infection is a major public health concern due to high fatality rates and limited effective treatment. the interferon-stimulated gene cholesterol 25-hydroxylase (ch25h) encodes an enzyme that catalyzes the production of 25-hydroxycholesterol (25hc). 25hc is involved in regulating cholesterol biosynthesis and has recently been identified as a potent antiviral targeting enveloped virus entry. here, we show a previously unrecognized role of ch25h in inhibiting lasv glycoprotein g ...201627999160
aseptic meningitis caused by lassa virus: case series report.the lassa virus is known to cause disease in different organ systems of the human body, with varying clinical manifestations. the features of severe clinical disease may include bleeding and/or central nervous system manifestations. whereas lassa fever encephalopathy and encephalitis are well described in the literature, there is paucity of data on lassa virus meningitis. we present the clinical description, laboratory diagnosis, and management of 4 consecutive cases of aseptic meningitis associ ...201627957363
lassa virus cell entry reveals new aspects of virus-host cell interaction.viral entry represents the first step of every viral infection and is a determinant for the host range and disease potential of a virus. here, we review the latest developments on cell entry of the highly pathogenic old world arenavirus lassa virus, providing novel insights into the complex virus-host cell interaction of this important human pathogen. we will cover new discoveries on the molecular mechanisms of receptor recognition, endocytosis, and the use of late endosomal entry factors.201727928003
comparison of magpix assays and enzyme-linked immunosorbent assay for detection of hemorrhagic fever viruses.viral hemorrhagic fevers, because of their high mortality rates, the lack of medical countermeasures, and their potential use as instruments of bioterrorism, pose a significant threat to the developed and the developing areas of the world. the key to preventing the spread of these diseases is early and accurate detection. for decades, the gold-standard immunoassay for hemorrhagic fever detection has been the enzyme-linked immunosorbent assay (elisa); however, newer technologies are emerging with ...201727795340
lassa and ebola virus inhibitors identified using minigenome and recombinant virus reporter systems.lassa virus (lasv) and ebola virus (ebov) infections are important global health issues resulting in significant morbidity and mortality. while several promising drug and vaccine trials for ebov are ongoing, options for lasv infection are currently limited to ribavirin treatment. a major factor impeding the development of antiviral compounds to treat these infections is the need to manipulate the virus under bsl-4 containment, limiting research to a few institutes worldwide. here we describe the ...201627771389
serosurveillance of viral pathogens circulating in west africa.sub-saharan africa is home to a variety of pathogens, but disease surveillance and the healthcare infrastructure necessary for proper management and control are severely limited. lassa virus, the cause of lassa fever, a severe hemorrhagic fever in humans is endemic in west africa. in sierra leone at the kenema government hospital lassa diagnostic laboratory, up to 70 % of acute patient samples suspected of lassa fever test negative for lassa virus infection. this large amount of acute undiagnose ...201627716429
a cell-based high-throughput protocol to screen entry inhibitors of highly pathogenic viruses with traditional chinese medicines.emerging viruses such as ebola virus (ebov), lassa virus (lasv), and avian influenza virus h5n1 (aiv) are global health concerns. since there is very limited options (either vaccine or specific therapy) approved for humans against these viruses, there is an urgent need to develop prophylactic and therapeutic treatments. previously we reported a high-throughput screening (hts) protocol to identify entry inhibitors for three highly pathogenic viruses (ebov, lasv, and aiv) using a human immunodefic ...201727704591
genome sequence of lassa virus isolated from the first domestically acquired case in germany.lassa virus (lasv) is a zoonotic, hemorrhagic fever-causing virus endemic in west africa, for which no approved vaccines or specific treatment options exist. here, we report the genome sequence of lasv isolated from the first case of acquired lassa fever disease outside of africa.201627660771
role of lamp1 binding and ph sensing by the spike complex of lassa virus.to effectively infect cells, lassa virus needs to switch in an endosomal compartment from its primary receptor, α-dystroglycan, to a protein termed lamp1. a unique histidine triad on the surface of the receptor-binding domain from the glycoprotein spike complex of lassa virus is important for lamp1 binding. here we investigate mutated spikes that have an impaired ability to interact with lamp1 and show that although lamp1 is important for efficient infectivity, it is not required for spike-media ...201627605678
residues k465 and g467 within the cytoplasmic domain of gp2 play a critical role in the persistence of lymphocytic choriomeningitis virus in mice.several arenaviruses, chiefly lassa virus (lasv), cause hemorrhagic fever disease in humans and pose serious public health concerns in their regions of endemicity. moreover, mounting evidence indicates that the worldwide-distributed prototypic arenavirus, lymphocytic choriomeningitis virus (lcmv), is a neglected human pathogen of clinical significance. we have documented that a recombinant lcmv containing the glycoprotein (gpc) gene of lasv within the backbone of the immunosuppressive clone 13 ( ...201627581982
structure-function relationship of the mammarenavirus envelope glycoprotein.mammarenaviruses, including lethal pathogens such as lassa virus and junín virus, can cause severe hemorrhagic fever in humans. entry is a key step for virus infection, which starts with binding of the envelope glycoprotein (gp) to receptors on target cells and subsequent fusion of the virus with target cell membranes. the gp precursor is synthesized as a polypeptide, and maturation occurs by two cleavage events, yielding a tripartite gp complex (gpc) formed by a stable signal peptide (ssp), gp1 ...201627562602
treatment of lassa virus infection in outbred guinea pigs with first-in-class human monoclonal antibodies.lassa fever is a significant health threat to west african human populations with hundreds of thousands of annual cases. there are no approved medical countermeasures currently available. compassionate use of the antiviral drug ribavirin or transfusion of convalescent serum has resulted in mixed success depending on when administered or the donor source, respectively. we previously identified several recombinant human monoclonal antibodies targeting the glycoprotein of lassa virus with strong ne ...201627531367
engaging market traders in lassa fever campaign: assessment of knowledge and risk behaviour.markets provide a forum for reaching a large adult population with information on lassa fever, and therefore understanding the food handling practices of traders may provide the foundation for an effective campaign against lassa fever. this study was undertaken to provide baseline information on knowledge and food handling practices of traders in local markets in a lassa fever endemic state of nigeria.201727492545
landscape determinants of fine-scale genetic structure of a small rodent in a heterogeneous landscape (hluhluwe-imfolozi park, south africa).small mammals provide ecosystem services, acting, for example, as pollinators and seed dispersers. in addition, they are also disease reservoirs that can be detrimental to human health and they can also act as crop pests. knowledge of their dispersal preferences is therefore useful for population management and landscape planning. genetic data were used alongside landscape data to examine the influence of the landscape on the demographic connectedness of the natal multimammate mouse (mastomys na ...201627406468
an outbreak of ebola virus disease in the lassa fever zone.kenema government hospital (kgh) has developed an advanced clinical and laboratory research capacity to manage the threat of lassa fever, a viral hemorrhagic fever (vhf). the 2013-2016 ebola virus (ebov) disease (evd) outbreak is the first to have occurred in an area close to a facility with established clinical and laboratory capacity for study of vhfs.201627402779
outbreak of lassa fever in nigeria: measures for prevention and control. 201627347299
comparative structural and functional analysis of bunyavirus and arenavirus cap-snatching endonucleases.segmented negative strand rna viruses of the arena-, bunya- and orthomyxovirus families uniquely carry out viral mrna transcription by the cap-snatching mechanism. this involves cleavage of host mrnas close to their capped 5' end by an endonuclease (en) domain located in the n-terminal region of the viral polymerase. we present the structure of the cap-snatching en of hantaan virus, a bunyavirus belonging to hantavirus genus. hantaan en has an active site configuration, including a metal co-ordi ...201627304209
small-molecule fusion inhibitors bind the ph-sensing stable signal peptide-gp2 subunit interface of the lassa virus envelope glycoprotein.arenavirus species are responsible for severe life-threatening hemorrhagic fevers in western africa and south america. without effective antiviral therapies or vaccines, these viruses pose serious public health and biodefense concerns. chemically distinct small-molecule inhibitors of arenavirus entry have recently been identified and shown to act on the arenavirus envelope glycoprotein (gpc) to prevent membrane fusion. in the tripartite gpc complex, ph-dependent membrane fusion is triggered thro ...201627194767
chimeric mice with competent hematopoietic immunity reproduce key features of severe lassa fever.lassa fever (lasf) is a highly severe viral syndrome endemic to west african countries. despite the annual high morbidity and mortality caused by lasf, very little is known about the pathophysiology of the disease. basic research on lasf has been precluded due to the lack of relevant small animal models that reproduce the human disease. immunocompetent laboratory mice are resistant to infection with lassa virus (lasv) and, to date, only immunodeficient mice, or mice expressing human hla, have sh ...201627191716
most neutralizing human monoclonal antibodies target novel epitopes requiring both lassa virus glycoprotein subunits.lassa fever is a severe multisystem disease that often has haemorrhagic manifestations. the epitopes of the lassa virus (lasv) surface glycoproteins recognized by naturally infected human hosts have not been identified or characterized. here we have cloned 113 human monoclonal antibodies (mabs) specific for lasv glycoproteins from memory b cells of lassa fever survivors from west africa. one-half bind the gp2 fusion subunit, one-fourth recognize the gp1 receptor-binding subunit and the remaining ...201627161536
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