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Stephan Günther - One of the best experts on this subject based on the ideXlab platform.
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biochemical characterization of the Lassa Virus l protein
Journal of Biological Chemistry, 2019Co-Authors: Dominik Vogel, Maria Rosenthal, Nadja Gogrefe, Sophia Reindl, Stephan GüntherAbstract:The L protein of arena- and bunyaViruses is structurally and functionally related to the orthomyxoVirus polymerase complex. It plays a central role in the viral life cycle, as it replicates the Virus genome and generates viral mRNA via a cap-snatching mechanism. Here, we aimed to biochemically characterize the L protein of Lassa Virus, a human-pathogenic arenaVirus endemic in West Africa. Full-length 250-kDa L protein was expressed using a baculoVirus expression system. A low-resolution structure calculated from small-angle X-ray scattering data revealed a conformation similar to that in the crystal structure of the orthomyxoVirus polymerase complex. Although the L protein did not exhibit cap-snatching endonuclease activity, it synthesized RNA in vitro RNA polymerization required manganese rather than magnesium ions, was independent of nucleotide primers, and was inhibited by viral Z protein. Maximum activity was mediated by double-stranded promoter sequences with a minimum length of 17 nucleotides, containing a nontemplated 5'-G overhang, as in the natural genome context, as well as the naturally occurring base mismatches between the complementary promoter strands. Experiments with various short primers revealed the presence of two replication initiation sites at the template strand and evidence for primer translocation as proposed by the prime-and-realign hypothesis. Overall, our findings provide the foundation for a detailed understanding of the mechanistic differences and communalities in the polymerase proteins of segmented negative-strand RNA Viruses and for the search for antiviral compounds targeting the RNA polymerase of Lassa Virus.
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small mammal diversity and dynamics within nigeria with emphasis on reservoirs of the Lassa Virus
Systematics and Biodiversity, 2018Co-Authors: Ayodeji Olayemi, Stephan Günther, Adeoba Obadare, Akinlabi Oyeyiola, Samuel Fasogbon, Joseph Igbokwe, Felix Igbahenah, Daniel Ortsega, Erik Verheyen, Elisabeth FichetcalvetAbstract:Nigeria has a rich small mammal community, with several species implicated as carriers of zoonotic microbes such as the Lassa Virus (LASV). We sought to elucidate the diversity and distribution of these animals (including known LASV reservoirs) geographically, habitat-wise and seasonally. Our DNA-assisted survey detected at least 19 small mammal species amongst 790 specimens. Diversity indices were similar between ecological zones and also between endemic and non-endemic areas for Lassa fever. Mastomys natalensis, the most renowned LASV host, was present in eight out of nine localities sampled. We also described the spatial occurrence of other known LASV hosts such as M. erythroleucus and Hylomyscus pamfi, including carriers of LASV-like arenaViruses such as Mus (Nannomys) spp. The most numerous rodents (Mastomys natalensis, M. erythroleucus, and Praomys daltoni) were captured mainly inside human dwellings. Reproductive activity occurred throughout the year, but led to population peaks for M. natalensis i...
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determining ribavirin s mechanism of action against Lassa Virus infection
Scientific Reports, 2017Co-Authors: Paola Carrillobustamante, Stephan Günther, Lisa Oestereich, Thi Huyen Tram Nguyen, Jeremie Guedj, Frederik GrawAbstract:Ribavirin is a broad spectrum antiviral which inhibits Lassa Virus (LASV) replication in vitro but exhibits a minor effect on viremia in vivo. However, ribavirin significantly improves the disease outcome when administered in combination with sub-optimal doses of favipiravir, a strong antiviral drug. The mechanisms explaining these conflicting findings have not been determined, so far. Here, we used an interdisciplinary approach combining mathematical models and experimental data in LASV-infected mice that were treated with ribavirin alone or in combination with the drug favipiravir to explore different putative mechanisms of action for ribavirin. We test four different hypotheses that have been previously suggested for ribavirin’s mode of action: (i) acting as a mutagen, thereby limiting the infectivity of new virions; (ii) reducing viremia by impairing viral production; (iii) modulating cell damage, i.e., by reducing inflammation, and (iv) enhancing antiviral immunity. Our analysis indicates that enhancement of antiviral immunity, as well as effects on viral production or transmission are unlikely to be ribavirin’s main mechanism mediating its antiviral effectiveness against LASV infection. Instead, the modeled viral kinetics suggest that the main mode of action of ribavirin is to protect infected cells from dying, possibly reducing the inflammatory response.
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International External Quality Assessment Study for Molecular Detection of Lassa Virus
2015Co-Authors: Sergejs Nikisins, Stephan Günther, Toni Rieger, Pranav Patel, Rolf Müller, Matthias NiedrigAbstract:Lassa Virus (LASV) is a causative agent of hemorrhagic fever in West Africa. In recent years, it has been imported several times to Europe and North America. The method of choice for early detection of LASV in blood is RT-PCR. Therefore, the European Network for Diagnostics of ‘Imported’ Viral Diseases (ENIVD) performed an external quality assessment (EQA) study for molecular detection of LASV. A proficiency panel of 13 samples containing various concentrations of inactivated LASV strains Josiah, Lib-1580/121, CSF, or AV was prepared. Samples containing the LASV-related lymphocytic choriomeningitis Virus (LCMV) and negative sera were included as specificity controls. Twenty-four laboratories from 17 countries (13 European, one African, one Asian, two American countries) participated in the study. Thirteen laboratories (54%) reported correct results, 4 (17%) laboratories reported 1 to 2 false-negative results, and 7 (29%) laboratories reported 3 to 5 false-negative results. This EQA study indicates that most participating laboratories have a good or acceptable performance in molecular detection of LASV. However, several laboratories need to review and improve their diagnostic procedures.
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role of the c terminus of Lassa Virus l protein in viral mrna synthesis
Journal of Virology, 2014Co-Authors: Maria Lehmann, Michaela Lelke, Carola Busch, Meike Pahlmann, Hanna Jerome, Stephan GüntherAbstract:The N terminus of arenaVirus L protein contains an endonuclease presumably involved in "cap snatching." Here, we employed the Lassa Virus replicon system to map other L protein sites that might be involved in this mechanism. Residues Phe-1979, Arg-2018, Phe-2071, Asp-2106, Trp-2173, Tyr-2179, Arg-2200, and Arg-2204 were important for viral mRNA synthesis but dispensable for genome replication. Thus, the C terminus of L protein is involved in the mRNA synthesis process, potentially by mediating cap binding.
Jan Ter Meulen - One of the best experts on this subject based on the ideXlab platform.
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Characterization of Lassa Virus cell entry and neutralization with Lassa Virus pseudoparticles.
Journal of Virology, 2009Co-Authors: François-loic Cosset, Philippe Marianneau, Noel Tordo, Vincent Deubel, Jan Ter Meulen, Geraldine Verney, Fabrice Gallais, Eve-isabelle Pécheur, Birke BartoschAbstract:The cell entry and humoral immune response of the human pathogen Lassa Virus (LV), a biosafety level 4 (BSL4) Old World arenaVirus, are not well characterized. LV pseudoparticles (LVpp) are a surrogate model system that has been used to decipher factors and routes involved in LV cell entry under BSL2 conditions. Here, we describe LVpp, which are highly infectious, with titers approaching those obtained with pseudoparticles displaying G protein of vesicular stomatitis Virus and their the use for the characterization of LV cell entry and neutralization. Upon cell attachment, LVpp utilize endocytic vesicles for cell entry as described for many pH-dependent Viruses. However, the fusion of the LV glycoproteins is activated at unusually low pH values, with optimal fusion occurring between pH 4.5 and 3, a pH range at which fusion characteristics of viral glycoproteins have so far remained largely unexplored. Consistent with a shifted pH optimum for fusion activation, we found wild-type LV and LVpp to display a remarkable resistance to exposure to low pH. Finally, LVpp allow the fast and quantifiable detection of neutralizing antibodies in human and animal sera and will thus facilitate the study of the humoral immune response in LV infections.
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reproductive characteristics of mastomys natalensis and Lassa Virus prevalence in guinea west africa
Vector-borne and Zoonotic Diseases, 2008Co-Authors: Elisabeth Fichetcalvet, Emilie Lecompte, Stephane Daffis, Lamine Koivogui, Jan Ter MeulenAbstract:We recently reported increased prevalence of Lassa Virus (LASV) infection in Mastomys natalensis during the rainy season in Guinea, West Africa. Here, the association of LASV prevalence with fecundity, fertility, and the age structure of the rodent population was analyzed using data from the previous study. The animals reproduced throughout the year, but highest fecundity was observed during the rainy season. Accordingly, the rodent population was aged at the beginning and young at the end of the rainy season. Lassa Virus infection was observed in all age groups, including the very young, which is compatible with vertical transmission. However, since the prevalence of infection showed a trend with increasing age in the younger age groups, horizontal transmission by yet unknown mechanisms may also play a role in LASV transmission. Multivariate analysis did not show an association of LASV prevalence with any demographic variable studied. Rodent behavior influencing Virus transmissibility and contaminated environment may therefore be responsible for spatial and seasonal variations in LASV prevalence in M. natalensis.
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rt pcr assay for detection of Lassa Virus and related old world arenaViruses targeting the l gene
Transactions of The Royal Society of Tropical Medicine and Hygiene, 2007Co-Authors: Simon Vieth, Stuart T. Nichol, Oliver Lenz, Jan Ter Meulen, Beate Beckerziaja, Christian Drosten, Meike Hass, Martin J Vincent, S A Omilabu, Herbert SchmitzAbstract:This study describes an RT-PCR assay targeting the L RNA segment of arenaViruses. Conserved regions were identified in the polymerase domain of the L gene on the basis of published sequences for Lassa Virus, lymphocytic choriomeningitis Virus (LCMV), Pichinde Virus and Tacaribe Virus, as well as 15 novel sequences for Lassa Virus, LCMV, Ippy Virus, Mobala Virus and Mopeia Virus determined in this study. Using these regions as target sites, a PCR assay for detection of all known Old World arenaViruses was developed and optimized. The concentration that yields 95% positive results in a set of replicate tests (95% detection limit) was determined to be 4290 copies of Lassa Virus L RNA per ml of serum, corresponding to 30 copies per reaction. The ability of the assay to detect various Old World arenaViruses was demonstrated with in vitro transcribed RNA, material from infected cell cultures and samples from patients with Lassa fever and monkeys with LCMV-associated callitrichid hepatitis. The L gene PCR assay may be applicable: (i) as a complementary diagnostic test for Lassa Virus and LCMV; (ii) to identify unknown Old World arenaViruses suspected as aetiological agents of disease; and (iii) for screening of potential reservoir hosts for unknown Old World arenaViruses.
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fluctuation of abundance and Lassa Virus prevalence in mastomys natalensis in guinea west africa
Vector-borne and Zoonotic Diseases, 2007Co-Authors: Elisabeth Fichetcalvet, Emilie Lecompte, Stephane Daffis, Lamine Koivogui, Fode Kourouma, Barre Soropogui, Amadou Dore, Oumar Sylla, Kekoura Koulemou, Jan Ter MeulenAbstract:Based on empiric surveillance data, the incidence of human Lassa fever (LF) cases in Guinea and other West African countries has been reported to increase during the dry season compared to the rainy season. To investigate possible links with the ecology of the rodent reservoir of the Virus, we conducted a 2-year longitudinal survey of Mastomys natalensis in a region of high human Lassa Virus (LASV) seropositivity in Guinea. Standardized rodent trapping with similar trapping efforts between seasons was performed in three villages and 53.5% (601/1123) of the animals were identified as M. natalensis using morphometric and molecular criteria. Mean trapping success (TS) of M. natalensis was always higher inside houses than in proximal cultivations. In the dry season, mean TS increased 2-fold inside houses and decreased up to 10-fold outside (p < 0.0001), suggesting aggregation of rodents inside houses due to restricted food supply. 14.5% (80/553) of M. natalensis were tested positive for Lassa Virus by reverse transcription-polymerase chain reaction (RT-PCR; range, 5%-30%) and prevalence of the Virus was two to three times higher in rodents captured in the rainy season than in the dry season (p < 0.05). Inside houses, however, the LASV prevalence fluctuated nonsignificantly with season. These data suggest that in Guinea the risk of LASV transmission from rodents to humans is present both in the rainy and the dry season, reflected by the occurrence of LF cases throughout the year. In the dry season, however, the increased risk of humans encountering Mastomys and their excreta inside of houses may result in an increase of human Lassa fever cases.
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characterization of the Lassa Virus matrix protein z electron microscopic study of Virus like particles and interaction with the nucleoprotein np
Virus Research, 2004Co-Authors: Robert Eichler, Thomas Strecker, Oliver Lenz, Hans-dieter Klenk, Wolfgang Garten, Jan Ter Meulen, Winfried Weissenhorn, Larissa Kolesnikova, Stephan BeckerAbstract:Lassa Virus is the causative agent of a hemorrhagic fever endemic in west Africa. The RNA genome of Lassa Virus encodes the glycoprotein precursor GP-C, a nucleoprotein (NP), the viral polymerase L and a small protein Z (11 kDa). Here, we analyze the role of Z protein for Virus maturation. We have recently shown that expression of Z protein in the absence of other viral proteins is sufficient for the release of enveloped Z-containing particles. In this study, we examined particles secreted into the supernatant of a stably Z protein-expressing CHO cell line by electron microscopy. The observed Z-induced Virus-like particles did not significantly differ in their morphology and size from Lassa Virus particles. Mutation of two proline-rich domains within Z which are known to drastically reduce the release of Virus-like particles, had no effect on the cellular localization of the protein nor on its membrane-association. Furthermore, we present evidence that Z interacts with the NP. We assume that Z recruits NP to cellular membranes where Virus assembly takes place. We conclude from our data that Lassa Virus Z protein plays an essential role in Lassa Virus maturation.
Connie S Schmaljohn - One of the best experts on this subject based on the ideXlab platform.
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immune mediated systemic vasculitis as the proposed cause of sudden onset sensorineural hearing loss following Lassa Virus exposure in cynomolgus macaques
Mbio, 2018Co-Authors: Kathleen A Cashman, Eric R Wilkinson, Xiankun Zeng, Anthony P Cardile, Paul Facemire, Todd M Bell, Jeremy J Bearss, Carl I Shaia, Connie S SchmaljohnAbstract:ABSTRACT 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 primates (NHPs) developed typical signs and symptoms of Lassa fever, and seven succumbed during the acute phase of disease. Three NHPs survived beyond the acute phase and became chronically ill but survived to the study endpoint, 45 days postexposure. All three of these survivors displayed continuous disease symptoms, and apparent hearing loss was observed using daily subjective measurements, including response to auditory stimulation and tuning fork tests. Objective measurements of profound unilateral or bilateral sensorineural hearing loss were confirmed for two of the survivors by brainstem auditory evoked response (BAER) analysis. Histologic examination of inner ear structures and other tissues revealed the presence of severe vascular lesions consistent with systemic vasculitides. These systemic immune-mediated vascular disorders have been associated with sudden hearing loss. Other vascular-specific damage was also observed to be present in many of the sampled tissues, and we were able to identify persistent Virus in the perivascular tissues in the brain tissue of survivors. Serological analyses of two of the three survivors revealed the presence of autoimmune disease markers. Our findings point toward an immune-mediated etiology for Lassa fever-associated sudden-onset hearing loss and lay the foundation for developing potential therapies to prevent and/or cure Lassa fever-associated sudden-onset hearing loss. IMPORTANCE Lassa Virus is one of the most common causes of viral hemorrhagic fever. A frequent, but as yet unexplained, consequence of infection with Lassa Virus is acute, sudden-onset sensorineural hearing loss in one or both ears. Deafness is observed in approximately 30% of surviving Lassa fever patients, an attack rate that is approximately 300% higher than mumps Virus infection, which was previously thought to be the most common cause of Virus-induced deafness. Here, we provide evidence from Lassa Virus-infected cynomolgus macaques implicating an immune-mediated vasculitis syndrome underlying the pathology of Lassa fever-associated deafness. These findings could change the way human Lassa fever patients are medically managed in order to prevent deafness by including diagnostic monitoring of human survivors for onset of vasculitides via available imaging methods and/or other diagnostic markers of immune-mediated vascular disease.
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Immune-Mediated Systemic Vasculitis as the Proposed Cause of Sudden-Onset Sensorineural Hearing Loss following Lassa Virus Exposure in Cynomolgus Macaques
'American Society for Microbiology', 2018Co-Authors: Kathleen A Cashman, Eric R Wilkinson, Xiankun Zeng, Anthony P Cardile, Paul Facemire, Todd M Bell, Jeremy J Bearss, Carl I Shaia, Connie S SchmaljohnAbstract:Lassa Virus is one of the most common causes of viral hemorrhagic fever. A frequent, but as yet unexplained, consequence of infection with Lassa Virus is acute, sudden-onset sensorineural hearing loss in one or both ears. Deafness is observed in approximately 30% of surviving Lassa fever patients, an attack rate that is approximately 300% higher than mumps Virus infection, which was previously thought to be the most common cause of Virus-induced deafness. Here, we provide evidence from Lassa Virus-infected cynomolgus macaques implicating an immune-mediated vasculitis syndrome underlying the pathology of Lassa fever-associated deafness. These findings could change the way human Lassa fever patients are medically managed in order to prevent deafness by including diagnostic monitoring of human survivors for onset of vasculitides via available imaging methods and/or other diagnostic markers of immune-mediated vascular disease.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 primates (NHPs) developed typical signs and symptoms of Lassa fever, and seven succumbed during the acute phase of disease. Three NHPs survived beyond the acute phase and became chronically ill but survived to the study endpoint, 45 days postexposure. All three of these survivors displayed continuous disease symptoms, and apparent hearing loss was observed using daily subjective measurements, including response to auditory stimulation and tuning fork tests. Objective measurements of profound unilateral or bilateral sensorineural hearing loss were confirmed for two of the survivors by brainstem auditory evoked response (BAER) analysis. Histologic examination of inner ear structures and other tissues revealed the presence of severe vascular lesions consistent with systemic vasculitides. These systemic immune-mediated vascular disorders have been associated with sudden hearing loss. Other vascular-specific damage was also observed to be present in many of the sampled tissues, and we were able to identify persistent Virus in the perivascular tissues in the brain tissue of survivors. Serological analyses of two of the three survivors revealed the presence of autoimmune disease markers. Our findings point toward an immune-mediated etiology for Lassa fever-associated sudden-onset hearing loss and lay the foundation for developing potential therapies to prevent and/or cure Lassa fever-associated sudden-onset hearing loss
David Safronetz - One of the best experts on this subject based on the ideXlab platform.
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immunobiology of ebola and Lassa Virus infections
Nature Reviews Immunology, 2017Co-Authors: Joseph Prescott, Heinz Feldmann, David Safronetz, Andrea Marzi, Shelly J Robertson, Sonja M BestAbstract: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 infection often results in a severe haemorrhagic fever in both cases. However, the contribution of specific immune responses to disease differs between EBOV and LASV. This Review examines innate and adaptive immune responses to these Viruses with the goal of delineating responses that are associated with protective versus pathogenic outcomes.
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annual incidence of Lassa Virus infection in southern mali
American Journal of Tropical Medicine and Hygiene, 2017Co-Authors: Kyle Rosenke, Robert F Garry, David Safronetz, Nafomon Sogoba, Sory Ibrahim Diawara, Sidy Bane, Ousmane Maiga, Matthew L Boisen, Luis M BrancoAbstract:AbstractPreviously, 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 frequently seen in preteenage children (12/23, 51.7%) and two household/familial clusters were identified. These results confirm active transmission of Lassa Virus is occurring in southern Mali and appropriate diagnostic testing should be established for this etiological agent of severe viral hemorrhagic fever.
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a recently isolated Lassa Virus from mali demonstrates atypical clinical disease manifestations and decreased virulence in cynomolgus macaques
The Journal of Infectious Diseases, 2013Co-Authors: David Safronetz, Nafomon Sogoba, James E Strong, Friederike Feldmann, Elaine Haddock, Douglas Brining, Thomas W Geisbert, Dana P Scott, Heinz FeldmannAbstract:The virulence of Soromba-R, a Lassa Virus strain recently isolated from southern Mali, was assessed in 2 animal models of Lassa fever: inbred strain 13 guinea pigs and cynomolgus macaques. In both models, the Malian isolate demonstrated tissue tropism and viral titers similar to those of historical Lassa Virus isolates from Sierra Leone (Josiah) and Liberia (Z-132); however, the Soromba-R isolate was found to be less pathogenic, as determined by decreased mortality and prolonged time to euthanasia in macaques. Interestingly, in addition to the classic indicators of Lassa fever, Soromba-R infection presented with moderate to severe pulmonary manifestations in the macaque model. Analysis of host responses demonstrated increased immune activation in Soromba-R–infected macaques, particularly in neutrophil-activating or -potentiating proinflammatory cytokines or growth factors, including tumor necrosis factor α, macrophage inflammatory protein 1α, interleukin 1β, and granulocyte colony-stimulating factor, as well as interleukin 5, which may be responsible for the decreased lethality and uncharacteristic clinical presentation. These results suggest that the strain of Lassa Virus circulating in Mali might be less pathogenic than strains circulating in the historical region of endemicity and may result in an atypical presentation for Lassa fever, which could complicate clinical diagnosis.
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detection of Lassa Virus mali
Emerging Infectious Diseases, 2010Co-Authors: David Safronetz, Hideki Ebihara, Robert F Garry, Luis M Branco, Job E Lopez, Nafomon Sogoba, Sekou F Traore, Sandra J Raffel, Elizabeth R Fischer, Tom G SchwanAbstract:To determine whether Lassa Virus was circulating in southern Mali, we tested samples from small mammals from 3 villages, including Soromba, where in 2009 a British citizen probably contracted a lethal Lassa Virus infection. We report the isolation and genetic characterization of Lassa Virus from an area previously unknown for Lassa fever.
Thomas Strecker - One of the best experts on this subject based on the ideXlab platform.
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Structure of the Lassa Virus glycan shield provides a model for immunological resistance.
Proceedings of the National Academy of Sciences of the United States of America, 2018Co-Authors: Yasunori Watanabe, Felipe Moser, Juha T. Huiskonen, Jayna Raghwani, Gemma E. Seabright, Joel D. Allen, Thomas Strecker, Sai Li, Thomas A. Bowden, Max CrispinAbstract:Lassa Virus is an Old World arenaVirus endemic to West Africa that causes severe hemorrhagic fever. Vaccine development has focused on the envelope glycoprotein complex (GPC) that extends from the virion envelope. The often inadequate antibody immune response elicited by both vaccine and natural infection has been, in part, attributed to the abundance of N-linked glycosylation on the GPC. Here, using a Virus-like−particle system that presents Lassa Virus GPC in a native-like context, we determine the composite population of each of the N-linked glycosylation sites presented on the trimeric GPC spike. Our analysis reveals the presence of underprocessed oligomannose-type glycans, which form punctuated clusters that obscure the proteinous surface of both the GP1 attachment and GP2 fusion glycoprotein subunits of the Lassa Virus GPC. These oligomannose clusters are seemingly derived as a result of sterically reduced accessibility to glycan processing enzymes, and limited amino acid diversification around these sites supports their role protecting against the humoral immune response. Combined, our data provide a structure-based blueprint for understanding how glycans render the glycoprotein spikes of Lassa Virus and other Old World arenaViruses immunologically resistant targets.
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new lineage of Lassa Virus togo 2016
Emerging Infectious Diseases, 2018Co-Authors: Shannon Whitmer, Thomas Strecker, Daniel Cadar, H P Dienes, Kelly Faber, Ketan Patel, Shelley M Brown, William G Davis, John D Klena, Pierre E RollinAbstract:We describe a strain of Lassa Virus representing a putative new lineage that was isolated from a cluster of human infections with an epidemiologic link to Togo. This finding extends the known range of Lassa Virus to Togo.
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genome sequence of Lassa Virus isolated from the first domestically acquired case in germany
Genome Announcements, 2016Co-Authors: Svenja Wolff, Markus Eickmann, Stephan Becker, Sarah Katharina Fehling, Tilman Schultze, Jan Philipp Mengel, Gerrit Kann, Timo Wolf, Torsten Hain, Thomas StreckerAbstract:ABSTRACT 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.
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Acidic pH-Induced Conformations and LAMP1 Binding of the Lassa Virus Glycoprotein Spike
PLoS pathogens, 2016Co-Authors: Z. Sun, Thomas A. Bowden, Wolfgang Garten, R. Pryce, Marie-laure Parsy, Sarah Katharina Fehling, Katrin Schlie, C. Alistair Siebert, Thomas StreckerAbstract:Lassa Virus is an enveloped, bi-segmented RNA Virus and the most prevalent and fatal of all Old World arenaViruses. Virus entry into the host cell is mediated by a tripartite surface spike complex, which is composed of two viral glycoprotein subunits, GP1 and GP2, and the stable signal peptide. Of these, GP1 binds to cellular receptors and GP2 catalyzes fusion between the viral envelope and the host cell membrane during endocytosis. The molecular structure of the spike and conformational rearrangements induced by low pH, prior to fusion, remain poorly understood. Here, we analyzed the three-dimensional ultrastructure of Lassa Virus using electron cryotomography. Sub-tomogram averaging yielded a structure of the glycoprotein spike at 14-A resolution. The spikes are trimeric, cover the virion envelope, and connect to the underlying matrix. Structural changes to the spike, following acidification, support a viral entry mechanism dependent on binding to the lysosome-resident receptor LAMP1 and further dissociation of the membrane-distal GP1 subunits.
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characterization of the Lassa Virus matrix protein z electron microscopic study of Virus like particles and interaction with the nucleoprotein np
Virus Research, 2004Co-Authors: Robert Eichler, Thomas Strecker, Oliver Lenz, Hans-dieter Klenk, Wolfgang Garten, Jan Ter Meulen, Winfried Weissenhorn, Larissa Kolesnikova, Stephan BeckerAbstract:Lassa Virus is the causative agent of a hemorrhagic fever endemic in west Africa. The RNA genome of Lassa Virus encodes the glycoprotein precursor GP-C, a nucleoprotein (NP), the viral polymerase L and a small protein Z (11 kDa). Here, we analyze the role of Z protein for Virus maturation. We have recently shown that expression of Z protein in the absence of other viral proteins is sufficient for the release of enveloped Z-containing particles. In this study, we examined particles secreted into the supernatant of a stably Z protein-expressing CHO cell line by electron microscopy. The observed Z-induced Virus-like particles did not significantly differ in their morphology and size from Lassa Virus particles. Mutation of two proline-rich domains within Z which are known to drastically reduce the release of Virus-like particles, had no effect on the cellular localization of the protein nor on its membrane-association. Furthermore, we present evidence that Z interacts with the NP. We assume that Z recruits NP to cellular membranes where Virus assembly takes place. We conclude from our data that Lassa Virus Z protein plays an essential role in Lassa Virus maturation.
