Structural basis for antibody-mediated neutralization of Lassa virus

Hastie, Kathryn M.; Zandonatti, Michelle; Kleinfelter, Lara M.; Heinrich, Megan L.; Rowland, Megan M.; Chandran, Kartik; Branco, Luis M.; Robinson, James E.; Garry, Robert F.; Saphire, Erica Ollmann

doi:10.1126/science.aam7260

Cited by 175 publications

(346 citation statements)

References 67 publications

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“…With the overarching goal of understanding the functional and spatial organization of the arenavirus prefusion glycoprotein structure, we utilized the trimeric GP prefusion crystal structure (32) to identify residues involved in receptor interactions.…”

Section: Resultsmentioning

confidence: 99%

“…(B) Cartoon of the SSP, GP1, and GP2 heterotrimer complex in the lipid bilayer. (C) Trimeric LASV GP1-GP2 crystal structure, viewed from the top down; GP1 is in purple and GP2 in green (PDB 5vk2) (32). (D) LASV GP1-GP2 crystal structure, side view (PDB 5vk2).…”

Section: Resultsmentioning

confidence: 99%

“…3). All glycosylation sites were predicted to be present on the surface of the GP1 model, although H141N, N148S, V187T, and Y253N had potential to impede trimer formation based on the new trimeric structure (32). The mutants were evaluated for the incorporation of the glycan, as well as processing with surface biotinylation assays (Fig.…”

Section: Figmentioning

confidence: 99%

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Mutational Analysis of Lassa Virus Glycoprotein Highlights Regions Required for Alpha-Dystroglycan Utilization

Acciani

Alston

Zhao

et al. 2017

J Virol

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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 (␣DG) and lysosome-associated membrane protein 1 (LAMP1). In order to define the regions within GP1 that interact with the cellular receptors, we implemented insertional mutagenesis, carbohydrate shielding, and alanine scanning mutagenesis. Eighty GP constructs were engineered and evaluated for GP1-GP2 processing, surface expression, and the ability to mediate cell-to-cell fusion after low-pH exposure. To examine virus-to-cell entry, 49 constructs were incorporated onto vesicular stomatitis virus (VSV) pseudoparticles and transduction efficiencies were monitored in HAP1 and HAP1-ΔDAG1 cells that differentially produce the ␣DG cell surface receptor. Seven constructs retained efficient transduction in HAP1-ΔDAG1 cells yet poorly transduced HAP1 cells, suggesting that they are involved in ␣DG utilization. Residues H141, N146, F147, and Y150 cluster at the predicted central core of the trimeric interface and are important for GP-␣DG interaction. Additionally, H92A-H93A, 150HA, 172HA, and 230HA displayed reduced transduction in both HAP1 and HAP1-ΔDAG1 cells, despite efficient cell-to-cell fusion activity. These mutations may interfere with interactions with the endosomal receptor LAMP1 or interfere at another stage in entry that is common to both cell lines. Insight gained from these data can aid in the development of more-effective entry inhibitors by blocking receptor interactions.IMPORTANCE Countries in which Lassa virus is endemic, such as Nigeria, Sierra Leone, Guinea, and Liberia, usually experience a seasonal outbreak of the virus from December to March. Currently, there is neither a preventative vaccine nor a therapeutic available to effectively treat severe Lassa fever. One way to thwart virus infection is to inhibit interaction with cellular receptors. It is known that the GP1 subunit of the Lassa glycoprotein complex plays a critical role in receptor recognition. Our results highlight a region within the Lassa virus GP1 protein that interacts with the cellular receptor alpha-dystroglycan. This information may be used for future development of new Lassa virus antivirals.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Mutational Analysis of Lassa Virus Glycoprotein Highlights Regions Required for Alpha-Dystroglycan Utilization

Acciani

Alston

Zhao

et al. 2017

J Virol

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“…These studies have revealed the higher order assembly of the GP spikes, with each spike consisting of three protomers of GP1-GP2 heterodimers organized into a tripartite complex, distributed randomly over the whole virion surface. The improvement in resolution of the spike complex from 32 Å (UHV) to 14 Å (LASV) has allowed the fitting of a crystal structure of the LASV (GP1-GP2) 3 trimeric ectodomain (Hastie et al, 2017). The resulting model places the GP1 receptor-binding glycoproteins to the membrane-distal region of the spike complex, where they sit atop the GP2 class I fusion glycoproteins that protrude from the virion membrane.…”

Section: Inherently Pleomorphic Virions and Their Glycoproteinsmentioning

confidence: 99%

Structures of enveloped virions determined by cryogenic electron microscopy and tomography

Stass

Kim

et al. 2019

Advances in Virus Research

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Enveloped viruses enclose their genomes inside a lipid bilayer which is decorated by membrane proteins that mediate virus entry. These viruses display a wide range of sizes, morphologies and symmetries. Spherical viruses are often isometric and their envelope proteins follow icosahedral symmetry. Filamentous and pleomorphic viruses lack such global symmetry but their surface proteins may display locally ordered assemblies. † These authors contributed equally.

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“…As the only antigen displayed on the viral surface, GP has https://doi.org/10.1016/j.imlet.2019.03.008 Received 27 January 2019; Received in revised form 14 March 2019; Accepted 17 March 2019 been the focus of recent LASV antiviral and vaccine research. Structural analyses of GP indicate that it is a primary target for neutralising antibody binding [17,18]. However, the role of NP-specific T cells in controlling acute infection and mediating heterosubtypic immunity in animal models and Lassa fever patients, offers some justification for the inclusion of NP in LASV vaccines [19][20][21].…”

Section: Introductionmentioning

confidence: 99%

Vaccine platforms for the prevention of Lassa fever

2019

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A B S T R A C TLassa 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 unprecedented mortality. Consequently, the World Health Organization (WHO) has listed LASV as a high priority pathogen for the development of treatments and prophylactics. Currently, there are no licensed vaccines to protect against LASV infection. Although numerous candidates have demonstrated efficacy in animal models, to date, only a single candidate has advanced to clinical trials. Lassa fever vaccine development efforts have been hindered by the high cost of biocontainment requirements, the absence of established correlates of protection, and uncertainty regarding the extent to which animal models are predictive of vaccine efficacy in humans. This review briefly discusses the epidemiology and biology of LASV infection and highlights recent progress in vaccine development.

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Structural basis for antibody-mediated neutralization of Lassa virus

Cited by 175 publications

References 67 publications

Mutational Analysis of Lassa Virus Glycoprotein Highlights Regions Required for Alpha-Dystroglycan Utilization

Mutational Analysis of Lassa Virus Glycoprotein Highlights Regions Required for Alpha-Dystroglycan Utilization

Structures of enveloped virions determined by cryogenic electron microscopy and tomography

Vaccine platforms for the prevention of Lassa fever

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