Lassa Fever Virus Binds Matriglycan—A Polymer of Alternating Xylose and Glucuronate—On α-Dystroglycan

Joseph, Soumya; Campbell, Kevin P.

doi:10.3390/v13091679

Cited by 10 publications

(8 citation statements)

References 61 publications

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“…Several host membrane proteins can serve as cell surface receptors or factors for LASV. Matriglycan on α-dystroglycan (α-DG) exhibits high binding affinity to LASV GPC and is considered as the major and most efficient cell surface receptor for viral entry (14)(15)(16)(17)(18)(19). After capture by surface receptors, the LASV virion is internalized into the endosome by endocytosis.…”

Section: Introductionmentioning

confidence: 99%

A cocktail of protective antibodies subverts the dense glycan shield of Lassa virus

Buck

Zandonatti

et al. 2022

Sci. Transl. Med.

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Developing potent therapeutics and effective vaccines are the ultimate goals in controlling infectious diseases. Lassa virus (LASV), the causative pathogen of Lassa fever (LF), infects hundreds of thousands annually, but effective antivirals or vaccines against LASV infection are still lacking. Furthermore, neutralizing antibodies against LASV are rare. Here, we describe biochemical analyses and high-resolution cryo-electron microscopy structures of a therapeutic cocktail of three broadly protective antibodies that target the LASV glycoprotein complex (GPC), previously identified from survivors of multiple LASV infections. Structural and mechanistic analyses reveal compatible neutralizing epitopes and complementary neutralization mechanisms that offer high potency, broad range, and resistance to escape. These antibodies either circumvent or exploit specific glycans comprising the extensive glycan shield of GPC. Further, they require mammalian glycosylation, native GPC cleavage, and proper GPC trimerization. These findings guided engineering of a next-generation GPC antigen suitable for future neutralizing antibody and vaccine discovery. Together, these results explain protective mechanisms of rare, broad, and potent antibodies and identify a strategy for the rational design of therapeutic modalities against LF and related infectious diseases.

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Section: Introductionmentioning

confidence: 99%

A cocktail of protective antibodies subverts the dense glycan shield of Lassa virus

Buck

Zandonatti

et al. 2022

Sci. Transl. Med.

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“…The absence or reduction of matriglycan can cause various forms of muscular dystrophy with or without abnormalities in brain development ( 7, 8 ). Additionally, matriglycan is a receptor for Lassa fever virus (LASV) and other Old-World mammarenaviruses ( 9, 10 ). Matriglycan polymer length appears to be cell-type specific and is physiologically regulated during development and regeneration ( 11 ) but can be pathologically decreased by the expression of LASV or the related lymphocytic choriomeningitis virus spike glycoproteins ( 12 ).…”

Section: Introductionmentioning

confidence: 99%

Structure and mechanism of LARGE1 matriglycan polymerase

Joseph

Schnicker

et al. 2022

Preprint

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Matriglycan is a linear polysaccharide of alternating xylose and glucuronate that binds extracellular matrix proteins and acts as a receptor for Lassa fever virus. LARGE1 synthesizes matriglycan on dystroglycan and mutations in LARGE1 cause muscular dystrophy with abnormal brain development. However, the mechanism of matriglycan polymerization by LARGE1 is unknown. Here, we report the cryo-EM structure of LARGE1. We show that LARGE1 functions as a dimer to polymerize matriglycan by alternating activities between the xylose transferase domain on one protomer and the glucuronate transferase domain on the other protomer. Biochemical analyses using a recombinant Golgi form of dystroglycan reveal that LARGE1 polymerizes matriglycan processively. Our results provide mechanistic insights into LARGE1 function and may facilitate novel therapeutic strategies for treating neuromuscular disorders or arenaviral infections.One-Sentence SummaryDimeric LARGE1 processively polymerizes matriglycan on dystroglycan using orthogonal active sites on alternate protomers.

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“…The primary cell surface receptor for LASV entry is matriglycan, an extended oligosaccharide located on a widely distributed peripheral membrane protein named α-dystroglycan (α-DG) 32 – 37 (Fig. 3 ).…”

Section: Structural Biology and Replication Cyclementioning

confidence: 99%

Lassa fever — the road ahead

Garry

2022

Nat Rev Microbiol

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Lassa virus (LASV) is endemic in the rodent populations of Sierra Leone, Nigeria and other countries in West Africa. Spillover to humans occurs frequently and results in Lassa fever, a viral haemorrhagic fever (VHF) associated with a high case fatality rate. Despite advances, fundamental gaps in knowledge of the immunology, epidemiology, ecology and pathogenesis of Lassa fever persist. More frequent outbreaks, the potential for further geographic expansion of Mastomys natalensis and other rodent reservoirs, the ease of procurement and possible use and weaponization of LASV, the frequent importation of LASV to North America and Europe, and the emergence of novel LASV strains in densely populated West Africa have driven new initiatives to develop countermeasures for LASV. Although promising candidates are being evaluated, as yet there are no approved vaccines or therapeutics for human use. This Review discusses the virology of LASV, the clinical course of Lassa fever and the progress towards developing medical countermeasures.

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Lassa Fever Virus Binds Matriglycan—A Polymer of Alternating Xylose and Glucuronate—On α-Dystroglycan

Cited by 10 publications

References 61 publications

A cocktail of protective antibodies subverts the dense glycan shield of Lassa virus

A cocktail of protective antibodies subverts the dense glycan shield of Lassa virus

Structure and mechanism of LARGE1 matriglycan polymerase

Lassa fever — the road ahead

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