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

Soumya Joseph,Kevin P Campbell

doi:10.3390/v13091679

Soumya Joseph, Kevin P Campbell

Open Access

https://doi.org/10.3390/v13091679

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Journal: Viruses	Publication Date: Aug 25, 2021
Citations: 9	License type: CC BY 4.0

Affiliation: Howard Hughes Medical Institute, University of Iowa

Abstract

Lassa fever virus (LASV) can cause life-threatening hemorrhagic fevers for which there are currently no vaccines or targeted treatments. The late Prof. Stefan Kunz, along with others, showed that the high-affinity host receptor for LASV, and other Old World and clade-C New World mammarenaviruses, is matriglycan—a linear repeating disaccharide of alternating xylose and glucuronic acid that is polymerized uniquely on α-dystroglycan by like-acetylglucosaminyltransferase-1 (LARGE1). Although α-dystroglycan is ubiquitously expressed, LASV preferentially infects vascular endothelia and professional phagocytic cells, which suggests that viral entry requires additional cell-specific factors. In this review, we highlight the work of Stefan Kunz detailing the molecular mechanism of LASV binding and discuss the requirements of receptors, such as tyrosine kinases, for internalization through apoptotic mimicry.

Highlights

The surfaces of host cells and pathogens are covered with glycoproteins
Unlike the calcium chelating mode in which LG domains bind matriglycan [4,51], GP1 from Lassa fever virus (LASV) and lymphocytic choriomeningitis virus (LCMV), which share ~50% sequence identity, likely bind matriglycan using a region formed at the central surface of the trimer
This deduction comes from the fact that the F260 [L/V/I] substitution in the LCMV GP1 increases the affinity for matriglycan by 2–2.5 orders of magnitude and promotes persistent infection in mice [3]

Summary

Introduction

The surfaces of host cells and pathogens are covered with glycoproteins. Glycans are well-known targets for virus binding and entry [1]. Kunz who showed the surface glycoprotein of Old World, including LASV, and New World clade-C mammarenaviruses, binds matriglycan [2,3,4,5]—a polysaccharide of alternating xylose and glucuronate—on the highly glycosylated mucin-like receptor, dystroglcyan on rodent and human hosts (Figure 1). Purified soluble α-dystroglycan blocked cell entry by acting as a decoy receptor These initial studies showed that bacterially expressed α-dystroglycan could not bind virus particles, suggesting that a mammalian-specific post-translational modification, perhaps glycosylation, was crucial to binding [2]. This formed the basis of Dr Kunz’ invaluable work on mammarenaviral cell entry.

LASV Binds Matriglycan and Is Internalized in Cells Co-Expressing Gas6-Axl

Hypothetical

Conclusions and Remarks