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Differential usage of carbohydrate co-receptors influences cellular tropism of Theiler's murine encephalomyelitis virus infection of the central nervous system

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Abstract

Theiler's murine encephalomyelitis viruses (TMEV) are ubiquitous pathogens of mice, producing either rapidly fatal encephalitis (high-neurovirulence strains) or persistent central nervous system infection and inflammatory demyelination (low-neurovirulence strains). Although a protein entry receptor has not yet been identified, carbohydrate co-receptors that effect docking and concentration of the virus on the cell surface are known for both TMEV neurovirulence groups. Low-neurovirulence TMEV use α2,3-linked N-acetylneuramic acid (sialic acid) on an N-linked glycoprotein, whereas high-neurovirulence TMEV use the proteoglycan heparan sulfate (HS) as a co-receptor. While the binding of low-neurovirulence TMEV to sialic acid can be inhibited completely, only a third of the binding of high-neurovirulence TMEV to HS is inhibitable, suggesting that high-neurovirulence strains use another co-receptor or bind directly to the putative protein entry receptor. Four amino acids on the surface (VP2 puff B) of low-neurovirulence strains make contact with sialic acid through non-covalent hydrogen bonds. Since these virus residues are conserved in all TMEV strains, the capsid conformation of this region is probably responsible for sialic acid binding. A persistence determinant that maps within the virus coat using recombinant TMEV is also conformational in nature. Low-neurovirulence virus variants that do not bind to sialic acid fail to persist in the central nervous system of mice, indicating a role for sialic acid binding in TMEV persistence. Analysis of high-neurovirulence variants that do not bind HS demonstrates that HS co-receptor usage influences neuronal tropism in brain, whereas, the HS co-receptor use is not required for the infection of spinal cord anterior horn cells associated with poliomyelitis.

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Abbreviations

BeAn virus:

low-neurovirulence TMEV strain

BHK-21:

baby hamster kidney fibroblast cells

CNS:

central nervous system

CHO:

Chinese hamster ovary cells

CSA:

chondroitin sulfate A

DA virus:

low-neurovirulence TMEV strain

DS:

dermatan stulfate

EMCV:

encephalomyocarditis virus (related Cardiovirus)

GAG:

glycosaminoglycan

GDVII virus:

high-neuroviruclence TMEV strain

HS:

heparan sulfate

KS:

keratin sulfate

Mengo virus:

related Cardiovirus

PG:

proteoglycan

PNGase:

N linked-specific endoglycosidase

TMEV:

Theiler's murine encephalomyelitis virus

UGT:

UDP-galactose transporter

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Authors and Affiliations

  1. Department of Neurology and Microbiology-Immunology, University of Illinois at Chicago, Chicago, IL, 60612-7344

    Howard L. Lipton, A. S. Manoj Kumar, Shannon Hertzler & Honey V. Reddi

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Lipton, H.L., Kumar, A.S.M., Hertzler, S. et al. Differential usage of carbohydrate co-receptors influences cellular tropism of Theiler's murine encephalomyelitis virus infection of the central nervous system. Glycoconj J 23, 39–49 (2006). https://doi.org/10.1007/s10719-006-5436-x

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