Envelope Protein Glycosylation Mediates Zika Virus Pathogenesis
| Autor: | Derek L. Carbaugh, Helen M. Lazear, Ralph S. Baric |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
Male
Glycosylation Immunology Virulence Receptors Cell Surface Biology Virus Replication Microbiology Zika virus Pathogenesis Mice 03 medical and health sciences chemistry.chemical_compound Cytopathogenic Effect Viral Viral Envelope Proteins Viral envelope Virology Chlorocebus aethiops Animals Humans Lectins C-Type Vero Cells 030304 developmental biology 0303 health sciences Zika Virus Infection 030306 microbiology Flavivirus Zika Virus biology.organism_classification Mice Inbred C57BL DC-SIGN chemistry A549 Cells Insect Science biology.protein Pathogenesis and Immunity Female Cell Adhesion Molecules Viral load |
| Zdroj: | Journal of Virology. 93 |
| ISSN: | 1098-5514 0022-538X |
| DOI: | 10.1128/jvi.00113-19 |
| Popis: | Zika virus (ZIKV) is an emerging mosquito-borne flavivirus. Recent ZIKV outbreaks have produced serious human disease, including neurodevelopmental malformations (congenital Zika syndrome) and Guillain-Barré syndrome. These outcomes were not associated with ZIKV infection prior to 2013, raising the possibility that viral genetic changes could contribute to new clinical manifestations. All contemporary ZIKV isolates encode an N-linked glycosylation site in the envelope (E) protein (N154), but this glycosylation site is absent in many historical ZIKV isolates. Here, we investigated the role of E protein glycosylation in ZIKV pathogenesis using two contemporary Asian-lineage strains (H/PF/2013 and PRVABC59) and the historical African-lineage strain (MR766). We found that glycosylated viruses were highly pathogenic in Ifnar1−/− mice. In contrast, nonglycosylated viruses were attenuated, producing lower viral loads in the serum and brain when inoculated subcutaneously but remaining neurovirulent when inoculated intracranially. These results suggest that E glycosylation is advantageous in the periphery but not within the brain. Accordingly, we found that glycosylation facilitated infection of cells expressing the lectins dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin (DC-SIGN) or DC-SIGN-related (DC-SIGNR), suggesting that inefficient infection of lectin-expressing leukocytes could contribute to the attenuation of nonglycosylated ZIKV in mice. IMPORTANCE It is unclear why the ability of Zika virus (ZIKV) to cause serious disease, including Guillain-Barré syndrome and birth defects, was not recognized until recent outbreaks. One contributing factor could be genetic differences between contemporary ZIKV strains and historical ZIKV strains. All isolates from recent outbreaks encode a viral envelope protein that is glycosylated, whereas many historical ZIKV strains lack this glycosylation. We generated nonglycosylated ZIKV mutants from contemporary and historical strains and evaluated their virulence in mice. We found that nonglycosylated viruses were attenuated and produced lower viral loads in serum and brains. Our studies suggest that envelope protein glycosylation contributes to ZIKV pathogenesis, possibly by facilitating attachment to and infection of lectin-expressing leukocytes. |
| Databáze: | OpenAIRE |
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