Shortening of Zika virus CD-loop reduces neurovirulence while preserving antigenicity

Kenneth H. Dinnon, Emily N. Gallichotte, Ethan J. Fritch, Vineet Menachery, Ralph S. Baric

Research output: Contribution to journalArticle

Abstract

Zika virus (ZIKV) is a mosquito-borne positive sense RNA virus. Recently, ZIKV emerged into the Western hemisphere as a human health threat, with severe disease associated with developmental and neurological complications. The structural envelope protein of ZIKV and other neurotropic flaviviruses contains an extended CD-loop relative to non-neurotropic flaviviruses, and has been shown to augment ZIKV stability and pathogenesis. Here we show that shortening the CD-loop in ZIKV attenuates the virus in mice, by reducing the ability to invade and replicate in the central nervous system. The CD-loop mutation was genetically stable following infection in mice, though secondary site mutations arise adjacent to the CD-loop. Importantly, while shortening of the CD-loop attenuates the virus, the CD-loop mutant maintains antigenicity in immunocompetent mice, eliciting an antibody response that similarly neutralizes both the mutant and wildtype ZIKV. These findings suggest that the extended CD-loop in ZIKV is a determinant of neurotropism and may be a target in live-attenuated vaccine design, for not only ZIKV, but for other neurotropic flaviviruses.

Original languageEnglish (US)
Pages (from-to)e0007212
JournalPLoS neglected tropical diseases
Volume13
Issue number3
DOIs
StatePublished - Mar 1 2019

Fingerprint

Flavivirus
Viruses
Attenuated Vaccines
Mutation
Zika Virus
RNA Viruses
Culicidae
Antibody Formation
Central Nervous System
Health
Infection
Proteins

ASJC Scopus subject areas

  • Public Health, Environmental and Occupational Health
  • Infectious Diseases

Cite this

Shortening of Zika virus CD-loop reduces neurovirulence while preserving antigenicity. / Dinnon, Kenneth H.; Gallichotte, Emily N.; Fritch, Ethan J.; Menachery, Vineet; Baric, Ralph S.

In: PLoS neglected tropical diseases, Vol. 13, No. 3, 01.03.2019, p. e0007212.

Research output: Contribution to journalArticle

Dinnon, Kenneth H. ; Gallichotte, Emily N. ; Fritch, Ethan J. ; Menachery, Vineet ; Baric, Ralph S. / Shortening of Zika virus CD-loop reduces neurovirulence while preserving antigenicity. In: PLoS neglected tropical diseases. 2019 ; Vol. 13, No. 3. pp. e0007212.
@article{80035efa6d9f4286bd1dbb2d67fda57a,
title = "Shortening of Zika virus CD-loop reduces neurovirulence while preserving antigenicity",
abstract = "Zika virus (ZIKV) is a mosquito-borne positive sense RNA virus. Recently, ZIKV emerged into the Western hemisphere as a human health threat, with severe disease associated with developmental and neurological complications. The structural envelope protein of ZIKV and other neurotropic flaviviruses contains an extended CD-loop relative to non-neurotropic flaviviruses, and has been shown to augment ZIKV stability and pathogenesis. Here we show that shortening the CD-loop in ZIKV attenuates the virus in mice, by reducing the ability to invade and replicate in the central nervous system. The CD-loop mutation was genetically stable following infection in mice, though secondary site mutations arise adjacent to the CD-loop. Importantly, while shortening of the CD-loop attenuates the virus, the CD-loop mutant maintains antigenicity in immunocompetent mice, eliciting an antibody response that similarly neutralizes both the mutant and wildtype ZIKV. These findings suggest that the extended CD-loop in ZIKV is a determinant of neurotropism and may be a target in live-attenuated vaccine design, for not only ZIKV, but for other neurotropic flaviviruses.",
author = "Dinnon, {Kenneth H.} and Gallichotte, {Emily N.} and Fritch, {Ethan J.} and Vineet Menachery and Baric, {Ralph S.}",
year = "2019",
month = "3",
day = "1",
doi = "10.1371/journal.pntd.0007212",
language = "English (US)",
volume = "13",
pages = "e0007212",
journal = "PLoS Neglected Tropical Diseases",
issn = "1935-2727",
publisher = "Public Library of Science",
number = "3",

}

TY - JOUR

T1 - Shortening of Zika virus CD-loop reduces neurovirulence while preserving antigenicity

AU - Dinnon, Kenneth H.

AU - Gallichotte, Emily N.

AU - Fritch, Ethan J.

AU - Menachery, Vineet

AU - Baric, Ralph S.

PY - 2019/3/1

Y1 - 2019/3/1

N2 - Zika virus (ZIKV) is a mosquito-borne positive sense RNA virus. Recently, ZIKV emerged into the Western hemisphere as a human health threat, with severe disease associated with developmental and neurological complications. The structural envelope protein of ZIKV and other neurotropic flaviviruses contains an extended CD-loop relative to non-neurotropic flaviviruses, and has been shown to augment ZIKV stability and pathogenesis. Here we show that shortening the CD-loop in ZIKV attenuates the virus in mice, by reducing the ability to invade and replicate in the central nervous system. The CD-loop mutation was genetically stable following infection in mice, though secondary site mutations arise adjacent to the CD-loop. Importantly, while shortening of the CD-loop attenuates the virus, the CD-loop mutant maintains antigenicity in immunocompetent mice, eliciting an antibody response that similarly neutralizes both the mutant and wildtype ZIKV. These findings suggest that the extended CD-loop in ZIKV is a determinant of neurotropism and may be a target in live-attenuated vaccine design, for not only ZIKV, but for other neurotropic flaviviruses.

AB - Zika virus (ZIKV) is a mosquito-borne positive sense RNA virus. Recently, ZIKV emerged into the Western hemisphere as a human health threat, with severe disease associated with developmental and neurological complications. The structural envelope protein of ZIKV and other neurotropic flaviviruses contains an extended CD-loop relative to non-neurotropic flaviviruses, and has been shown to augment ZIKV stability and pathogenesis. Here we show that shortening the CD-loop in ZIKV attenuates the virus in mice, by reducing the ability to invade and replicate in the central nervous system. The CD-loop mutation was genetically stable following infection in mice, though secondary site mutations arise adjacent to the CD-loop. Importantly, while shortening of the CD-loop attenuates the virus, the CD-loop mutant maintains antigenicity in immunocompetent mice, eliciting an antibody response that similarly neutralizes both the mutant and wildtype ZIKV. These findings suggest that the extended CD-loop in ZIKV is a determinant of neurotropism and may be a target in live-attenuated vaccine design, for not only ZIKV, but for other neurotropic flaviviruses.

UR - http://www.scopus.com/inward/record.url?scp=85063255114&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85063255114&partnerID=8YFLogxK

U2 - 10.1371/journal.pntd.0007212

DO - 10.1371/journal.pntd.0007212

M3 - Article

VL - 13

SP - e0007212

JO - PLoS Neglected Tropical Diseases

JF - PLoS Neglected Tropical Diseases

SN - 1935-2727

IS - 3

ER -