A Single Amino Acid Substitution in the Core Protein of West Nile Virus Increases Resistance to Acidotropic Compounds

Miguel A. Martín-Acebes, Ana Belén Blázquez, Nereida Jiménez de Oya, Estela Escribano-Romero, Pei-Yong Shi, Juan Carlos Saiz

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

West Nile virus (WNV) is a worldwide distributed mosquito-borne flavivirus that naturally cycles between birds and mosquitoes, although it can infect multiple vertebrate hosts including horses and humans. This virus is responsible for recurrent epidemics of febrile illness and encephalitis, and has recently become a global concern. WNV requires to transit through intracellular acidic compartments at two different steps to complete its infectious cycle. These include fusion between the viral envelope and the membrane of endosomes during viral entry, and virus maturation in the trans-Golgi network. In this study, we followed a genetic approach to study the connections between viral components and acidic pH. A WNV mutant with increased resistance to the acidotropic compound NH4Cl, which blocks organelle acidification and inhibits WNV infection, was selected. Nucleotide sequencing revealed that this mutant displayed a single amino acid substitution (Lys 3 to Glu) on the highly basic internal capsid or core (C) protein. The functional role of this replacement was confirmed by its introduction into a WNV infectious clone. This single amino acid substitution also increased resistance to other acidification inhibitor (concanamycin A) and induced a reduction of the neurovirulence in mice. Interestingly, a naturally occurring accompanying mutation found on prM protein abolished the resistant phenotype, supporting the idea of a genetic crosstalk between the internal C protein and the external glycoproteins of the virion. The findings here reported unveil a non-previously assessed connection between the C viral protein and the acidic pH necessary for entry and proper exit of flaviviruses.

Original languageEnglish (US)
Article numbere69479
JournalPLoS One
Volume8
Issue number7
DOIs
StatePublished - Jul 18 2013
Externally publishedYes

Fingerprint

West Nile virus
amino acid substitution
Amino Acid Substitution
Viruses
Substitution reactions
Amino Acids
Flavivirus
Protein C
Proteins
Culicidae
proteins
acidification
Acidification
Flaviviridae
trans-Golgi Network
Virus Internalization
Viral Structures
viruses
mutants
endosomes

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Martín-Acebes, M. A., Blázquez, A. B., de Oya, N. J., Escribano-Romero, E., Shi, P-Y., & Saiz, J. C. (2013). A Single Amino Acid Substitution in the Core Protein of West Nile Virus Increases Resistance to Acidotropic Compounds. PLoS One, 8(7), [e69479]. https://doi.org/10.1371/journal.pone.0069479

A Single Amino Acid Substitution in the Core Protein of West Nile Virus Increases Resistance to Acidotropic Compounds. / Martín-Acebes, Miguel A.; Blázquez, Ana Belén; de Oya, Nereida Jiménez; Escribano-Romero, Estela; Shi, Pei-Yong; Saiz, Juan Carlos.

In: PLoS One, Vol. 8, No. 7, e69479, 18.07.2013.

Research output: Contribution to journalArticle

Martín-Acebes, Miguel A. ; Blázquez, Ana Belén ; de Oya, Nereida Jiménez ; Escribano-Romero, Estela ; Shi, Pei-Yong ; Saiz, Juan Carlos. / A Single Amino Acid Substitution in the Core Protein of West Nile Virus Increases Resistance to Acidotropic Compounds. In: PLoS One. 2013 ; Vol. 8, No. 7.
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