A single amino acid substitution in the core protein of West Nile virus increases resistance to acidotropic compounds.
Authors: Martín-Acebes Miguel A, Blázquez Ana-Belén, de Oya Nereida Jiménez, Escribano-Romero Estela, Shi Pei-Yong, Saiz Juan-Carlos
Journal: PloS one
Summary
# West Nile Virus Acidification Resistance: Implications for Understanding Viral Replication and Potential Therapeutic Targets West Nile virus requires passage through acidic intracellular compartments twice during its replication cycle—once during viral entry via endosomal fusion and again during maturation in the trans-Golgi network—making pH management a critical vulnerability in the viral lifecycle. Using a genetic selection approach with acidotropic compounds (NH₄Cl and concanamycin A) that inhibit organellar acidification, researchers identified a WNV mutant displaying a single amino acid substitution in the core (C) protein (lysine-3 to glutamate), which conferred resistance to these inhibitors and reduced neurovirulence in mice models. Notably, a naturally occurring accompanying mutation in the prM protein could abolish this resistant phenotype, indicating functional crosstalk between the internal capsid protein and the external viral glycoproteins. These findings establish the core protein as a previously unrecognised player in flavivirus pH-dependence, opening new avenues for understanding how viral architecture orchestrates the pH-dependent entry and maturation processes essential for infection. For equine practitioners managing WNV cases, this work may eventually inform development of antivirals targeting viral replication mechanisms, though further investigation into how these molecular adaptations affect natural infection in horses would strengthen clinical applicability.
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Practical Takeaways
- •This research identifies a specific viral genetic mechanism affecting WNV pathogenicity that may inform future antiviral drug development targeting intracellular pH regulation
- •The reduced neurovirulence associated with this mutation suggests potential applications in understanding WNV neurological complications in infected horses and humans
- •Understanding viral protein interactions and pH-dependence may lead to therapeutic strategies for preventing WNV infection during epidemic cycles
Key Findings
- •A single amino acid substitution (Lys 3 to Glu) in the WNV core protein increased resistance to acidotropic compounds NH4Cl and concanamycin A
- •The core protein mutation reduced neurovirulence in mice models
- •A naturally occurring accompanying mutation in prM protein abolished the resistant phenotype, indicating genetic crosstalk between internal and external viral proteins
- •The C protein plays a previously uncharacterized role in regulating acidic pH requirements for flavivirus entry and maturation