An inability to maintain an expanding nucleocapsid pool contributes to the evolution and pathogenesis of pandemic RNA viruses

Blanco-Melo D, Nilsson-Payant BE*, Uhl S, Escudero-Pérez B, Olschewski S, Thibault P, Panis M, Danziger O, Rosenberg BR, Rosenthal M, Muñoz-Fontela C, Lee B, tenOever BR

bioRxiv 13/03/2020

Abstract

SUMMARY

Cellular biology has a uniformity not shared amongst viruses. This is perhaps best exemplified by negative-sense RNA viruses that encode their genetic material as a ribonucleoprotein complex composed of genome, RNA-dependent RNA polymerase, and the nucleoprotein. Here we demonstrate that limiting nucleoprotein availability not only universally culminates in a replicative catastrophe for negative-sense RNA viruses, but it results in the production of aberrant genomic material and induction of the interferon-based host defenses. This dynamic illustrates the tremendous stress imposed on negative-sense RNA viruses during replication as genomic products accumulate in an environment that requires an increasing demand on nucleoprotein availability. We show that limiting NP by RNA interference or drug targeting blocks replication and primes neighboring cells through the production of interferon. Together, these results demonstrate that the nucleoprotein represents the Achilles heel of the entire phylum of negative-sense RNA viruses. Here we establish this principle for a diverse collection of human pathogens and propose that the nucleoprotein should be a primary target for the development of future antiviral drugs.

HIGHLIGHTS

• Limited levels of NP result in production of defective viral genomes
• Defective viral genomes and viral antagonists are key determinants of the host antiviral response
• The host response and defective viral genome generation further exasperate NP availability
• NP is an optimal drug target for the whole phylum of negative-sense RNA viruses