Nucleoprotein is important in regulating transcription and replication of Negative-sense RNA viruses. Although the viral RNA-dependent RNA-polymerase can induce the synthesis of viral RNA in the absence of nucleoprotein, its processivity is severely impaired. During the early stages of infection, nucleoprotein supports transcription of viral proteins, which thereafter package and protect replication products. This study shows that limited levels of nucleoprotein in Influenza A and Sendai viruses result in impaired replication and formation of defective viral genomes which are detected by the host, hence inducing a robust Interferon response. Seven different viruses (with limited nucleoprotein levels) belonging to five families in the phylum Negarnaviricota infected a significantly low number of cells, except for two viruses, further confirming the importance of nucleoprotein in the replication of these viruses. Reduced levels of nucleocapsid expression in SARS-CoV-2 resulted in reduced replication, with no induction of interferon response, due to the non-inflammatory nature of positive-sense viral genomes. This highlights the importance of nucleoprotein and nucleocapsid in efficient viral replication while playing a critical role of protecting the virus from recognition by the host’s defense mechanism. These insights provide a new rationale for developing anti-viral strategies targeting the nucleoprotein.
(MRM)
