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Reduced Nucleoprotein Availability Impairs Negative-Sense RNA Virus Replication and Promotes Host Recognition
- Source :
- Journal of Virology
- Publication Year :
- 2021
- Publisher :
- American Society for Microbiology, 2021.
-
Abstract
- Negative-sense RNA viruses comprise some of the most important known human pathogens, including influenza A virus, measles virus, and Ebola virus. These viruses possess RNA genomes that are unreadable to the host, as they require specific viral RNA-dependent RNA polymerases in conjunction with other viral proteins, such as nucleoprotein, to be replicated and transcribed.<br />Negative-sense RNA viruses (NSVs) rely on prepackaged viral RNA-dependent RNA polymerases (RdRp) to replicate and transcribe their viral genomes. Their replication machinery consists of an RdRp bound to viral RNA which is wound around a nucleoprotein (NP) scaffold, forming a viral ribonucleoprotein complex. NSV NP is known to regulate transcription and replication of genomic RNA; however, its role in maintaining and protecting the viral genetic material is unknown. Here, we exploited host microRNA expression to target NP of influenza A virus and Sendai virus to ascertain how this would impact genomic levels and the host response to infection. We find that in addition to inducing a drastic decrease in genome replication, the antiviral host response in the absence of NP is dramatically enhanced. Additionally, our data show that insufficient levels of NP prevent the replication machinery of these NSVs to process full-length genomes, resulting in aberrant replication products which form pathogen-associated molecular patterns in the process. These dynamics facilitate immune recognition by cellular pattern recognition receptors leading to a strong host antiviral response. Moreover, we observe that the consequences of limiting NP levels are universal among NSVs, including Ebola virus, Lassa virus, and measles virus. Overall, these results provide new insights into viral genome replication of negative-sense RNA viruses and highlight novel avenues for developing effective antiviral strategies, adjuvants, and/or live-attenuated vaccines. IMPORTANCE Negative-sense RNA viruses comprise some of the most important known human pathogens, including influenza A virus, measles virus, and Ebola virus. These viruses possess RNA genomes that are unreadable to the host, as they require specific viral RNA-dependent RNA polymerases in conjunction with other viral proteins, such as nucleoprotein, to be replicated and transcribed. As this process generates a significant amount of pathogen-associated molecular patterns, this phylum of viruses can result in a robust induction of the intrinsic host cellular response. To circumvent these defenses, these viruses form tightly regulated ribonucleoprotein replication complexes in order to protect their genomes from detection and to prevent excessive aberrant replication. Here, we demonstrate the balance that negative-sense RNA viruses must achieve both to replicate efficiently and to avoid induction of the host defenses.
- Subjects :
- filovirus
viruses
Immunology
Cellular Response to Infection
Biology
Virus Replication
medicine.disease_cause
Respirovirus Infections
Sendai virus
Microbiology
Madin Darby Canine Kidney Cells
IFN response
paramyxovirus
Dogs
Influenza A Virus, H1N1 Subtype
Virology
negative-strand RNA virus
Chlorocebus aethiops
Influenza, Human
medicine
Animals
Humans
arenavirus
innate immunity
Vero Cells
miRNA
Ribonucleoprotein
Arenavirus
Ebola virus
RNA
Nucleocapsid Proteins
biology.organism_classification
Nucleoprotein
Viral Tropism
HEK293 Cells
Viral replication
A549 Cells
Insect Science
viral replication
influenza
Viral genome replication
HeLa Cells
Subjects
Details
- ISSN :
- 10985514 and 0022538X
- Volume :
- 95
- Database :
- OpenAIRE
- Journal :
- Journal of Virology
- Accession number :
- edsair.doi.dedup.....48c115ddfd1f93d5bfc22f8b2b81742e