The influenza virus RNA polymerase as an innate immune agonist and antagonist

Elshina, Elizaveta; Velthuis, Aartjan J.W. te

doi:10.1007/s00018-021-03957-w

Cited by 18 publications

(12 citation statements)

References 155 publications

(244 reference statements)

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“…This phenomenon underlies the lethal pathology of infections with the 1918 H1N1 pandemic or the highly pathogenic avian IAV (7,8). Various viral and host factors have been implicated in causing immunopathology, including the products of aberrant viral replication (9)(10)(11).…”

Section: Introductionmentioning

confidence: 99%

Transient RNA structures cause aberrant influenza virus replication and innate immune activation

et al. 2022

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During infection, the influenza A virus RNA polymerase produces both full-length and aberrant RNA molecules, such as defective viral genomes (DVGs) and mini viral RNAs (mvRNAs). Subsequent innate immune activation involves the binding of host pathogen receptor retinoic acid–inducible gene I (RIG-I) to viral RNAs. However, it is not clear what factors determine which influenza A virus RNAs are RIG-I agonists. Here, we provide evidence that RNA structures, called template loops (t-loops), stall the viral RNA polymerase and contribute to innate immune activation by mvRNAs during influenza A virus infection. Impairment of replication by t-loops depends on the formation of an RNA duplex near the template entry and exit channels of the RNA polymerase, and this effect is enhanced by mutation of the template exit path from the RNA polymerase active site. Overall, these findings are suggestive of a mechanism involving polymerase stalling that links aberrant viral replication to the activation of the innate immune response.

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Section: Introductionmentioning

confidence: 99%

Transient RNA structures cause aberrant influenza virus replication and innate immune activation

et al. 2022

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“…Next, we explored whether the likelihood of being BP and RP can be attributed to specific sequences. The richness in A/U sequences around breakpoints was documented previously for influenza virus (Elshina and te Velthuis, 2021) and previous studies with coronaviruses pointed the UUG triplet as the preferred sequence for spanning junction start positions and a significant A increase in the end positions (Gribble et al, 2021). Following that, we analyzed the distribution of nucleotides (k-mer analysis) of the surroundings of the recombination points (Fig.…”

Section: Factors Influencing the Occurrence Of Deletionsmentioning

confidence: 77%

Accumulation dynamics of defective genomes during experimental evolution of two betacoronaviruses

Hillung,

Olmo-Uceda,

Muñoz-Sánchez

et al. 2024

Preprint

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Virus-encoded replicases often generate aberrant RNA genomes, known as defective viral genomes (DVGs). When coinfected with a helper virus providing necessary proteins, DVGs can multiply and spread. While DVGs depend on the helper virus for propagation, they can disrupt infectious virus replication, impact immune responses, and affect viral persistence or evolution. Understanding the dynamics of DVGs alongside standard viral genomes during infection remains unclear. To address this, we conducted a long-term experimental evolution of two betacoronaviruses, the human coronavirus OC43 (HCoV-OC43) and the murine hepatitis virus (MHV), in cell culture at both high and low multiplicities of infection (MOI). We then performed RNA-seq at regular time intervals, reconstructed DVGs, and analyzed their accumulation dynamics. Our findings indicate that DVGs evolved to exhibit greater diversity and abundance, with deletions and insertions being the most common types. Notably, some high MOI deletions showed very limited temporary existence, while others became prevalent over time. We observed differences in DVG abundance between high and low MOI conditions in HCoV-OC43 samples. The size distribution of HCoV-OC43 genomes with deletions differed between high and low MOI passages. In low MOI lineages, short and long DVGs were most common, with an additional cluster in high MOI lineages which became more prevalent along evolutionary time. MHV also showed variations in DVG size distribution at different MOI conditions, though less pronounced compared to HCoV-OC43, suggesting a more random distribution of DVG sizes. We identified hotspot regions for deletions that evolved at high MOI, primarily within cistrons encoding structural and accessory proteins. In conclusion, our study illustrates the widespread formation of DVGs during betacoronavirus evolution, influenced by MOI and cell- and virus-specific factors.

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“…The innate immune system detects viral RNA molecules using pattern recognition receptors (PRRs), such as RIG-I-like receptors (RLRs) ( 112 , 113 ). Upon binding to viral RNA, these PRRs trigger the expression of innate immune genes, including interferon genes ( 112 , 113 ). Interestingly, temperature was found to directly impact the host response against RNA virus infections.…”

Section: Effect Of Temperature On Innate Immune Responsementioning

confidence: 99%

Decoding the Role of Temperature in RNA Virus Infections

Bisht

Velthuis

2022

mBio

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RNA viruses include respiratory viruses, such as coronaviruses and influenza viruses, as well as vector-borne viruses, like dengue and West Nile virus. RNA viruses like these encounter various environments when they copy themselves and spread from cell to cell or host to host. Ex vivo differences, such as geographical location and humidity, affect their stability and transmission, while in vivo differences, such as pH and host gene expression, impact viral receptor binding, viral replication, and the host immune response against the viral infection.

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The influenza virus RNA polymerase as an innate immune agonist and antagonist

Cited by 18 publications

References 155 publications

Transient RNA structures cause aberrant influenza virus replication and innate immune activation

Transient RNA structures cause aberrant influenza virus replication and innate immune activation

Accumulation dynamics of defective genomes during experimental evolution of two betacoronaviruses

Decoding the Role of Temperature in RNA Virus Infections

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