Aartjan J. W. te Velthuis

Princeton University

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Common and unique features of viral RNA-dependent polymerases

Cellular and Molecular Life Sciences (2014)

Aartjan J. W. te Velthuis

Eukaryotes and bacteria can be infected with a wide variety of RNA viruses. On average, these pathogens share little sequence similarity and use different replication and transcription strategies. Nevertheless, the members of nearly all RNA virus families depend on the activity of a virally encoded RNA-dependent polymerase for the condensation of nucleotide triphosphates. This review provides an overview of our current understanding of the viral RNA-dependent polymerase structure and the biochemistry and biophysics that is involved in replicating and transcribing the genetic material of RNA viruses.

Transcription

RNA polymerase I

10.1007/s00018-014-1695-z

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Citations (242)

Structural insights into RNA polymerases of negative-sense RNA viruses

Nature Reviews Microbiology (2021)

Aartjan J. W. te Velthuis J.M. Grimes Ervin Fodor

Nucleoprotein

RNA virus

Transcription

Human virome

10.1038/s41579-020-00501-8

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Citations (100)

Evolution of highly pathogenic H5N1 influenza A virus in the central nervous system of ferrets

PLoS Pathogens (2023)

Jurre Y. Siegers Lucas M. Ferreri Dirk Eggink Edwin J. B. Veldhuis Kroeze Aartjan J. W. te Velthuis

Central nervous system (CNS) disease is the most common extra-respiratory tract complication of influenza A virus infections in humans. Remarkably, zoonotic highly pathogenic avian influenza (HPAI) H5N1 virus infections are more often associated with CNS disease than infections with seasonal influenza viruses. Evolution of avian influenza viruses has been extensively studied in the context of respiratory infections, but evolutionary processes in CNS infections remain poorly understood. We have previously observed that the ability of HPAI A/Indonesia/5/2005 (H5N1) virus to replicate in and spread throughout the CNS varies widely between individual ferrets. Based on these observations, we sought to understand the impact of entrance into and replication within the CNS on the evolutionary dynamics of virus populations. First, we identified and characterized three substitutions–PB1 E177G and A652T and NP I119M - detected in the CNS of a ferret infected with influenza A/Indonesia/5/2005 (H5N1) virus that developed a severe meningo-encephalitis. We found that some of these substitutions, individually or collectively, resulted in increased polymerase activity in vitro. Nevertheless, in vivo, the virus bearing the CNS-associated mutations retained its capacity to infect the CNS but showed reduced dispersion to other anatomical sites. Analyses of viral diversity in the nasal turbinate and olfactory bulb revealed the lack of a genetic bottleneck acting on virus populations accessing the CNS via this route. Furthermore, virus populations bearing the CNS-associated mutations showed signs of positive selection in the brainstem. These features of dispersion to the CNS are consistent with the action of selective processes, underlining the potential for H5N1 viruses to adapt to the CNS.

10.1371/journal.ppat.1011214

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Citations (14)

Mini viral RNAs act as innate immune agonists during influenza virus infection

bioRxiv (Cold Spring Harbor Laboratory) (2018)

Aartjan J. W. te Velthuis Joshua C. D. Long David L.V. Bauer Rebecca L. Y. Fan Hui‐Ling Yen

Influenza A virus infection usually causes a mild to moderately severe respiratory disease in humans. However, infection with the 1918 H1N1 pandemic or highly pathogenic avian influenza viruses (HPAIV) of the H5N1 subtype, can lead to viral pneumonia, systemic disease and death. The molecular processes that determine the outcome of influenza virus infection are multifactorial and involve a complex interplay between host, viral, and bacterial factors 1 . However, it is generally accepted that a strong innate immune dysregulation known as ‘cytokine storm’ contributes to the pathology of pandemic and avian influenza virus infections 2–4 . The RNA sensor Retinoic acid-inducible gene I (RIG-I) plays an important role in sensing viral infection and initiating a signalling cascade that leads to interferon (IFN) expression 5 . Here we show that short aberrant RNAs (mini viral RNAs; mvRNAs), produced by the viral RNA polymerase during the replication of the viral RNA genome, bind and activate the intracellular pathogen sensor RIG-I, and lead to the expression of interferon-β. We find that erroneous polymerase activity, dysregulation of viral RNA replication, or the presence of avian-specific amino acids underlie mvRNA generation and cytokine expression in mammalian cells and propose an intramolecular copy-choice mechanism for mvRNA generation. By deep-sequencing RNA samples from lungs of ferrets infected with influenza viruses we show that mvRNAs are generated during infection of animal models. We propose that mvRNAs act as main agonists of RIG-I during influenza virus infection and the ability of influenza virus strains to generate mvRNAs should be considered when assessing their virulence potential.

RIG-I

RNA virus

10.1101/385716

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Citations (1)

OTUB1 Is a Key Regulator of RIG-I-Dependent Immune Signaling and Is Targeted for Proteasomal Degradation by Influenza A NS1

Cell Reports (2020)

Akhee Sabiha Jahan Élise Biquand Raquel Muñoz-Moreno Agathe Le Quang Chris Mok

Deubiquitylases (DUBs) regulate critical signaling pathways at the intersection of host immunity and viral pathogenesis. Although RIG-I activation is heavily dependent on ubiquitylation, systematic analyses of DUBs that regulate this pathway have not been performed. Using a ubiquitin C-terminal electrophile, we profile DUBs that function during influenza A virus (IAV) infection and isolate OTUB1 as a key regulator of RIG-I-dependent antiviral responses. Upon infection, OTUB1 relocalizes from the nucleus to mitochondrial membranes together with RIG-I, viral PB2, and NS1. Its expression depends on competing effects of interferon stimulation and IAV-triggered degradation. OTUB1 activates RIG-I via a dual mechanism of K48 polyubiquitin hydrolysis and formation of an E2-repressive complex with UBCH5c. We reconstitute this mechanism in a cell-free system comprising [35S]IRF3, purified RIG-I, mitochondrial membranes, and cytosol expressing OTUB1 variants. A range of IAV NS1 proteins trigger proteasomal degradation of OTUB1, antagonizing the RIG-I signaling cascade and antiviral responses.

RIG-I

IRF3

Deubiquitinating enzyme

10.1016/j.celrep.2020.01.015

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Citations (58)

Single-molecule FRET reveals the pre-initiation and initiation conformations of influenza virus promoter RNA

Nucleic Acids Research (2016)

Nicole C. Robb Aartjan J. W. te Velthuis Ralph Wieneke Robert Tampé Thorben Cordes

Influenza viruses have a segmented viral RNA (vRNA) genome, which is replicated by the viral RNA-dependent RNA polymerase (RNAP). Replication initiates on the vRNA 3΄ terminus, producing a complementary RNA (cRNA) intermediate, which serves as a template for the synthesis of new vRNA. RNAP structures show the 3΄ terminus of the vRNA template in a pre-initiation state, bound on the surface of the RNAP rather than in the active site; no information is available on 3΄ cRNA binding. Here, we have used single-molecule Förster resonance energy transfer (smFRET) to probe the viral RNA conformations that occur during RNAP binding and initial replication. We show that even in the absence of nucleotides, the RNAP-bound 3΄ termini of both vRNA and cRNA exist in two conformations, corresponding to the pre-initiation state and an initiation conformation in which the 3΄ terminus of the viral RNA is in the RNAP active site. Nucleotide addition stabilises the 3΄ vRNA in the active site and results in unwinding of the duplexed region of the promoter. Our data provide insights into the dynamic motions of RNA that occur during initial influenza replication and has implications for our understanding of the replication mechanisms of similar pathogenic viruses.

10.1093/nar/gkw884

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Citations (38)

The Rna-Dependent RNA Polymerase of the Influenza a Virus

Future Virology (2014)

Thomas M. Stubbs Aartjan J. W. te Velthuis

The influenza A virus causes a highly contagious respiratory disease that significantly impacts our economy and health. Its replication and transcription is catalyzed by the viral RNA polymerase. This enzyme is also crucial for the virus, because it is involved in the adaptation of zoonotic strains. It is thus of major interest for the development of antiviral therapies and is being intensively studied. In this article, we will discuss recent advances that have improved our knowledge of the structure of the RNA polymerase and how mutations in the polymerase help the virus to spread effectively among new hosts.

RNA polymerase I

10.2217/fvl.14.66

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Citations (37)

Stopping the beating heart of the influenza virus

Impact (2017)

Aartjan J. W. te Velthuis

10.21820/23987073.2017.2.59

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Citations (0)

Erratum: The RNA polymerase activity of SARS-coronavirus nsp12 is primer dependent

Carolina Digital Repository (University of North Carolina at Chapel Hill) (2011)

Aartjan J. W. te Velthuis Jamie J. Arnold Craig E. Cameron Sjoerd H. E. van den Worm Eric J. Snijder

Primer (cosmetics)

Coronavirus

Coronavirus Infections

Coronaviridae

2019-20 coronavirus outbreak

10.17615/rbr0-x011

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Long-term evolution of human seasonal influenza virus A(H3N2) is associated with an increase in polymerase complex activity

Virus Evolution (2024)

René M. Vigeveno Alvin X. Han Robert P. de Vries Edyth Parker Karen de Haan

Abstract Since the influenza pandemic in 1968, influenza A(H3N2) viruses have become endemic. In this state, H3N2 viruses continuously evolve to overcome immune pressure as a result of prior infection or vaccination, as is evident from the accumulation of mutations in the surface glycoproteins hemagglutinin (HA) and neuraminidase (NA). However, phylogenetic studies have also demonstrated ongoing evolution in the influenza A(H3N2) virus RNA polymerase complex genes. The RNA polymerase complex of seasonal influenza A(H3N2) viruses produces mRNA for viral protein synthesis and replicates the negative sense viral RNA genome (vRNA) through a positive sense complementary RNA intermediate (cRNA). Presently, the consequences and selection pressures driving the evolution of the polymerase complex remain largely unknown. Here, we characterize the RNA polymerase complex of seasonal influenza A(H3N2) viruses representative of nearly 50 years of influenza A(H3N2) virus evolution. The H3N2 polymerase complex is a reassortment of human and avian influenza virus genes. We show that since 1968, influenza A(H3N2) viruses have increased the transcriptional activity of the polymerase complex while retaining a close balance between mRNA, vRNA, and cRNA levels. Interestingly, the increased polymerase complex activity did not result in increased replicative ability on differentiated human airway epithelial (HAE) cells. We hypothesize that the evolutionary increase in polymerase complex activity of influenza A(H3N2) viruses may compensate for the reduced HA receptor binding and avidity that is the result of the antigenic evolution of influenza A(H3N2) viruses.

Seasonal influenza

10.1093/ve/veae030

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Citations (2)