Influenza virus infection causes global RNAPII termination defects

Zhao, Nan; Sebastiano, Vittorio; Moshkina, Natasha; Mena, Ignacio; Hultquist, Judd F.; Jimenez-Morales, David; Ma, Yixuan; Rialdi, Alex; Albrecht, Randy A.; Fenouil, Romain; Sánchez-Aparicio, María Teresa; Ayllón, Juan; Ravisankar, Sweta; Haddad, Bahareh; Ho, Jessica; Low, Diana; Jin, Jian; Yurchenko, Vyacheslav; Prinjha, Rab K.; Tarakhovsky, Alexander; Squatrito, Massimo; Pinto, Dalila; Allette, Kimaada; Byun, Minji; Smith, Melissa; Sebra, Robert; Guccione, Ernesto; Tumpey, Terrence M.; Krogan, Nevan J.; Greenbaum, Benjamin; Bakel, Harm van; Garcı́a-Sastre, Adolfo; Marazzi, Ivan

doi:10.1038/s41594-018-0124-7

Cited by 51 publications

(76 citation statements)

References 100 publications

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“…There is evidence in the literature that IAV infection results in reduced host transcription and mRNA processing by inhibiting the host RNA polymerase II (Pol II) function (60,61). Related to this, a recent study found that several strains of IAV elicit global deregulation of Poll II transcription termination by impairing 3=-end cleavage and termination, and this effect was dependent on NS1 expression (62). These studies could partially explain the global negative correlation that we found between viral genes and cellular genes.…”

Section: Discussionmentioning

confidence: 99%

Innate Immune Response to Influenza Virus at Single-Cell Resolution in Human Epithelial Cells Revealed Paracrine Induction of Interferon Lambda 1

Ramos

Smith

Ruf-Zamojski

et al. 2019

J Virol

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Early interactions of influenza A virus (IAV) with respiratory epithelium might determine the outcome of infection. The study of global cellular innate immune responses often masks multiple aspects of the mechanisms by which populations of cells work as organized and heterogeneous systems to defeat virus infection, and how the virus counteracts these systems. In this study, we experimentally dissected the dynamics of IAV and human epithelial respiratory cell interaction during early infection at the single-cell level. We found that the number of viruses infecting a cell (multiplicity of infection [MOI]) influences the magnitude of virus antagonism of the host innate antiviral response. Infections performed at high MOIs resulted in increased viral gene expression per cell and stronger antagonist effect than infections at low MOIs. In addition, single-cell patterns of expression of interferons (IFN) and IFN-stimulated genes (ISGs) provided important insights into the contributions of the infected and bystander cells to the innate immune responses during infection. Specifically, the expression of multiple ISGs was lower in infected than in bystander cells. In contrast with other IFNs, IFN lambda 1 (IFNL1) showed a widespread pattern of expression, suggesting a different cell-to-cell propagation mechanism more reliant on paracrine signaling. Finally, we measured the dynamics of the antiviral response in primary human epithelial cells, which highlighted the importance of early innate immune responses at inhibiting virus spread. IMPORTANCE Influenza A virus (IAV) is a respiratory pathogen of high importance to public health. Annual epidemics of seasonal IAV infections in humans are a significant public health and economic burden. IAV also causes sporadic pandemics, which can have devastating effects. The main target cells for IAV replication are epithelial cells in the respiratory epithelium. The cellular innate immune responses induced in these cells upon infection are critical for defense against the virus, and therefore, it is important to understand the complex interactions between the virus and the host cells. In this study, we investigated the innate immune response to IAV in the respiratory epithelium at the single-cell level, providing a better understanding on how a population of epithelial cells functions as a complex system to orchestrate the response to virus infection and how the virus counteracts this system.

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Section: Discussionmentioning

confidence: 99%

Innate Immune Response to Influenza Virus at Single-Cell Resolution in Human Epithelial Cells Revealed Paracrine Induction of Interferon Lambda 1

Ramos

Smith

Ruf-Zamojski

et al. 2019

J Virol

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“…Recent studies revealed that transcription termination is regulated by viral infections and cellular stresses [13][14][15]40 , and that increased DoTT is associated with cancer 16 . To understand the underlying mechanisms, we carried out an in-depth study of HSV-1-induced DoTT.…”

Section: Discussionmentioning

confidence: 99%

“…mRNA 3′ processing factors are also targeted by other viruses. For example, influenza virus infection or ectopic expression of the influenza viral protein NS1 causes transcription termination defects of host genes 40,41 . NS1 inhibits host mRNA 3′ processing by specifically binding to the CPSF subunit CPSF30 (ref.…”

Section: Discussionmentioning

confidence: 99%

Herpes simplex virus blocks host transcription termination via the bimodal activities of ICP27

et al. 2020

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Infection by viruses, including herpes simplex virus-1 (HSV-1), and cellular stresses cause widespread disruption of transcription termination (DoTT) of RNA polymerase II (RNAPII) in host genes. However, the underlying mechanisms remain unclear. Here, we demonstrate that the HSV-1 immediate early protein ICP27 induces DoTT by directly binding to the essential mRNA 3' processing factor CPSF. It thereby induces the assembly of a dead-end 3' processing complex, blocking mRNA 3' cleavage. Remarkably, ICP27 also acts as a sequencedependent activator of mRNA 3' processing for viral and a subset of host transcripts. Our results unravel a bimodal activity of ICP27 that plays a key role in HSV-1-induced host shutoff and identify CPSF as an important factor that mediates regulation of transcription termination. These findings have broad implications for understanding the regulation of transcription termination by other viruses, cellular stress and cancer.

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“…Recent studies observing altered genome architecture, transcript 3’ end defects, and PA-X targeted transcript degradation during infection all have links to splicing (Gaucherand et al, 2019; Heinz et al, 2018; Zhao et al, 2018). One observation was that of transgenic, defective, and unannotated splicing in relation to transcription termination (Heinz et al, 2018; Zhao et al, 2018). While our splicing analyses did not account for these specific splicing types, we would predict for them to be present in our experiments to some extent.…”

Section: Discussionmentioning

confidence: 99%

Viral-Induced Alternative Splicing of Host Genes Promotes Influenza Replication

Thompson

Dittmar

Mallory

et al. 2020

Preprint

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Viral infection induces the expression of numerous host genes that impact the outcome of infection. Here we show that infection of human lung epithelial cells with Influenza A virus (IAV) also induces a broad program of alternative splicing of host genes. While these splicing-regulated genes are not enriched for canonical regulators of viral infection, we find that many of these genes do impact replication of IAV. Moreover, specific inhibition of the IAV-induced splicing in several cases also attenuates viral infection. We further show that approximately a quarter of the IAV-induced splicing events are regulated by hnRNP K, a host protein that required for efficient splicing of the IAV M transcript in nuclear speckles. Notably, we find that hnRNP K accumulates in nuclear speckles upon IAV infection, which is likely to alter the accessibility of hnRNP K for host transcripts thereby leading to a program of host splicing changes that promote IAV replication.

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Influenza virus infection causes global RNAPII termination defects

Cited by 51 publications

References 100 publications

Innate Immune Response to Influenza Virus at Single-Cell Resolution in Human Epithelial Cells Revealed Paracrine Induction of Interferon Lambda 1

Innate Immune Response to Influenza Virus at Single-Cell Resolution in Human Epithelial Cells Revealed Paracrine Induction of Interferon Lambda 1

Herpes simplex virus blocks host transcription termination via the bimodal activities of ICP27

Viral-Induced Alternative Splicing of Host Genes Promotes Influenza Replication

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