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Influenza virus infection causes global RNAPII termination defects.

ABSTRACT: Viral infection perturbs host cells and can be used to uncover regulatory mechanisms controlling cellular responses and susceptibility to infections. Using cell biological, biochemical, and genetic tools, we reveal that influenza A virus (IAV) infection induces global transcriptional defects at the 3' ends of active host genes and RNA polymerase II (RNAPII) run-through into extragenic regions. Deregulated RNAPII leads to expression of aberrant RNAs (3' extensions and host-gene fusions) that ultimately cause global transcriptional downregulation of physiological transcripts, an effect influencing antiviral response and virulence. This phenomenon occurs with multiple strains of IAV, is dependent on influenza NS1 protein, and can be modulated by SUMOylation of an intrinsically disordered region (IDR) of NS1 expressed by the 1918 pandemic IAV strain. Our data identify a strategy used by IAV to suppress host gene expression and indicate that polymorphisms in IDRs of viral proteins can affect the outcome of an infection.

SUBMITTER: Zhao N

PROVIDER: S-EPMC10754036 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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Influenza virus infection causes global RNAPII termination defects.

Zhao Nan N Sebastiano Vittorio V Moshkina Natasha N Mena Nacho N Hultquist Judd J Jimenez-Morales David D Ma Yixuan Y Rialdi Alex A Albrecht Randy R Fenouil Romain R Sánchez-Aparicio Maria Teresa MT Ayllon Juan J Ravisankar Sweta S Haddad Bahareh B Ho Jessica Sook Yuin JSY Low Diana D Jin Jian J Yurchenko Vyacheslav V Prinjha Rab K RK Tarakhovsky Alexander A Squatrito Massimo M Pinto Dalila D Allette Kimaada K Byun Minji M Smith Melissa Laird ML Sebra Robert R Guccione Ernesto E Tumpey Terrence T Krogan Nevan N Greenbaum Benjamin B van Bakel Harm H García-Sastre Adolfo A Marazzi Ivan I

Nature structural & molecular biology 20180903 9

Viral infection perturbs host cells and can be used to uncover regulatory mechanisms controlling cellular responses and susceptibility to infections. Using cell biological, biochemical, and genetic tools, we reveal that influenza A virus (IAV) infection induces global transcriptional defects at the 3' ends of active host genes and RNA polymerase II (RNAPII) run-through into extragenic regions. Deregulated RNAPII leads to expression of aberrant RNAs (3' extensions and host-gene fusions) that ulti ...[more]

PMID: 30177761

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Project description:BackgroundMicrobiota integrity is essential for a growing number of physiological processes. Consequently, disruption of microbiota homeostasis correlates with a variety of pathological states. Importantly, commensal microbiota provide a shield against invading bacterial pathogens, probably by direct competition. The impact of viral infections on host microbiota composition and dynamics is poorly understood. Influenza A viruses (IAV) are common respiratory pathogens causing acute infections. Here, we show dynamic changes in respiratory and intestinal microbiota over the course of a sublethal IAV infection in a mouse model.ResultsUsing a combination of 16S rRNA gene-specific next generation sequencing and qPCR as well as culturing of bacterial organ content, we found body site-specific and transient microbiota responses. In the lower respiratory tract, we observed only minor qualitative changes in microbiota composition. No quantitative impact on bacterial colonization after IAV infection was detectable, despite a robust antimicrobial host response and increased sensitivity to bacterial super infection. In contrast, in the intestine, IAV induced robust depletion of bacterial content, disruption of mucus layer integrity, and higher levels of antimicrobial peptides in Paneth cells. As a functional consequence of IAV-mediated microbiota depletion, we demonstrated that the small intestine is rendered more susceptible to bacterial pathogen invasion, in a Salmonella typhimurium super infection model.ConclusionWe show for the first time the consequences of IAV infection for lower respiratory tract and intestinal microbiobiota in a qualitative and quantitative fashion. The discrepancy of relative 16S rRNA gene next-generation sequencing (NGS) and normalized 16S rRNA gene-specific qPCR stresses the importance of combining qualitative and quantitative approaches to correctly analyze composition of organ associated microbial communities. The transiently induced dysbiosis underlines the overall stability of microbial communities to effects of acute infection. However, during a short-time window, specific ecological niches might lose their microbiota shield and remain vulnerable to bacterial invasion.

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Influenza virus infection causes global RNAPII termination defects.

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Influenza virus infection causes global RNAPII termination defects.

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