Global Impact of Influenza Virus on Cellular Pathways Is Mediated by both Replication-Dependent and -Independent Events

Abstract

Influenza virus, the causative agent of the common flu, is a worldwide health problem with significant economic consequences. Studies of influenza virus biology have revealed elaborate mechanisms by which the virus interacts with its host cell as it inhibits the synthesis of cellular proteins, evades the innate antiviral response, and facilitates production of viral RNAs and proteins. With the advent of DNA array technology it is now possible to obtain a large-scale view of how viruses alter the environment within the host cell. In this study, the cellular response to influenza virus infection was examined by monitoring the steady-state mRNA levels for over 4,600 cellular genes. Infections with active and inactivated influenza viruses identified changes in cellular gene expression that were dependent on or independent of viral replication, respectively. Viral replication resulted in the downregulation of many cellular mRNAs, and the effect was enhanced with time postinfection. Interestingly, several genes involved in protein synthesis, transcriptional regulation, and cytokine signaling were induced by influenza virus replication, suggesting that some may play essential or accessory roles in the viral life cycle or the host cell's stress response. The gene expression pattern induced by inactivated viruses revealed induction of the cellular metallothionein genes that may represent a protective response to virus-induced oxidative stress. Genome-scale analyses of virus infections will help us to understand the complexities of virus-host interactions and may lead to the discovery of novel drug targets or antiviral therapies.Although it has been nearly 7 decades since the isolation of human influenza virus (34), it remains a world health threat with large economic consequences (28, 43, 52). Although vaccine and drug strategies have managed to contain the spread of the disease and the severity of its symptoms, recent outbreaks, such as the one in Hong Kong in 1997, emphasize the need for continued research efforts for influenza prevention. An abundant but often overlooked source of potential antiviral targets are those cellular genes whose expression is most affected by viral infection. With DNA microarray technology it is now possible to measure the mRNA levels of thousands of cellular genes under a variety of experimental conditions. This approach is increasingly being used to monitor cellular gene expression in response to viral infections (5,19,20,25,30,55,59), expression of viral genes (21, 31, 58), or treatment with antiviral compounds such as interferon (12).Influenza virus is a negative-stranded RNA virus that induces a profound inhibitory effect on the synthesis of cellular proteins. Much of this effect occurs at a posttranscriptional level, as viral RNAs are selectively translated while the initiation and elongation of cellular proteins are inhibited (15). On the other hand, viral proteins carry out a variety of functions within the nucleus, such as removing 5Ј methyl caps from host cell mRNAs (50), blocking ...

Influenza Virus Infection Induces Metallothionein Gene Expression in the Mouse Liver and Lung by Overlapping but Distinct Molecular Mechanisms

“…To our knowledge, the present study is the first demonstration of the activation of MT genes in response to an experimental viral infection in an animal model and elucidation of the molecular mechanisms for the induction process. One recent study using DNA microarray technology has identified MT-IIA as one of the genes induced in HeLa cells infected with influenza A virus (20). This study does not, however, address the molecular mechanisms of MT induction in specific tissues of organisms.…”

Essential Impact of NF-κB Signaling on the H5N1 Influenza A Virus-Induced Transcriptome

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Involvement of Toll-like Receptor 3 in the Immune Response of Lung Epithelial Cells to Double-stranded RNA and Influenza A Virus

“…Previous studies have shown that production of inflammatory mediators in response to a viral infection can occur in the presence or absence of multiplication of the pathogen (22). We tested whether viral contact with the plasma membrane and/or viral penetration of the host cell was sufficient to trigger the inflammatory response.…”