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. 2001 May;75(9):4321-31.
doi: 10.1128/JVI.75.9.4321-4331.2001.

Global impact of influenza virus on cellular pathways is mediated by both replication-dependent and -independent events

G K Geiss  1 , M C An, R E Bumgarner, E Hammersmark, D Cunningham, M G Katze
Affiliations

Global impact of influenza virus on cellular pathways is mediated by both replication-dependent and -independent events

G K Geiss et al. J Virol. 2001 May.

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.

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Figures

FIG. 1
FIG. 1
Effect of inactivation of influenza virus on the synthesis of host cell proteins and viral hemagglutination titers. (A) Protein extracts from mock-infected cells (lanes 1 and 4), cells infected with heat-inactivated virus (lanes 2 and 5), and cells infected with active influenza virus (lanes 3 and 6) were examined by [35S]methionine-cysteine pulse-labeling at 4 and 8 h p.i.. The relative positions of four viral proteins, HA, nucleoprotein (NP), membrane protein 1 (M1), and NS1, are indicated by arrows. (B) Comparison of HA titers. Serial dilutions of medium alone (mock), FACT virus, and FHT virus were mixed with chicken red blood cells to determine relative HA titers. As an additional negative control, an influenza virus preparation was heated in a boiling water bath for 90 min (boiled). All reactions were performed in triplicate in 96-well plates; one replica is shown here.
FIG. 2
FIG. 2
Schematic representation of experimental design and classification of differentially expressed genes. Microarray experiments were performed in a pairwise fashion with RNA from mock-infected cells (M), cells infected with FHT virus, and cells infected with FACT virus. A set of differentially expressed genes was generated for each of the three possible comparisons. The whole set of experiments was then repeated with RNA from independent infections. The lists of differentially expressed genes for each time point and condition were combined, and the pattern of expression for each gene was used to determine whether it was dependent on viral replication. A gene that is dependent on viral replication should be differentially regulated in the experiments depicted in the left and center panels but not during experiments depicted on the right, whereas a replication-independent gene should be differentially regulated under the conditions shown at center and right but not in FHT-versus-FACT experiments. The same pattern of expression had to be observed in both independent infections in order to be considered in this study (Table 1).
FIG. 3
FIG. 3
Example of microarray results and determination of replication-dependent and -independent differentially expressed genes. False-color images for a portion of the microarray for the three pairwise conditions using FHT virus are shown in panels A (4 h p.i.) and B (8 h p.i.). Replica microarrays were hybridized with FHT virus (green) versus FACT virus (red), mock infection (green) versus FACT virus (red), and mock infection (green) versus FHT virus (red). A list of differentially expressed genes was generated for each set of samples using Spot-on software (see Materials and Methods). Examples of differentially expressed genes that are independent of or dependent on viral replication are shown (arrows 1 and 2, respectively). (C) RNA from mock-infected cells (M) or cells infected with FHT virus or FACT virus were run in 1% agarose gels under denaturing conditions and transferred to nylon membranes. Blots were hybridized with 32P-labeled DNA specific for IL-6 or metallothionein IG (MT-IG). Northern analysis was performed on RNA from the 4-h time point.
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