Virus infection elicits an immediate cellular response termed the innate immune response. This response is typified by the induction of interferon which in turn induces a cascade of gene expression resulting in the production of protein products involved in eliminating virus infection. Not surprisingly, many viruses have evolved mechanisms to counteract this response. In the case of influenza virus, there is considerable evidence that the viral NS1 protein functions as an interferon antagonist. A virus that lacks NS1 (delNS1) replicates poorly in interferon-competent cells, but replicates efficiently in cells that are defective in interferon signaling. In this project, we propose to use microarrays, consisting of over 15,000 human cDNAs, to identify cellular genes that are differentially expressed in response to infection with influenza virus, respiratory syncytial virus (RSV), or interferon treatment.
In Specific Aim 1, we will analyze the effects of virus infection on cellular gene expression in primary human adenoid cells. Viruses to be used include influenza virus strains A, B, and C, and RSV strains A and B. Since there are significant cell-type-specific differences in the interferon response, we will also examine the effects of interferon treatment on these cells, in the presence or absence of virus infection.
In Specific Aim 2, we will determine the effects of influenza virus delNS1 or RSV delNS2, delNS1, or delNS1/NS2 on cellular gene expression in primary human adenoid cells and in mouse cells or mice deficient in one or more components of the interferon response, including Mx, PKR, RnaseL, STAT1, or IFNAR. Microarrays of mouse cDNAs will be used for analysis of gene expression in mouse cells and tissues. The goal of this project is to gain new insight into how respiratory viruses modulate cellular gene expression, with particular emphasis on the interferon response, and the role of specific viral gene products in this process. These studies may ultimately lead to the development of new strategies for controlling virus infection and may aid in efforts to design novel influenza virus or RSV vaccines based on modifications of virus-encoded interferon antagonists.
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