Journal article
P58IPK: A Novel “CIHD” Member of the Host Innate Defense Response against Pathogenic Virus Infection
PLoS pathogens, Vol.5(5), p.e1000438
05/2009
Handle:
https://hdl.handle.net/2376/110004
PMID: 19461876
Abstract
To support their replication, viruses take advantage of numerous cellular factors and processes. Recent large-scale screens have identified hundreds of such factors, yet little is known about how viruses exploit any of these. Influenza virus infection post-translationally activates P58
IPK
, a cellular inhibitor of the interferon-induced, dsRNA-activated eIF2α kinase, PKR. Here, we report that infection of P58
IPK
knockout mice with influenza virus resulted in increased lung pathology, immune cell apoptosis, PKR activation, and mortality. Analysis of lung transcriptional profiles, including those induced by the reconstructed 1918 pandemic virus, revealed increased expression of genes associated with the cell death, immune, and inflammatory responses. These experiments represent the first use of a mammalian infection model to demonstrate the role of P58
IPK
in the antiviral response. Our results suggest that P58
IPK
represents a new class of molecule, a cellular inhibitor of the host defense (CIHD), as P58
IPK
is activated during virus infection to inhibit virus-induced apoptosis and inflammation to prolong host survival, even while prolonging viral replication.
Respiratory illness caused by influenza virus is the seventh leading cause of death in the United States, and there is considerable interest in determining how the virus and host interact during infection and how the virus causes disease. Because influenza virus encodes only eight genes, it is dependent upon cellular proteins and processes for the generation of new viruses. One of these proteins is P58
IPK
, the activation of which has long been thought to be required for efficient viral replication. To study how P58
IPK
affects the ability of influenza virus to replicate and cause disease, we infected a strain of mice that lacks the gene for P58
IPK
. We found that viruses replicated just as efficiently in mice lacking the P58
IPK
gene, but that these mice were more susceptible to a fatal infection. The increased mortality rate in these mice was due to greater lung pathology and a heightened inflammatory response. Our results show that P58
IPK
represents a new type of protein that benefits the host by reducing pathology and prolonging survival, even though it may also benefit the virus by allowing it to replicate for a longer period of time.
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Details
- Title
- P58IPK: A Novel “CIHD” Member of the Host Innate Defense Response against Pathogenic Virus Infection
- Creators
- Alan G GoodmanJamie L FornekGuruprasad R MedigeshiLucy A PerroneXinxia PengMatthew D DyerSean C ProllSue E KnoblaughVictoria S CarterMarcus J KorthJay A NelsonTerrence M TumpeyMichael G Katze
- Publication Details
- PLoS pathogens, Vol.5(5), p.e1000438
- Academic Unit
- Molecular Biosciences, School of
- Publisher
- Public Library of Science; San Francisco, USA
- Identifiers
- 99900547291901842
- Language
- English
- Resource Type
- Journal article