The long term goal of this application is to elucidate the mechanisms and biological significance of crosstalk between the innate immune response and nuclear hormone receptors in host defense against infections and in pathogen-associated metabolic diseases. Preliminary data in our lab has identified a novel Interferon Regulatory Factor 3(IRF3)-dependent but type I interferon independent pathway induced during innate immune response to viral product stimulation or viral infection, leading to strong transcriptional repression of Retinoid X Receptor 1 (RXR1). As RXR1 is the major heterodimer partner for most of the nuclear hormone receptors involved in numerous cellular metabolic processes, we hypothesize that repression of RXR1 and its regulated genes during viral infections can have strong impacts on host metabolisms especially drug metabolisms. We further suggest this can contribute to the pathogenesis of viral associated metabolic diseases such as Reye's Syndrome, a hepatotoxicity disease that occurs when children are given aspirin in the context of a viral infection, or acetaminophen (APAP)-induced hepatotoxicity, which accounts for about half of the acute liver failures in US. Interestingly, our preliminary studies indicate that innate immune responses to viral products can potentiate aspirin-induced but protect APAP-induced hepatotoxicity, which may explain why during viral infections patients are safer to use Tylenol than Aspirin. These results further suggest that, depending upon the nature of the drugs, viral infections may differentially affect the accumulation of the drug's intermediate metabolites, which could lead to opposite toxic effects on host tissues. In this application, we will first develop mouse models that mimic Reye's Syndrome and acetaminophen (APAP)-induced hepatotoxicity. We will then use these two opposite drug metabolism models as examples to determine how innate immune responses to viral infection could differentially alter stability or toxicity of different drugs. Furthermore, additional preliminary data in our lab showed that nuclear hormone receptor agonists can suppress the induction of antiviral genes and promote viral replications. We therefore also hypothesize that repression of nuclear hormone receptors by the innate immune response may contribute to an effective anti-viral response. We will further analyze the effects of nuclear hormone receptors and their agonists on anti-viral innate immune responses to determine if the repression of nuclear hormone receptors by innate immune response is necessary for the proper host defense against viral infections. We believe our investigation of the crosstalk between the innate immune response and nuclear hormone receptor-mediated metabolism will not only help us to understand the mechanisms responsible for virally induced metabolic diseases and drug induced immuno-suppressions but will also provide novel strategies to prevent or treat patients with viral infections and their associated metabolic diseases.

Public Health Relevance

Numerous diseases including metabolic diseases are associated with virus infections. On the other hand, many metabolic products and drugs can also affect our body's ability to defend against invading viruses. However, the molecular mechanisms responsible for such associations are not clear. We recently found a novel crosstalk between host immune response and metabolisms, which could explain not only viral associated liver diseases such as Reye's Syndrome but also how metabolic drugs can inhibit host response against viral infections. Further investigation on such crosstalk will provide novel strategies to prevent or treat patients with viral infections and their associated metabolic diseases such as acetaminophen (APAP)-induced hepatotoxicity, which accounted for about half of all acute liver failures in America.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI078389-03
Application #
8091282
Study Section
Innate Immunity and Inflammation Study Section (III)
Program Officer
Palker, Thomas J
Project Start
2009-07-01
Project End
2014-06-30
Budget Start
2011-07-01
Budget End
2012-06-30
Support Year
3
Fiscal Year
2011
Total Cost
$367,469
Indirect Cost
Name
University of California Los Angeles
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
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