Abstract
The innate immune response plays a critical role in fighting infection; however, innate immunity also can affect the pathogenesis of a variety of diseases, including sepsis, asthma, cancer, and atherosclerosis. To identify novel regulators of innate immunity, we performed comparative genomics RNA interference screens in the nematode Caenorhabditis elegans and mouse macrophages. These screens have uncovered many candidate regulators of the response to lipopolysaccharide (LPS), several of which interact physically in multiple species to form an innate immunity protein interaction network. This protein interaction network contains several proteins in the canonical LPS-responsive TLR4 pathway as well as many novel interacting proteins. Using RNAi and overexpression studies, we show that almost every gene in this network can modulate the innate immune response in mouse cell lines. We validate the importance of this network in innate immunity regulation in vivo using available mutants in C. elegans and mice.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Biological Evolution
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Caenorhabditis elegans / drug effects
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Caenorhabditis elegans / genetics
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Caenorhabditis elegans / immunology*
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Caenorhabditis elegans / metabolism
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Caenorhabditis elegans Proteins / genetics
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Caenorhabditis elegans Proteins / immunology*
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Caenorhabditis elegans Proteins / metabolism
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Cell Line
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Gene Expression / drug effects
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Gene Expression / immunology
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Humans
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Immunity, Innate* / drug effects
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Lipopolysaccharides / pharmacology
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Macrophages / cytology
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Macrophages / drug effects
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Macrophages / metabolism*
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Mice
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Mutation
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Oligonucleotide Array Sequence Analysis
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Protein Interaction Maps / genetics
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Protein Interaction Maps / immunology*
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RNA Interference*
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RNA, Small Interfering / genetics
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Signal Transduction / drug effects
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Signal Transduction / immunology
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Toll-Like Receptor 4 / genetics
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Toll-Like Receptor 4 / immunology
Substances
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Caenorhabditis elegans Proteins
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Lipopolysaccharides
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RNA, Small Interfering
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Toll-Like Receptor 4