Identification of innate immunity genes and pathways using a comparative genomics approach

*Laboratory of Environmental Lung Disease, National Heart Lung and Blood Institute, and
^¶Laboratory of Molecular Toxicology, National Institutes of Environmental Health Sciences, National Institutes of Health, 111 TW Alexander Drive, Durham, NC 27709;
^†Department of Medicine, Duke University, Durham, NC 27707; and
^§Department of Biology, Duke University, Durham, NC 27708

Communicated by Cynthia J. Kenyon, University of California, San Francisco, CA, March 12, 2008 (received for review July 17, 2007)

Abstract

To reveal regulators of innate immunity, we used RNAi assays to monitor the immune response when genes are inhibited in Caenorhabditis elegans and mouse macrophages. Genes that altered innate immune responsiveness in C. elegans were validated in murine macrophages, resulting in the discovery of 11 genes that regulate the innate immune response in both systems and the subsequent identification of a protein interaction network with a conserved role in innate immunity regulation. We confirmed the role of four of these 11 genes in antimicrobial gene regulation using available mutants in C. elegans. Several of these genes (acy-1, tub-2, and tbc-1) also regulate susceptibility to the pathogen Pseudomonas aeruginosa. These genes may prove critical to understanding host defense and represent potential therapeutic targets for infectious and immunological diseases.

Footnotes

^‡To whom correspondence should be addressed. E-mail: alpers{at}nhlbi.nih.gov
Author contributions: S.A., J.H.F., and D.A.S. designed research; S.A., R.L., B.L., and P.D. performed research; S.A. and W.A.B. contributed new reagents/analytic tools; S.A. and R.L. analyzed data; and S.A. wrote the paper.
The authors declare no conflict of interest.
This article contains supporting information online at www.pnas.org/cgi/content/full/0802405105/DCSupplemental.
Freely available online through the PNAS open access option.