Overview
The primary research interest of my laboratory is to understand the common mechanisms that phylogenetically diverse organisms employ to defend themselves against microbial pathogens.  Our experimental focus is the immune system of the nematode Caenorhabditis elegans.  We take a genetic approach to identify determinants of immunity in the worm, making use of recent technological advances such as RNA interference that facilitate the genome-wide characterization of gene function.  We anticipate that the investigation of pathogen resistance in C. elegans will provide important insights into evolutionarily conserved host organism responses to pathogen infection, with implications for the understanding of the evolution and function of vertebrate innate immunity.

Research Summary
Genetic and functional genomic analysis of innate immunity in C. elegans. The mammalian innate immune system serves as the first line of defense against infection, functioning in the initial recognition of pathogens and subsequent mobilization of the adaptive immune system. Innate immunity is thus critical for normal host defense, but derangement of the innate immune system is implicated in a number of pathological states, ranging from septic shock to chronic inflammatory disorders. In addition, the innate immune system has attracted attention as a potential target for immunomodulatory therapeutics that might improve the efficacy of vaccines.

An emerging theme from the study of mammalian innate immunity and the immune system of Drosophila is that key signaling pathways of the innate immune system have a high degree of homology with the immune response pathways of insects. Our initial genetic studies of immunity in C. elegans have revealed that conserved innate immune signaling pathways also function in the nematode in response to bacterial infection. We anticipate that the study of immunity in C. elegans will reveal mechanisms of innate immune defense that have been conserved in mammalian innate immunity.

In our experiments we replace the standard laboratory bacterial food source with pathogenic isolates of bacteria that kill C. elegans, such as the human opportunistic pathogen Pseduomonas aeruginosa. We carry out genetic analysis to characterize the mechanisms that modulate the ability of C. elegans to survive in the presence of bacterial infection. We carried out a forward genetic approach to isolate “immunocompromised” worm mutants that led to the identification and characterization of a requirement for a conserved p38 mitogen-activated protein kinase (MAPK) pathway in C. elegans defense against bacterial infection. The critical role that this pathway plays in innate immune signaling pathways of mammals suggested that the study of the genetic determinants of pathogen resistance in C. elegans would illuminate evolutionarily conserved mechanisms of innate immunity.

We have initiated the genome-wide analysis of the immune system of C. elegans, focusing on the upstream inputs that may be involved in the recognition of pathogenic infection and the regulatory mechanisms of immune signaling that converge on p38 MAPK. A major technological advance in the functional genomic analysis of C. elegans has been the development of methodology enabling the systematic analysis of gene function using RNA interference (RNAi). Using a transgenic worm strain carrying a green fluorescent protein reporter gene fused to the promoter of a presumptive antimicrobial peptide identified from a genome-wide microarray analysis of p38 MAPK-regulated genes, we have assayed the effect of RNAi on each of over 16,000 genes on p38 MAPK signaling in the intact organism under conditions of infection by the pathogen P. aeruginosa. The detailed characterization of candidate immune genes represents a major focus of the laboratory.

Whereas studies of mammalian innate immunity have focused largely on Toll-like receptor (TLR) signaling, TLR-independent signaling pathways have remained relatively unexplored. Recent work suggests that conserved TLR-independent signaling plays a key role in C. elegans immunity, and thus the identification of TLR-independent signaling pathways in innate immunity is of particular interest to us. In addition, we anticipate that the genetic dissection of pathogen resistance in C. elegans will illuminate the physiological interactions between innate immunity and potentially related processes such as the organism response to abiotic stresses, ancient antiviral defense mediated by RNAi pathways, and aging.

Selected Publications
Troemel E.R., Chu S.W., Reinke V., Lee S.S., Ausubel F.M., Kim D.H. p38 MAPK
regulates expression of immune response genes and contributes to longevity in
C. elegans. PLoS Genetics 2(11): e183, 1725-1739. (2006).

Kim, D.H., Ausubel, F.M. Evolutionary perspectives on innate immunity from the study of Caenorhabditis elegans. Curr Opin Immunol. 17(1), 4-10. (2005)

Kim, D.H., Liberati, N.T., Mizuno, T., Inoue, H., Hisamoto, N., Matsumoto, K., Ausubel, F.M.Integration of Caenorhabditis elegans MAPK pathways mediating immunity and stress resistance by MEK-1 MAPK kinase and VHP-1 MAPK phosphatase. Proc. Natl. Acad. Sci. U S A. 101, 10990-4. (2004)
[See also related commentary: Young, J.A., Dillin, A.MAPping innate immunity. Proc. Natl. Acad. Sci. U S A. 101, 12781-12782.] (2004)

Kim, D.H., Feinbaum, R., Alloing, G., Emerson, F.E., Garsin, D.A., Inoue, H., Tanaka-Hino, M., Hisamoto, N., Matsumoto, K., Tan, M.W., Ausubel, F.M. A conserved p38 MAP kinase pathway in Caenorhabditis elegans innate immunity. Science 297, 623-626. (2002)
[See also related commentary: Nicholas, H.R., Hodgkin, J. Innate immunity: The worm fights back. Curr Biol. 12, R731-732.] (2002)

See Google Scholar for Kim publications.

Intestinal infection of C. elegans with Pseudomonas aeruginosa expressing GFP, visualized under differential interference contrast microscopy (top) and fluorescence microscopy (bottom).