Jeffrey J Coleman1,2,3, Tomomi Komura1, Julia Munro2, Michael P Wu2, Rakhee R Busanelli4, Angela N Koehler4,5, Méryl Thomas4, Florence F Wagner4, Edward B Holson4,6, Eleftherios Mylonakis1,2. 1. Division of Infectious Diseases, Warren Alpert Medical School of Brown University, Rhode Island Hospital, Providence, RI 02903, USA. 2. MIT Division of Health Sciences and Technology, Harvard Medical School, Boston, MA 02115, USA. 3. Department of Entomology & Plant Pathology, Auburn University, Auburn, AL 36849, USA. 4. Chemical Biology Program, Broad Institute of MIT & Harvard, Cambridge, MA 02142, USA. 5. Department of Biological Engineering, Koch Institute for Integrative Cancer Research at MIT, Cambridge, MA 02139, USA. 6. Atlas Venture, Cambridge MA 02139, USA.
Abstract
AIM: Caffeic acid (3,4-dihydroxycinnamic acid) phenethyl ester (CAPE), the major constituent of propolis, is able to increase the survival of the nematode Caenorhabditis elegans after infection with the fungal pathogen Candida albicans. RESULTS: CAPE increases the expression of several antimicrobial proteins involved in the immune response to C. albicans. Structural derivatives of CAPE were synthesized to identify structure-activity relationships and decrease metabolic liability, ultimately leading to a compound that has similar efficacy, but increased in vivo stability. The CED-10(Rac-1)/PAK1 pathway was essential for immunomodulation by CAPE and was a critical component involved in the immune response to fungal pathogens. CONCLUSION: Caenorhabditis elegans is an efficient heterologous host to evaluate immunomodulatory compounds and identify components of the pathway(s) involved in the mode of action of compounds.
AIM: Caffeic acid (3,4-dihydroxycinnamic acid) phenethyl ester (CAPE), the major constituent of propolis, is able to increase the survival of the nematode Caenorhabditis elegans after infection with the fungal pathogen Candida albicans. RESULTS:CAPE increases the expression of several antimicrobial proteins involved in the immune response to C. albicans. Structural derivatives of CAPE were synthesized to identify structure-activity relationships and decrease metabolic liability, ultimately leading to a compound that has similar efficacy, but increased in vivo stability. The CED-10(Rac-1)/PAK1 pathway was essential for immunomodulation by CAPE and was a critical component involved in the immune response to fungal pathogens. CONCLUSION:Caenorhabditis elegans is an efficient heterologous host to evaluate immunomodulatory compounds and identify components of the pathway(s) involved in the mode of action of compounds.
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