TY - JOUR
T1 - Pathogen-Derived Effectors Trigger Protective Immunity via Activation of the Rac2 Enzyme and the IMD or Rip Kinase Signaling Pathway
AU - Boyer, Laurent
AU - Magoc, Lorin
AU - Dejardin, Stephanie
AU - Cappillino, Michael
AU - Paquette, Nicholas
AU - Hinault, Charlotte
AU - Charriere, Guillaume M.
AU - Ip, W. K.Eddie
AU - Fracchia, Shannon
AU - Hennessy, Elizabeth
AU - Erturk-Hasdemir, Deniz
AU - Reichhart, Jean Marc
AU - Silverman, Neal
AU - Lacy-Hulbert, Adam
AU - Stuart, Lynda M.
N1 - Funding Information:
We would like to thank D. Ferrandon, J.L. Imler, and C. Kocks for sharing fly stocks, K. Fitzgerald, J. Tschopp, G. Gacon, and the Drosophila Genomics Resource Center for plasmids and E. Lemichez and G. Flatau for providing CNF1 and CNF1 mutant purified proteins and cDNA and anti-CNF1 antibody. We thank J. Dejardin, O. Visvikis, P. Leopold, M. Maddugoda, A. Mettouchi, B. Ferrua, P. Munro, and A. Doye for technical suggestions and F. Ausubel, A Ezekowitz, and E. Lemichez for critical discussion and reading the manuscript. Technical support was provided by the C3M Cell Imaging Facility (Francois Prodon) and the Taplin Mass Spectrometric Facility (Ross Tomaino). L.B. was supported by Fondation Recherche Medical, MGH ECOR Fund for Medical Discovery and Ligue Nationale Contre le Cancer. This work was supported by NIH/NIAID grants to J-M.R. (PO1: A104420) and N.S (RO1: A160025) and grants to L.S from MGH ECOR and NIH/NIAID. All experiments were designed and interpreted by L.B. and L.M.S. L.M.S. supervised the work with assistance from A.L.-H. L.B. and L.M.S. wrote the manuscript with input from A.L.-H. and N.S. In vitro experiments were performed by L.B., S.D., C.H., G.M.C., E.H., and W.K.I. Flies were generated and maintained by L.B., M.C., and L.M. In vivo experiments were performed by L.B., L.M., M.C., N.P., and S.F. IMD, Relish, Dorsal and PGRP-LC reagents (constructs antibodies, etc.) were generated and supplied by D.E.-H., J.M.R., and N.S.
PY - 2011/10/28
Y1 - 2011/10/28
N2 - Although infections with virulent pathogens often induce a strong inflammatory reaction, what drives the increased immune response to pathogens compared to nonpathogenic microbes is poorly understood. One possibility is that the immune system senses the level of threat from a microorganism and augments the response accordingly. Here, focusing on cytotoxic necrotizing factor 1 (CNF1), an Escherichia coli-derived effector molecule, we showed the host indirectly sensed the pathogen by monitoring for the effector that modified RhoGTPases. CNF1 modified Rac2, which then interacted with the innate immune adaptors IMD and Rip1-Rip2 in flies and mammalian cells, respectively, to drive an immune response. This response was protective and increased the ability of the host to restrict pathogen growth, thus defining a mechanism of effector-triggered immunity that contributes to how metazoans defend against microbes with pathogenic potential.
AB - Although infections with virulent pathogens often induce a strong inflammatory reaction, what drives the increased immune response to pathogens compared to nonpathogenic microbes is poorly understood. One possibility is that the immune system senses the level of threat from a microorganism and augments the response accordingly. Here, focusing on cytotoxic necrotizing factor 1 (CNF1), an Escherichia coli-derived effector molecule, we showed the host indirectly sensed the pathogen by monitoring for the effector that modified RhoGTPases. CNF1 modified Rac2, which then interacted with the innate immune adaptors IMD and Rip1-Rip2 in flies and mammalian cells, respectively, to drive an immune response. This response was protective and increased the ability of the host to restrict pathogen growth, thus defining a mechanism of effector-triggered immunity that contributes to how metazoans defend against microbes with pathogenic potential.
UR - http://www.scopus.com/inward/record.url?scp=80755163546&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=80755163546&partnerID=8YFLogxK
U2 - 10.1016/j.immuni.2011.08.015
DO - 10.1016/j.immuni.2011.08.015
M3 - Article
C2 - 22018470
AN - SCOPUS:80755163546
SN - 1074-7613
VL - 35
SP - 536
EP - 549
JO - Immunity
JF - Immunity
IS - 4
ER -