MARDI 11 OCTOBRE 2016 – 12 heures 00
Salle Jules Bordet – Bâtiment Metchnikoff – RDC
Initiation of Innate Immunity and Host Defenses
Boston Children’s Hospital, Harvard Medical School, Boston, Etats-Unis
Invité par : Caroline Demangel poste 30 66
I have been studying Pattern Recognition Receptor signaling pathways as a means of understating the earliest events that initiate immunity to infection. Our work focuses on studies of the RIG-I like Receptor (RLR) and Toll-like Receptor (TLR) signaling networks, which operate to detect microorganisms that enter our bodies. The organizing principles that govern RLR and TLR signaling are entirely unknown and their elucidation will likely reveal answers to several fundamental questions that apply to the study of vaccine design. My research has focused primarily on defining the subcellular sites of RLR and TLR signal transduction. We have established that TLR adaptor proteins function as pairs of sorting and signaling adaptors, where the sorting adaptor functions to recruit the signaling adaptor to a subcellular site that contains an activated TLR. Our work provided the first in vivo evidence that the localization of these adaptor proteins in important for controlling microbial infections. In addition, we have defined a new signal transduction pathway activated when mammalian cells are exposed to bacterial LPS. This new pathway is most notable in that signal transduction is not initiated by the classic LPS receptor TLR4, but is rather triggered by the LPS binding protein CD14. Upon encountering LPS, CD14 triggers a signaling response that internalizes TLR4 into endosomes, where the classic TRIF-mediated signaling events that lead to interferon expression are activated. These studies provide the first evidence that TLR4 does not control all cellular responses to bacterial LPS, an observation that may have broad implications for the understanding of signal transduction in general. Using a similar logic that we have applied to the TLR network in our studies of RLRs, we have discovered a new subcellular site of antiviral signal transduction. In addition to the previously described mitochondria, RLR signaling also occurs from peroxisomes, an organelle never before implicated in innate immunity. We found that the signaling pathway emanating from peroxisomes is distinct from that induced from mitochondria, and specifically induces the expression of Type III Interferon genes, which are critical regulators of mucosal defense.