XIAP Promotes the Innate Immune Response during Cytosolic Bacterial Infection.

The role of the innate immune system is to coordinate recognition and control of invading pathogens, and to instruct the development of adaptive immunity. Pathogens are detected by pattern recognition receptors on membranes or in the cytosol of host cells. The Toll-like receptor (TLR) family senses pathogens at the plasma membrane or within the vacuole, while surveillance of the cytosol is provided by the NOD-like receptors (NLR) and RIG-I-like receptors. The TLR family is well characterized, however the proteins involved in detection of intracellular pathogens and activation of the innate immune signaling pathways have only recently been described. We performed an affinity-based method to identify components of the cytosolic innate immune signaling pathway that associated with Listeria monocytogenes (Lm), an intracellular pathogen. We identified several classes of candidate proteins, and determined that one protein, the X-linked inhibitor of apoptosis (XIAP), is critical for in vivo innate immunity to Lm infection. Mice deficient in XIAP display a greater susceptibility to Lm infection. In response to cytosolic Lm, XIAP enhanced signaling through the NF-κB and Jun N-terminal kinase (JNK) pathways. Additionally, XIAP promoted maximal production of pro-inflammatory cytokines upon bacterial infection in vitro or in vivo, or in response to combined treatment with Nod2 and TLR2 ligands. In vivo, we observed that XIAP regulates the expression of proinflammatory cytokines and is required for proper trafficking of Lm infected phagocytes to the white pulp of the spleen. Taken together, our results indicate that XIAP regulates the cytosolic innate immune response to Lm infection by promoting production of proinflammatory cytokines and coordinating TLR and NLR signaling. XIAP enhances proinflammatory cytokine production in vivo, promoting control of Lm replication and trafficking of infected phagocytes to the T cell zone of splenic follicles.Ph.D.Microbiology & ImmunologyUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/62254/1/lauradel_1.pd