| The innate immune system uses pathogen recognition receptors (PRRs) that recognize conserved microbial structures called pathogen-associated molecular patterns (PAMPs). PRRs include the membrane-associated Toll-like receptors (TLRs) family and the intracellular cytosolic sensors: retinoic acid inducible gene I (RIG-I)-like receptors (RLRs), the IFN-inducible double-stranded RNA (dsRNA)-dependent protein kinase (PKR), DNA-dependent activator of IRFs (DAI), and nucleotide-binding oligomerization domain (Nod)-like receptors (NLRs). One of these NLR proteins, the Neuronal Apoptosis Inhibitory Protein 5 (Naip5), has been first identified as a locus controlling susceptibility to Legionella pneumophila in mice. The work described in this thesis covers three aspects of host-pathogen interaction study based on Naip5/Legionella model: (1) Morphological and biochemical characterization of Legionella--containing phagosomes in Naip5 transgenic and non transgenic murine macrophages by fluorescence and electron microscopy; (2) Identification of the transcriptional regulators Irf1 and Irf8 as essential for restriction of Legionella pneumophila replication in macrophages in addition to the Nod-Like receptors Naip5 and Nlrc4; (3) Analysis of global cellular changes induced by Legionella pneumophila infection of bone marrow-derived macrophages at the transcriptional level and the protein expression and phosphorylation level. |
