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Summary Mycobacterium tuberculosis produces several bacterial effectors impacting the colonization of phagocytes. Here, we report that the putative lipoprotein LppM hinders phagocytosis by macrophages in a toll‐like receptor 2‐dependent manner. Moreover, recombinant LppM is able to functionally complement the phenotype of the mutant, when exogenously added during macrophage infection. LppM is also implicated in the phagosomal maturation, as a lppM deletion mutant is more easily addressed towards the acidified compartments of the macrophage than its isogenic parental strain. In addition, this mutant was affected in its ability to induce the secretion of pro‐inflammatory chemokines, interferon‐gamma‐inducible protein‐10, monocyte chemoattractant protein‐1 and macrophage inflammatory protein‐1α. Thus, our results describe a new mycobacterial protein involved in the early trafficking of the tubercle bacillus and its manipulation of the host immune response.

Summary Mycobacterium tuberculosis produces several bacterial effectors impacting the colonization of phagocytes. Here, we report that the putative lipoprotein LppM hinders phagocytosis by macrophages in a toll-like receptor 2-dependent manner. Moreover, recombinant LppM is able to functionally complement the phenotype of the mutant, when exogenously added during macrophage infection. LppM is also implicated in the phagosomal maturation, as a lppM deletion mutant is more easily addressed towards the acidified compartments of the macrophage than its isogenic parental strain. In addition, this mutant was affected in its ability to induce the secretion of pro-inflammatory chemokines, interferon-gamma-inducible protein-10, monocyte chemoattractant protein-1 and macrophage inflammatory protein-1α. Thus, our results describe a new mycobacterial protein involved in the early trafficking of the tubercle bacillus and its manipulation of the host immune response.

Summary The innate immune system is the most ancestral and ubiquitous system of defence against microbial infec- tion. The microbial sensing proteins involved in innate immunity recognize conserved and often structural components of microorganisms. One class of these pattern-recognition molecules, the Toll-like receptors (TLRs), are involved in detection of microbes in the extracellular compartment whereas a newly discov- ered family of proteins, the NBS-LRR proteins (for nucleotide-binding site and leucine-rich repeat), are involved in intracellular recognition of microbes and their products. NBS-LRR proteins are characterized by three structural domains: a C-terminal leucine-rich repeat (LRR) domain able to sense a microbial motif, an intermediary nucleotide binding site (NBS) essen- tial for the oligomerization of the molecule that is necessary for the signal transduction induced by dif- ferent N-terminal effector motifs, such as a pyrin domain (PYD), a caspase-activating and recruitment domain (CARD) or a baculovirus inhibitor of apopto- sis protein repeat (BIR) domain. Two of these family members, Nod1 and Nod2, play a role in the regulation of pro-inflammatory pathways through NF- k B induced by bacterial ligands. Recently, it was shown that Nod2 recognizes a specific peptidoglycan motif from bac- teria, muramyl dipeptide (MDP). A surprising number of human genetic disorders have been linked to NBS- LRR proteins. For example, mutations in Nod2, which render the molecule insensitive to MDP and unable to induce NF- k B activation when stimulated, are associ- ated with susceptibility to a chronic intestinal inflam- matory disorder, Crohn's disease. Conversely, mutations in the NBS region of Nod2 induce a consti- tutive activation of NF- k k k B and are responsible for Blau syndrome, another auto-inflammatory disease. Nalp3, which is an NBS-LRR protein with an N-terminal Pyrin domain, is also implicated in rare auto-inflammatory disorders. In conclusion, NBS-LRR molecules appear as a new family of intracellular receptors of innate immunity able to detect specific bacterial compounds and induce inflammatory response; the dysregulation of these processes due to mutations in the genes encoding these proteins is involved in numerous auto-inflammatory disorders.