MyD88-dependent and -independent innate immune responses to Legionella pneumophila infection.

摘要

The intracellular Gram-negative bacterium, Legionella pneumophila is an opportunistic pathogen of humans. L. pneumophila is cleared rapidly from the mammalian host, thus it is predicted that the innate immune system is important for the recognition and initiation of an inflammatory response against this bacterium. Host pattern recognition receptors including those belonging to the Toll-like receptor (TLR) family likely contribute to the detection of L. pneumophila. To determine whether TLRs provide protection against L. pneumophila infection, we infected mice that were lacking individual TLRs or the common adapter protein, MyD88. We found that MyD88-deficient mice had severe defects in inflammatory cytokine production including IFN-gamma and exhibited robust bacterial growth following L. pneumophila infection. Mice lacking TLR2 had reduced cytokine production by macrophages and increased bacterial burdens compared to TLR2-sufficient mice, suggesting that TLR2 is partially responsible for MyD88-dependent host protection. To examine whether the phenotype in MyD88deficient mice is a result of the loss of IFN-gamma production, we infected mice lacking IFN-gamma with L. pneumophila. IFN-gamma-deficient mice had higher bacterial numbers in the lungs than wild-type mice; however, these mice were less susceptible to death compared to MyD88-deficient mice, suggesting that MyD88 controls both IFN-gamma-dependent and IFN-gamma-independent mechanisms of protection. Since MyD88-deficient mice were still able to mount an immune response to L. pneumophila, we tested the role of MyD88-independent immune pathways in L. pneumophila detection and restriction by using mice lacking the NOD-like receptor adapter protein, Rip2. We found that mice deficient in both Rip2 and MyD88 were more susceptible to L. pneumophila infection compared to mice only lacking MyD88, suggesting that NOD-like receptors also contribute to the innate immune response to L. pneumophila. Our data indicate that the dominant inflammatory response to L. pneumophila is initiated through MyD88 signaling which lead to both IFN-gammadependent and IFN-gamma-independent mechanisms of bacterial clearance in a pulmonary mouse model. In addition, MyD88-independent responses such as those initiated through Rip2 also play a role in providing host protection against L. pneumophila infection.