Previous studies had shown that macrophages limit the replication of L. pneumophila through the induction of inflammasome-mediated cell death involving the pattern recognition receptor NAIP5 (NLR family, apoptosis inhibitory protein 5; which responds to bacterial flagellin in the cytoplasm) and caspase 1. However, DCs could undergo apoptosis and control bacterial growth in the absence of NAIP5 or caspase 1 following infection with L. pneumophila, with faster kinetics than those observed in macrophages. To examine this further, the authors investigated the effect of loss of caspase 3, a downstream mediator of apoptosis, in DCs from mice with defective NAIP5 signalling. Although caspase 3-deficient DCs showed similar responses to caspase 3-sufficient DCs from NAIP5 signalling-deficient mice 2 hours after infection, they showed significantly higher rates of infection and lower levels of apoptosis 10 hours after infection. This observation suggests that the caspase 3-dependent apoptotic pathway is important for inducing DC death, and therefore restricting pathogen replication, early after infection.
Caspase 3 can be activated by the intrinsic (or mitochondrial) pathway of apoptosis, which involves the pro-apoptotic proteins BAK (BCL-2 antagonist/killer) and BAX (BCL-2-associated X protein). DCs deficient in BAK and BAX showed similar levels of apoptosis to wild-type DCs after infection, suggesting that the NAIP5-dependent pathway remains functional and compensates for the loss of BAK and BAX. However, the BAX- and BAK-deficient DCs showed significantly lower levels of apoptosis and supported increased bacterial replication when infected with a strain of L. pneumophila that has a mutation in the flagellin-encoding gene flaA (and consequently cannot trigger NAIP5 activation). Therefore, the NAIP5-dependent and intrinsic pathways are two independent pathways of apoptosis that can both restrict L. pneumophila replication. Interestingly, overproduction of B cell lymphoma 2 (BCL-2), which is a pro-survival protein that counteracts the effects of BAX and BAK, by DCs infected with the flaA-mutant strain of L. pneumophila limited apoptosis and therefore resulted in enhanced intracellular bacterial replication, confirming the importance of the intrinsic apoptotic pathway in this process.
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