Dendritic cells activate pyroptosis and effector-triggered apoptosis to restrict <i>Legionella</i> infection

The innate immune system relies on pattern recognition receptors (PRRs) to detect pathogen-associated molecular patterns (PAMPs) and guard proteins to monitor pathogen disruption of host cell processes. How different immune cell types engage PRRs and guard proteins to respond to infection is poorly understood. Here, we show that macrophages and dendritic cells (DCs) distinctly respond to bacterial virulence activities. In macrophages, the bacterial pathogen <i>Legionella pneumophila</i> deploys its Dot/Icm type IV secretion system (T4SS) to deliver effector proteins that facilitate robust intracellular replication. In contrast, T4SS activity triggers rapid death of DCs, which potently restricts <i>Legionella</i> replication. Intriguingly, we found that infected DCs exhibit considerable heterogeneity at the single-cell level. Initially, some DCs activate caspase-11 and NLRP3 inflammasome-dependent pyroptosis early during infection. At later time points, other DCs undergo apoptosis driven by T4SS effectors that block host protein synthesis, thereby depleting the pro-survival proteins Mcl-1 and cFLIP. Together, pyroptosis and effector-triggered apoptosis robustly restrict <i>Legionella</i> replication in DCs. Collectively, our findings suggest a model where Mcl-1 and cFLIP guard host translation in DCs. Furthermore, our work shows that macrophages and DCs distinctly employ innate immune sensors and guard proteins to mount divergent responses to <i>Legionella</i> infection.IMPORTANCEThe innate immune system senses bacterial pathogens by employing pattern recognition receptors that detect pathogen-associated molecular patterns (PAMPs) and guard proteins that monitor pathogen disruption of host cell processes. How different immune cell types engage pattern recognition receptors (PRRs) and guard proteins to respond to infection is poorly understood. Here, we reveal how dendritic cells (DCs) detect and restrict the intracellular bacterial pathogen <i>Legionella pneumophila</i>. At the single-cell level, we find that early during infection, some DCs activate caspase-11 pyroptosis. At later time points, other DCs undergo apoptosis driven by type IV secretion system (T4SS) effectors that block host protein synthesis, which depletes levels of the pro-survival proteins Mcl-1 and cFLIP. Our findings suggest Mcl-1 and cFLIP safeguard mRNA translation in DCs and highlight differences in how macrophages and DCs employ PRRs and guard proteins to respond to bacterial infection.