Dendritic cells activate pyroptosis and effector-triggered apoptosis to restrict Legionella infection
ABSTRACT 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 i...
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| Format: | Article |
| Language: | English |
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American Society for Microbiology
2025-07-01
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| Series: | mBio |
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| Online Access: | https://journals.asm.org/doi/10.1128/mbio.01257-25 |
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| author | Víctor R. Vázquez Marrero Jessica Doerner Kimberly A. Wodzanowski Jenna Zhang Allyson Lu Frankie D. Boyer Isabel Vargas Suzana Hossain Karly B. Kammann Madison V. Dresler Sunny Shin |
| author_facet | Víctor R. Vázquez Marrero Jessica Doerner Kimberly A. Wodzanowski Jenna Zhang Allyson Lu Frankie D. Boyer Isabel Vargas Suzana Hossain Karly B. Kammann Madison V. Dresler Sunny Shin |
| author_sort | Víctor R. Vázquez Marrero |
| collection | DOAJ |
| description | ABSTRACT 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 Legionella pneumophila 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 Legionella 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 Legionella 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 Legionella 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 Legionella pneumophila. 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. |
| format | Article |
| id | doaj-art-c3df6df4de204657a589c3ae19cccaa2 |
| institution | Kabale University |
| issn | 2150-7511 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | American Society for Microbiology |
| record_format | Article |
| series | mBio |
| spelling | doaj-art-c3df6df4de204657a589c3ae19cccaa22025-08-20T03:28:41ZengAmerican Society for MicrobiologymBio2150-75112025-07-0116710.1128/mbio.01257-25Dendritic cells activate pyroptosis and effector-triggered apoptosis to restrict Legionella infectionVíctor R. Vázquez Marrero0Jessica Doerner1Kimberly A. Wodzanowski2Jenna Zhang3Allyson Lu4Frankie D. Boyer5Isabel Vargas6Suzana Hossain7Karly B. Kammann8Madison V. Dresler9Sunny Shin10Department of Microbiology, University of Pennsylvania, Perelman School of Medicine, Philadelphia, Pennsylvania, USADepartment of Microbiology, University of Pennsylvania, Perelman School of Medicine, Philadelphia, Pennsylvania, USADepartment of Microbiology, University of Pennsylvania, Perelman School of Medicine, Philadelphia, Pennsylvania, USADepartment of Microbiology, University of Pennsylvania, Perelman School of Medicine, Philadelphia, Pennsylvania, USADepartment of Microbiology, University of Pennsylvania, Perelman School of Medicine, Philadelphia, Pennsylvania, USADepartment of Microbiology, University of Pennsylvania, Perelman School of Medicine, Philadelphia, Pennsylvania, USADepartment of Microbiology, University of Pennsylvania, Perelman School of Medicine, Philadelphia, Pennsylvania, USADepartment of Microbiology, University of Pennsylvania, Perelman School of Medicine, Philadelphia, Pennsylvania, USADepartment of Microbiology, University of Pennsylvania, Perelman School of Medicine, Philadelphia, Pennsylvania, USADepartment of Microbiology, University of Pennsylvania, Perelman School of Medicine, Philadelphia, Pennsylvania, USADepartment of Microbiology, University of Pennsylvania, Perelman School of Medicine, Philadelphia, Pennsylvania, USAABSTRACT 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 Legionella pneumophila 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 Legionella 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 Legionella 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 Legionella 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 Legionella pneumophila. 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.https://journals.asm.org/doi/10.1128/mbio.01257-25Legionella pneumophiladendritic cellspyroptosisapoptosisguard immunityinnate immunity |
| spellingShingle | Víctor R. Vázquez Marrero Jessica Doerner Kimberly A. Wodzanowski Jenna Zhang Allyson Lu Frankie D. Boyer Isabel Vargas Suzana Hossain Karly B. Kammann Madison V. Dresler Sunny Shin Dendritic cells activate pyroptosis and effector-triggered apoptosis to restrict Legionella infection mBio Legionella pneumophila dendritic cells pyroptosis apoptosis guard immunity innate immunity |
| title | Dendritic cells activate pyroptosis and effector-triggered apoptosis to restrict Legionella infection |
| title_full | Dendritic cells activate pyroptosis and effector-triggered apoptosis to restrict Legionella infection |
| title_fullStr | Dendritic cells activate pyroptosis and effector-triggered apoptosis to restrict Legionella infection |
| title_full_unstemmed | Dendritic cells activate pyroptosis and effector-triggered apoptosis to restrict Legionella infection |
| title_short | Dendritic cells activate pyroptosis and effector-triggered apoptosis to restrict Legionella infection |
| title_sort | dendritic cells activate pyroptosis and effector triggered apoptosis to restrict legionella infection |
| topic | Legionella pneumophila dendritic cells pyroptosis apoptosis guard immunity innate immunity |
| url | https://journals.asm.org/doi/10.1128/mbio.01257-25 |
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