Flexible Usage and Interconnectivity of Diverse Cell Death Pathways Protect against Intracellular Infection
Marcel Doerflinger1, Yexuan Deng2, Paul Whitney3
1The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia.
Abstract:
Programmed cell death contributes to host defense against pathogens. To investigate the relative importance of pyroptosis, necroptosis, and apoptosis during Salmonella infection, we infected mice and macrophages deficient for diverse combinations of caspases-1, -11, -12, and -8 and receptor interacting serine/threonine kinase 3 (RIPK3). Loss of pyroptosis, caspase-8-driven apoptosis, or necroptosis had minor impact on Salmonella control. However, combined deficiency of these cell death pathways caused loss of bacterial control in mice and their macrophages, demonstrating that host defense can employ varying components of several cell death pathways to limit intracellular infections. This flexible use of distinct cell death pathways involved extensive cross-talk between initiators and effectors of pyroptosis and apoptosis, where initiator caspases-1 and -8 also functioned as executioners when all known effectors of cell death were absent. These findings uncover a highly coordinated and flexible cell death system with in-built fail-safe processes that protect the host from intracellular infections.
Insights
Host defense uses multiple programmed cell death pathways, including pyroptosis, apoptosis, and necroptosis, to control Salmonella infections. Combined deficiencies in these pathways compromise bacterial control, revealing a flexible, fail-safe system.
Area of Science:
- Immunology
- Cell Biology
- Microbiology
Background:
- Programmed cell death is crucial for host defense against intracellular pathogens like Salmonella.
- Distinct cell death pathways (pyroptosis, necroptosis, apoptosis) play roles in infection control.
Purpose of the Study:
- To investigate the individual and combined roles of pyroptosis, necroptosis, and apoptosis in Salmonella infection.
- To understand the interplay between different cell death pathways during host defense.
Main Methods:
- Infection of mice and macrophages deficient in caspases-1, -11, -12, -8, and RIPK3.
- Assessment of Salmonella control in various genetic knockout models.
Main Results:
- Individual deficiencies in pyroptosis, apoptosis, or necroptosis had minimal impact on Salmonella control.
- Combined deficiency of these cell death pathways led to a significant loss of bacterial control.
- Extensive cross-talk was observed between pyroptosis and apoptosis pathways, with caspases acting as both initiators and executioners.
Conclusions:
- Host defense against Salmonella infection is flexible, utilizing multiple cell death pathways.
- A coordinated cell death system with built-in fail-safe mechanisms protects the host from intracellular pathogens.
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