Caspase-Dependent Innate Immune Mechanisms Against Bacterial Pathogens

The innate immune system relies on proteolytic enzymes known as caspases to detect and eliminate bacterial invaders. Caspase-1, activated within canonical inflammasomes such as NLRP3 or NLRC4, processes pro-interleukin-1β and pro-interleukin-18 into their active forms and induces pyroptotic cell death. In parallel, non-canonical inflammasomes employ caspase-4 and caspase-5 in humans (caspase-11 in mice) to sense cytosolic lipopolysaccharide (LPS), directly cleave gasdermin D and drive inflammatory cell lysis. These pathways operate in concert with upstream pattern-recognition receptors and interferon-induced factors, including guanylate-binding proteins, to restrict bacterial proliferation, orchestrate cytokine release and signal to adaptive immunity. Dysregulation of caspase-dependent responses underpins severe outcomes such as septicaemia and tissue injury, rendering components of the inflammasome machinery attractive targets for novel anti-infective and anti-inflammatory therapies.

Research from Nature Portfolio

Recent studies have shown that enterohaemorrhagic Escherichia coli deploy a secreted autotransporter, EhaF, which enters host cytosol to inhibit a MiT/TFE family transcription factor, thereby suppressing type I interferon expression and downstream inflammasome priming. This reveals a bacterial strategy to subvert caspase-mediated defences at the transcriptional level. Complementarily, work on human epithelial cells has demonstrated that interferon-induced guanylate-binding protein 1 (GBP1) binds cytosolic LPS with high affinity, nucleating a multiprotein coat that recruits and activates caspase-4 on bacterial surfaces. These findings provide mechanistic insight into non-canonical inflammasome assembly and highlight divergent host and microbial tactics that shape caspase-dependent immunity.

Caspase-Dependent Innate Immune Mechanisms Against Bacterial Pathogens publication trend

The graph below shows the total number of articles in caspase-dependent innate immune mechanisms against bacterial pathogens across all publications each year (not limited to Nature Index journals).

Technical terms

Caspase: A family of cysteine proteases that activate inflammatory cytokines and drive programmed cell death.

Inflammasome: A cytosolic multiprotein complex that senses danger signals and activates inflammatory caspases.

Pyroptosis: A lytic form of programmed cell death mediated by inflammatory caspases and membrane pore formation.

Gasdermin D (GSDMD): A pore-forming effector protein cleaved by caspases to execute pyroptotic cell death.

References

1. A bacterial autotransporter impairs innate immune responses by targeting the transcription factor TFE3. Nature Communications (2023).
2. Plexin C1 influences immune response to intracellular LPS and survival in murine sepsis. Journal of Biomedical Science (2024).
3. Human GBP1 binds LPS to initiate assembly of a caspase-4 activating platform on cytosolic bacteria. Nature Communications (2020).
4. An overview of the non-canonical inflammasome. Molecular Aspects of Medicine (2020).
5. Caspase-11 Activation in Response to Bacterial Secretion Systems that Access the Host Cytosol. PLOS Pathogens (2013).