Abstract
Sensing bacterial products in the cytosol of mammalian cells by NOD-like receptors leads to the activation of caspase-1 inflammasomes, and the production of the pro-inflammatory cytokines interleukin (IL)-18 and IL-1β. In addition, mouse caspase-11 (represented in humans by its orthologs, caspase-4 and caspase-5) detects cytosolic bacterial LPS directly. Activation of caspase-1 and caspase-11 initiates pyroptotic host cell death that releases potentially harmful bacteria from the nutrient-rich host cell cytosol into the extracellular environment. Here we use single cell analysis and time-lapse microscopy to identify a subpopulation of host cells, in which growth of cytosolic Salmonella Typhimurium is inhibited independently or prior to the onset of cell death. The enzymatic activities of caspase-1 and caspase-11 are required for growth inhibition in different cell types. Our results reveal that these proteases have important functions beyond the direct induction of pyroptosis and proinflammatory cytokine secretion in the control of growth and elimination of cytosolic bacteria.
Highlights
Sensing bacterial products in the cytosol of mammalian cells by nucleotide-binding oligomerization domain (NOD)-like receptors leads to the activation of caspase-1 inflammasomes, and the production of the pro-inflammatory cytokines interleukin (IL)-18 and IL-1b
In the present work we analysed the fate of host cells and cytosolic bacterial growth at both whole population and single cell levels
Caspase-mediated processing of cytokines did not appear to be required as the absence of the adaptor protein ASC, the cytokine IL-18 or the receptor for IL-1b (IL-1r) did not yield increased growth of cytosolic bacteria
Summary
Sensing bacterial products in the cytosol of mammalian cells by NOD-like receptors leads to the activation of caspase-1 inflammasomes, and the production of the pro-inflammatory cytokines interleukin (IL)-18 and IL-1b. Proteins of the nucleotide-binding oligomerization domain (NOD)-like receptor (NLR; nucleotidebinding domain leucine-rich repeat containing receptor) family detect intracellular bacterial products that are either shed or delivered by secretion systems into the host cell cytosol, as well as other stress or danger-associated signals. Salmonella enterica serovar Typhimurium (Salmonella) has been used extensively, as a model Gram-negative pathogen to help elucidate the molecular mechanisms of virulence and immunity It replicates within a variety of host cells in membrane-bound compartments termed Salmonella-containing vacuoles (SCVs). Caspase-11 on the other hand is transcriptionally upregulated through TLR4-TRIF and STAT signalling[14,15,16] Both caspase-1 and caspase-11 mediate pro-inflammatory immune responses and initiate a form of inflammatory cell death termed pyroptosis[17] in response to Salmonella[16]. Cytosolic LPS-induced pyroptosis and IL-1a release requires caspase-11 but not caspase-1 activity[13,20]
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