Growth inhibition of cytosolic Salmonella by caspase-1 and caspase-11 precedes host cell death

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.

Differential roles of caspase-1 and caspase-11 in infection and inflammation

“…However, others have reported a protective role for caspase-11 during salmonellosis exclusively in the intestine6387. In mouse macrophages or embryonic fibroblasts, both caspase-1 and caspase-11 contribute to cell-autonomous control of intracellular replication of S. Typhimurium and other bacteria2158888990.…”

Molecular mechanisms of inflammasome signaling

“…Pyroptosis mediated by caspase‐11 provides effective host defense against cytosolic Gram‐negative bacteria in vivo . The enzymatic activity of caspase‐11, along with that of caspase‐1, synergistically restricts the growth of intracellular Gram‐negative bacteria in macrophages, intestinal epithelial cells, and fibroblasts …”

Molecular mechanisms and functions of pyroptosis, inflammatory caspases and inflammasomes in infectious diseases

“…A further study has shown that the catalytic activity of caspase-1 and caspase-11 is essential for dampening the intracellular growth of S . Typhimurium Δ sifA (133). In response to infection by L. pneumophila , caspase-11 regulates actin polymerization via cofilin to promote fusion between the vacuole containing L. pneumophila and lysosomes (125).…”