Caspase-1-Dependent and -Independent Cell Death Pathways in Infection of Macrophages

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Inflammasome activation is important for host defence against bacterial infection. Many gram-negative pathogens use secretion systems to inject bacterial proteins such as flagellin or structural components of the secretion machinery itself into the host cytosol leading to caspase-1 activation and pyroptotic cell death. However, little is known about the B. pseudomallei factors that trigger caspase-1 activation as well as downstream signalling pathways and effector mechanisms of caspase-1. Here, we identified the B. pseudomallei T3SS3 inner rod protein BsaK as an early activator of caspase-1-dependent cell death and IL-1β secretion in primary macrophages and as a virulence factor in murine melioidosis. We could show that upon infection of macrophages, caspase-7 is activated downstream of the NLRC4/caspase-1 inflammasome and requires caspase-9 processing. Although caspase-7 was essential for cleavage of the DNA damage sensor PARP during pyroptosis, it did neither contribute to cytokine production nor B. pseudomallei growth restriction by promoting early macrophage death. In addition to a rapid NLRC4/caspase-1 -⁠ dependent induction of pyroptosis in wild-type macrophages, we observed a delayed activation of classical apoptosis in macrophages lacking caspase-1/11. Thus, initiation of different cell death pathways seems to be an effective strategy to limit intracellular B. pseudomallei infection.

Vyšlo v časopise: Caspase-1-Dependent and -Independent Cell Death Pathways in Infection of Macrophages. PLoS Pathog 10(3): e32767. doi:10.1371/journal.ppat.1003986
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1003986

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