Abstract
Shigella infection, the cause of bacillary dysentery, induces caspase-1 activation and cell death in macrophages, but the precise mechanisms of this activation remain poorly understood. We demonstrate here that caspase-1 activation and IL-1β processing induced by Shigella are mediated through Ipaf, a cytosolic pattern-recognition receptor of the nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) family, and the adaptor protein apoptosis-associated speck-like protein containing a C-terminal caspase recruitment domain (ASC). We also show that Ipaf was critical for pyroptosis, a specialized form of caspase-1-dependent cell death induced in macrophages by bacterial infection, whereas ASC was dispensable. Unlike that observed in Salmonella and Legionella, caspase-1 activation induced by Shigella infection was independent of flagellin. Notably, infection of macrophages with Shigella induced autophagy, which was dramatically increased by the absence of caspase-1 or Ipaf, but not ASC. Autophagy induced by Shigella required an intact bacterial type III secretion system but not VirG protein, a bacterial factor required for autophagy in epithelial-infected cells. Treatment of macrophages with 3-methyladenine, an inhibitor of autophagy, enhanced pyroptosis induced by Shigella infection, suggesting that autophagy protects infected macrophages from pyroptosis. Thus, Ipaf plays a critical role in caspase-1 activation induced by Shigella independently of flagellin. Furthermore, the absence of Ipaf or caspase-1, but not ASC, regulates pyroptosis and the induction of autophagy in Shigella-infected macrophages, providing a novel function for NLR proteins in bacterial–host interactions.
Highlights
An effective immune response against microbial pathogens relies on the ability of the host to sense the presence of the infectious agent as well as the ability to destroy the invading pathogen
The recognition of bacterial pathogen-associated molecular pattern (PAMP) is mediated by several host molecules, including Toll-like receptors (TLRs) that are present on the cell surface and endosomal compartments, as well as nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs) that sense the presence of PAMPs in the cytosol [1,2]
A cytosolic pattern-recognition receptor of the nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) family, is a crucial host factor that activates caspase-1 through the sensing of flagellin produced by some bacteria, such as Salmonella or Legionella
Summary
An effective immune response against microbial pathogens relies on the ability of the host to sense the presence of the infectious agent as well as the ability to destroy the invading pathogen. The presence of infection is detected through pathogen recognition molecules that sense unique microbial components called pathogen-associated molecular patterns (PAMPs) [1,2]. The recognition of bacterial PAMPs is mediated by several host molecules, including Toll-like receptors (TLRs) that are present on the cell surface and endosomal compartments, as well as nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs) that sense the presence of PAMPs in the cytosol [1,2]. NLR proteins contain C-terminal leucine-rich repeats that are linked to microbial recognition, a centrally located NOD domain that mediates oligomerization, and an N-terminal effector domain that includes caspase-activation and recruitment domain or pyrin domain [3,4,5]. NLR proteins such as cryopyrin and Ipaf play a crucial role in processing mature IL-1b ( IL-18), which are important inflammatory cytokines in host
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