NLRC4 is an innate immune detector of the bacterial type III secretion apparatus (135.72)

The mammalian innate immune system uses Toll-like receptors (TLRs) and Nod-LRRs (NLRs) to detect microbial components during infection. Often these molecules work in concert; for example, the TLRs can stimulate the production of the pro-forms of the cytokines IL-1β and IL-18, whereas certain NLRs trigger their subsequent proteolytic processing via caspase 1. Gram negative bacteria utilize type III secretion systems (T3SS) to deliver virulence factors to the cytosol of host cells, where they modulate cell physiology to favour the pathogen. We show here that NLRC4/Ipaf detects the basal body rod component of the T3SS apparatus (rod protein) from S. typhimurium (PrgJ), Escherichia coli (EprJ and EscI), Burkholderia pseudomallei (BsaK), and Shigella flexneri (MxiI). These rod proteins share a sequence motif that is essential for detection by NLRC4; a similar motif is found in flagellin which is also detected by NLRC4. S. typhimurium has two T3SS: Salmonella pathogenicity island-1 (SPI-1), which encodes the rod protein PrgJ, and SPI-2, which encodes the rod protein SsaI. While PrgJ is detected by NLRC4, SsaI is not, and this evasion is required for virulence in mice. Our results indicate that macrophages respond to the activity of T3SS, not by sensing the specific translocated virulence factors, but rather by detecting the translocation apparatus that is conserved between pathogens. This reduces the number of host detectors required, a survival strategy that is divergent from that used by plants, where translocated effectors are detected on a gene for gene basis. Furthermore, the specific detection of the virulence machinery permits the discrimination between pathogenic and non pathogenic bacteria.