Innate Immune Detection of Bacterial Virulence Factors Via the NLRC4 Inflammasome

Cytokine production by innate immune cells is initiated by signaling downstream of pattern recognition receptors, including Toll-like receptors. A subset of cytokines, including IL-1β and IL-18, require post-translational proteolysis before secretion, which provides a second mechanism of regulation. This proteolysis is dependent upon caspase 1, which is activated by Nod-like receptor (NLR) signaling. NLRC4 (previously named Ipaf) activates caspase 1 in response to bacterial virulence factors including type III and IV secretion systems (T3SS and T4SS). NLRC4 recognizes T3SS/T4SS in two ways: indirectly by detecting flagellin, and directly by detecting the T3SS rod protein. Both flagellin and rod protein are unintentionally delivered to the mammalian cytosol by the bacterium through the T3SS.