Recognizing the presence of invading pathogens is key to mounting an effective immune response1. The mammalian innate immune system employs several classes of germline-encoded pattern recognition receptors (PRRs) to monitor the extracellular and intracellular compartments of host cells for signs of infection. A subset of these, the NOD-like receptors, detects the presence of pathogens in the cytoplasm and assembles so-called inflammasome complexes, which activate the mammalian cysteine protease caspase-1. Active caspase-1 is a key determinant of inflammation, since it promotes the secretion of pro-inflammaotory cytokines like interleukin (IL)-1b and IL-18, and induces an inflammatory cell death called “pyroptosis”1.

Recently, a novel non-canonical inflammasome pathway has been identified which leads to the activation of caspase-112. We and others have shown that this pathway specifically responds to intracellular Gram-negative bacteria but not to Gram-positive pathogens3,4. Consistently, caspase-11 has been shown to promote lethality in a murine model of Lipopolysaccharaide (LPS)-induced septic shock 2. In line with these observations, it has been recently reported that cytoplasmic LPS is most likely the trigger of the non-canonical inflammasome5.

Interestingly, activation of caspase-11 also requires preceding production of type-I-interferon, indicating an important role for one or several interferon-induced genes in caspase-11 activation 3,4. We have recently carried out a siRNA screen with the goal of defining factors necessary for caspase-11 activation. This led to the identification of a family of interferon-inducible GTPases that control a number of bacteriocidal mechanisms and restrict growth of pathogens in cells6. Based on these data, we propose a novel and original hypothesis in that the cytosolic detection of bacteria by PRRs requires preceding killing of bacteria by interferon-induced cell autonomous defense mechanisms, thus establishing a so-far unrecognized link between these distinct arms of innate immunity.