PT  - JOURNAL ARTICLE
AU  - Elif Eren
AU  - Rémi Planès
AU  - Julien Buyck
AU  - Pierre-Jean Bordignon
AU  - André Colom
AU  - Olivier Cunrath
AU  - Roland F. Dreier
AU  - José C. Santos
AU  - Valérie Duplan-Eche
AU  - Emmanuelle Näser
AU  - Antonio Peixoto
AU  - Dirk Bumann
AU  - Céline Cougoule
AU  - Agnès Coste
AU  - Olivier Neyrolles
AU  - Petr Broz
AU  - Etienne Meunier
TI  - Type-3 Secretion System–induced pyroptosis protects Pseudomonas against cell-autonomous immunity
AID  - 10.1101/650333
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 650333
4099  - http://biorxiv.org/content/early/2019/05/28/650333.short
4100  - http://biorxiv.org/content/early/2019/05/28/650333.full
AB  - Inflammasome-induced pyroptosis comprises a key cell-autonomous immune process against intracellular bacteria, namely the generation of dying cell structures. These so-called pore-induced intracellular traps (PITs) entrap and weaken intracellular microbes. However, the immune importance of pyroptosis against extracellular pathogens remains unclear. Here, we report that Type-3 secretion system (T3SS)-expressing Pseudomonas aeruginosa (P. aeruginosa) escaped PIT immunity by inducing a NLRC4 inflammasome-dependent macrophage pyroptosis response in the extracellular environment. To the contrary, phagocytosis of Salmonella Typhimurium promoted NLRC4-dependent PIT formation and the subsequent bacterial caging. Remarkably, T3SS-deficient Pseudomonas were efficiently sequestered within PIT-dependent caging, which favored exposure to neutrophils. Conversely, both NLRC4 and caspase-11 deficient mice presented increased susceptibility to T3SS-deficient P. aeruginosa challenge, but not to T3SS-expressing P. aeruginosa. Overall, our results uncovered that P. aeruginosa uses its T3SS to overcome inflammasome-triggered pyroptosis, which is primarily effective against intracellular invaders.Importance Although innate immune components confer host protection against infections, the opportunistic bacterial pathogen Pseudomonas aeruginosa (P. aeruginosa) exploits the inflammatory reaction to thrive. Specifically the NLRC4 inflammasome, a crucial immune complex, triggers an Interleukin (IL)-1β and -18 deleterious host response to P. aeruginosa. Here, we provide evidence that, in addition to IL-1 cytokines, P. aeruginosa also exploits the NLRC4 inflammasome-induced pro-inflammatory cell death, namely pyroptosis, to avoid efficient uptake and killing by macrophages. Therefore, our study reveals that pyroptosis-driven immune effectiveness mainly depends on P. aeruginosa localization. This paves the way toward our comprehension of the mechanistic requirements for pyroptosis effectiveness upon microbial infections and may initiate targeted approaches in order to ameliorate the innate immune functions to infections.Graphical abstract Macrophages infected with T3SS-expressing P. aeruginosa die in a NLRC4-dependent manner, which allows bacterial escape from PIT-mediated cell-autonomous immunity and neutrophil efferocytosis. However, T3SS-deficient P. aeruginosa is detected by both NLRC4 and caspase-11 inflammasomes, which promotes bacterial trapping and subsequent efferocytosis of P. aeruginosa-containing-PITs by neutrophils.