Post-phagocytosis activation of NLRP3 inflammasome by two novel T6SS effectors

Abstract

The type VI secretion system (T6SS) is used by bacteria to deliver toxic effectors directly into target cells. Most T6SSs mediate antibacterial activities, whereas the potential anti-eukaryotic role of T6SS remains understudied. Here, we found a Vibrio T6SS that delivers two novel effectors into mammalian host immune cells. We showed that these effectors induce a pyroptotic cell death in a phagocytosis-dependent manner; we identified the NLRP3 inflammasome as being the underlying mechanism leading to the T6SS-induced pyroptosis. Moreover, we identified a compensatory T6SS-induced pathway that is activated upon inhibition of the canonical pyroptosis pathway. Genetic analyses revealed possible horizontal spread of this T6SS and its anti-eukaryotic effectors into emerging pathogens in the marine environment. Our findings reveal novel T6SS effectors that activate the host inflammasome and possibly contribute to virulence and to the emergence of bacterial pathogens.

A new class of polymorphic T6SS effectors and tethers

“…Although T6SS was originally described as an anti-eukaryotic determinant, allowing V. cholerae to escape predation by grazing amoeba 1 , most Vibrio T6SSs investigated to date were shown to play a role in interbacterial competitions [46][47][48][49][50][51][52] , and only a handful of Vibrio T6SSs have been implicated in anti-eukaryotic activities. These Vibrio T6SSs include T6SS1 and T6SS3 in V. proteolyticus 48,53 , T6SS1 in V. tasmanienses 54 , and T6SS in V. crassostreae 55 . Several additional Vibrio T6SSs were also suggested to play a role in interactions with eukaryotes based on the presence of a predicted anti-eukaryotic MIX-effector in their genome 23 .…”

Vibrio parahaemolyticusT6SS2 effector repertoires

“…Most T6SSs investigated to date deliver effectors with antibacterial activities and have therefore been implicated in interbacterial competitions (7,(21)(22)(23)(24). However, several Vibrio T6SSs have also been shown to deliver effectors that target eukaryotic cells, indicating that they also mediate interactions with eukaryotes (13,23,25,26). Notably, antibacterial effectors are encoded in bi-cistronic units together with cognate immunity proteins that antagonize their toxic activity to prevent self or kin-intoxication (14,27).…”