Defending against the Type Six Secretion System: beyond Immunity Genes

Abstract

The bacterial type six secretion system (T6SS) delivers toxic effector proteins into neighboring cells, but bacteria must protect themselves against their own T6SS. Immunity genes are the best-characterized defenses, protecting against specific cognate effectors. However, the prevalence of the T6SS and the coexistence of species with heterologous T6SSs suggest evolutionary pressure selecting for additional defenses against it. Here we review defenses against the T6SS beyond self-associated immunity genes, such as diverse stress responses that can recognize T6SS-inflicted damage and coordinate induction of molecular armor, repair pathways, and overall survival. Some of these stress responses are required for full survival even in the presence of immunity genes. Finally, we propose that immunity gene-independent protection is, mechanistically, bacterial innate immunity and that such defenses and the T6SS have co-evolved and continue to shape one another in polymicrobial communities.

Large-scale discovery of candidate type VI secretion effectors with antibacterial activity

“…This could be due to the fact that the immunity protein was either encoded somewhere else in the genome, but also could be due to non-immunityprotein-based immunity, i.e. by general mechanisms of immunity (Le et al 2020;Toska, Ho, and Mekalanos 2018;Hersch, Manera, and Dong 2020;Flaugnatti et al 2021).…”

High throughput identification of genes conferring resistance or sensitivity to toxic effectors delivered by the type VI secretion system

“…While immunity genes remain the gold standard of defence against T6SS effectors, numerous non-immunity defences have also been discovered (5,6): These include stress responses that help cells survive damage caused by effectors (7)(8)(9)(10), physical separation mechanisms (11)(12)(13), exopolysaccharides that act as armour to deflect incoming T6SS attacks (7,14,15), cell wall modifying enzymes that render the target molecules resistant to effectors (16), and proteins that play a role in survival by unclear mechanisms such as the periplasmic chaperone, Spy, the periplasmic protease inhibitor, Ecotin, and the outer membrane maltose porin, LamB, amongst others (7,17,18). Prey cell proteins can also play a role in activating incoming effectors: The ClpAP protease complex was shown to enhance susceptibility to the A. tumefaciens T6SS (19), and the Serratia marcescens effectors, Ssp2 and Ssp4, get activated in prey cells when their DsbA protein generates an intramolecular disulfide bridge (20).…”

Abiotic factors modulate interspecies competition mediated by the type VI secretion system effectors inVibrio cholerae

“…The T6SS is one such crucial mechanism exhibiting anti-bacterial, anti-fungal and other anti-eukaryotic functions [5,24,[49][50][51]. From a molecular ecological perspective, the T6SS-mediated interspecies competition is a complex and multifaced process whose outcome is determined by diverse factors including the number and type of the secreted effectors [31], the frequency of T6SS firing correlated with energy state [31], the immunity protein-dependent specific protection [24], the non-specific stress response pathways in killer and prey cells [18,20], and the availability of nutrients [52] [53]. Here, we add on to this list by showing that abiotic environmental factors can modulate prey cell sensitivity to effector toxicities, thereby affecting T6SS-mediated competition (Figure 6).…”