Effector-triggered versus pattern-triggered immunity: how animals sense pathogens

Abstract

A fundamental question regarding any immune system is how it can discriminate between pathogens and non-pathogens. Here, we discuss how this discrimination can be mediated by a surveillance system distinct from pattern-recognition receptors that recognize conserved microbial patterns. It can be based instead on the ability of the host to sense perturbations in host cells induced by bacterial toxins or 'effectors' that are encoded by pathogenic microorganisms. Such 'effector-triggered immunity' was previously demonstrated mainly in plants, but recent data confirm that animals can also use this strategy.

Figure 1. An integrated model of the detection of virulent bacteria

a, During a bacterial infection, microorganism-associated molecular patterns (MAMPs) ligate pattern recognition receptors (PRRs) and induce immune signalling pathways and pattern-triggered immunity (PTI). b, Secreted effector proteins from evolved bacteria suppress the immune response induced by PRRs to promote infection. c, Resistant hosts can sense the presence of effectors and activate effector-triggered immunity (ETI). ETI can occur independently of the primary immune signalling pathways or by amplifying the ongoing PTI. d, In non-immune cells that do not express a full compliment of PRRs (such as epithelial cells), detection of pathogenic bacteria may occur primarily through ETI response pathways.

Figure 2. The outputs of effector-triggered immune responses are specific to the initiating type of damage

Different ETI responses are associated with different outputs that can specifically counteract the original insult. Left, After translocation into the cytoplasm, Escherichia coli-derived CNF1 deamidates RAC, which disrupts its intrinsic GTPase activity and locks it in an active GTP-bound state. Rac then interacts with RIP to induce immune signalling and nuclear factor-κB (NF-κB) activation that results in a robust antibacterial response. Center, Translation inhibition cause by Legionella pneumophila effectors induces a stress response through mitogen-activated protein kinase (MAPK) and associated pathways and amplifies NF-κB activation by causing loss of the NF-κB inhibitor, IκB. Right, Bacterial pore-forming toxins cause potassium efflux and decreased intracellular potassium concentrations. This low potassium is sensed through an unknown mechanism and induces a stress response (a p38 MAPK signalling pathways in mammals and JNK MAPK in C. elegans), and activation of the NLRP3 inflammasome. Inflammasome activation is associated with both an antimicrobial IL-1β response and cell autonomous membrane repair through SREBP. The figure focuses primarily on the mechanisms that have been shown in mammals and does not represent the totality of pathways demonstrated in all species. As an example, ETI in response to translational inhibition in worms is mediated by ZIP2 and is not shown.

Figure 3. The co-evolution of pathogenic bacteria with the host’s immune response

In the absence of an immune response bacteria quickly overwhelm their host. To contain these infections the host has evolved pattern-triggered immunity such as TLRs. To deal with the threat from the host, bacteria become more virulent by evolving inhibitory effector proteins, which disrupt host immune defenses. This effector-triggered susceptibility [G] promotes infection. In the next step of co-evolution, the host evolves the ability to detect the presence of effector proteins and induce effector-triggered immunity. In a final evolutionary step, hyper-virulent bacteria, such as Shigella spp. and Salmonella typhimurium have acquired the ability to deliberately activate immune signalling via activating effector proteins. This inflammatory response is associated with effector-triggered immune-pathology, which promotes both the colonization of the bacteria and aids their dissemination.