Effector-triggered immunity and pathogen sensing in metazoans

Abstract

Microbial pathogens possess an arsenal of strategies to invade their hosts, evade immune defences and promote infection. In particular, bacteria use virulence factors, such as secreted toxins and effector proteins, to manipulate host cellular processes and establish a replicative niche. Survival of eukaryotic organisms in the face of such challenge requires host mechanisms to detect and counteract these pathogen-specific virulence strategies. In this Review, we focus on effector-triggered immunity (ETI) in metazoan organisms as a mechanism for pathogen sensing and distinguishing pathogenic from non-pathogenic microorganisms. For the purposes of this Review, we adopt the concept of ETI formulated originally in the context of plant pathogens and their hosts, wherein specific host proteins 'guard' central cellular processes and trigger inflammatory responses following pathogen-driven disruption of these processes. While molecular mechanisms of ETI are well-described in plants, our understanding of functionally analogous mechanisms in metazoans is still emerging. In this Review, we present an overview of ETI in metazoans and discuss recently described cellular processes that are guarded by the host. Although all pathogens manipulate host pathways, we focus primarily on bacterial pathogens and highlight pathways of effector-triggered immune defence that sense disruption of core cellular processes by pathogens. Finally, we discuss recent developments in our understanding of how pathogens can evade ETI to overcome these host adaptations.

Fig. 1 |. Host cells possess multiple mechanisms of pathogen detection and immune defence.

a, PRRs represent an evolutionarily conserved mechanism to directly detect microbial products (termed PAMPs) that serve as general structural features of specific categories or classes of microorganisms (i). PAMP sensing by host PRRs triggers release of inflammatory mediators from the host cell. These mediators can, in turn, activate other cells to amplify the immune response. Certain intracellular molecules associated with damaged tissues or cells that are released as a consequence of microbial infection or other kinds of acute stress stimuli also contribute to innate immune activation (ii). These molecules, termed DAMPs, are also sensed by receptors on neighbouring cells and contribute to immune activation. b, ‘Patterns of pathogenesis’ provides an additional framework for understanding immune sensing of microbial pathogens, which manipulate cellular physiology to colonize the host but provide specific signals that enable the host to detect the pathogen. Such patterns include: (1) invasion of pathogens into the host cell, (2) altered vacuole trafficking, (3) vacuole disruption or cytosolic escape of the pathogen, (4) cytosolic replication of the pathogen and (5) disruption of host cellular processes by microbial effectors.

Fig. 2 |. Microbial threat checkpoints gauge the level of threat posed by a pathogen and fine-tune the host immune response.

Host immune responses are tuned according to the microbial threat level. (1) Low-level threats, such as PAMPs and dead microorganisms, lead to upregulation of cytokines and pro-survival factors. Negative regulators—such as IL-10, suppressor of cytokine signalling (SOCS) proteins and dual specificity phosphatases (DUSPs)—control and prevent excessive responses under such conditions. (2) Intracellular, viable non-pathogens and vita-PAMPs (for example, bacterial mRNA) pose a moderate level threat to the host and therefore lead to limited inflammasome activation (i) and release of proinflammatory cytokines and IL-1 signalling with limited levels of cell death or, in the absence of cell death, hyperactivation. The release of IL-1 cytokines is mediated by GSDMD, which forms pores in the cell membrane. (3) Pathogens that possess secretion systems and toxins that disrupt barrier tissues and membranes, or perturb host cellular processes, lead to robust inflammasome activation (ii), resulting in cell lysis and release of intracellular DAMPs (for example, HMGB1, calreticulin and ATP, together with IL-1). Notably, both pathogenic and sterile events that alter cellular homeostasis can trigger these immune responses. An alternative framework for thinking about these types of responses is as factors that indicate disruption of cellular homeostasis or HAMPs. These checkpoints allow the host to modulate the immune response based on the level of threat posed by a microorganism or other cellular stresses.

Fig. 3 |. Effector-triggered immunity engages inflammasomes, but can also be targeted by other pathogen virulence factors.

(i) Excessive injection of the Yersinia translocon proteins YopB and YopD damages intracellular endosomal membranes, leading to recruitment of GBPs and downstream activation of the caspase-11 inflammasome. Caspase-11-induced GSDMD pores also trigger K⁺ efflux, thereby secondarily activating the NLRP3 inflammasome. Yersinia suppresses this defence mechanism by preventing hypertranslocation of YopB and YopD via another effector, YopK. (ii) The NLRP1B inflammasome is activated by bacterial effectors such as B. anthracis LeTx or Shigella IpaH7.8, which cleave or degrade its N terminus, respectively. (iii) Effectors, such as YopE and TcdB, modulate the actin cytoskeleton by suppressing Rho GTPases and, consequently, trigger the pyrin inflammasome by inactivating the PKNs, which are sensitive to GTPase activity. Notably, Yersinia YopM overrides this sensing pathway by directly activating PKNs, thereby maintaining pyrin suppression.

Fig. 4 |. Pathogen manipulation of core cellular processes and signalling pathways induces host immune responses.

In addition to inflammasomes, the host has a myriad of other cellular defence pathways activated in response to virulent activity. Many of these pathways trigger signalling cascades that upregulate a subset of innate immune genes that promote host cell defence. Furthermore, other mechanisms, such as autophagy and cell death, serve to eliminate invading pathogens and infected cells. The following are examples of effector-triggered responses in these categories and pathogenic adaptations to evade these host responses. (i) Pathogen-induced amino acid starvation suppresses mTOR, activates autophagy and activates GCN2, leading to a block in host protein synthesis. Inhibiting protein translation may be useful against pathogens that co-opt host cellular processes for their own protein production, such as viral pathogens. Some pathogen effectors, such as Listeria PlcA and PlcB, can block mTOR signalling and autophagy, respectively, in order to evade detection and destruction. (ii) Similarly, pathogens that co-opt the host ER, such as Legionella and Brucella, induce ER stress and consequently trigger a block in protein translation. This activity triggers NF-κB and MAPK signalling and induces expression of subset of proinflammatory cytokines. To counteract this immune response, Legionella also possesses effectors that suppress ER stress and host protein translation, thereby partially masking itself from effector-triggered immunity. (iii) Activation of Rho GTPases by SopE and CNF1 similarly activates the NF-κB pathway to induce inflammatory cytokines and promote cell survival. Several pathogens have evolved to suppress immune signalling pathways in order to limit inflammation. However, in doing so, they activate an ETI pathway mediated by RIPK1 kinase activity, which induces host cell death. Effectors, such as YopJ, that suppress NF-κB and MAPK pathways induce RIPK1-dependent apoptosis. Pathogens that inhibit apoptosis may induce a back-up cell death mechanism, namely RIPK1-dependent necroptosis. Despite these fail-safes, some pathogens have evolved to suppress both of these responses: EPEC inhibits both apoptosis and necroptosis with the effectors NleB, NleF and EspL; the virus murine cytomegalovirus (mCMV) uses its effector viral inhibitor of RIP activation (vIRA) to suppress necroptosis.

Effector-triggered immunity models in plants.

Several mechanisms of effector-triggered immune responses have been proposed in plants, including two well-studied models. a, In the ‘gene-for-gene’ model, a pathogen avirulence (Avr) protein directly interacts with a host resistance (R) protein. This interaction activates a subsequent immune response from the host. b, In a second model, the guard model proposes that host proteins ‘guard’ cellular processes, and the disruption of these processes by virulence factors can be sensed by the host. For example, a pathogen effector that modifies a host protein can trigger recognition of this modification by the host cell, which then initiates an immune response. Since the activity of the effector, rather than the effector itself, is detected, this model of ETI does not rely on direct effector recognition.