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Tricked or trapped—Two decoy mechanisms in host–pathogen interactions

Antagonistic interactions between hosts and pathogens frequently result in arms races. The host attempts to recognise the pathogen and inhibit its growth and spread, whereas the pathogen tries to subvert recognition and suppress host responses. These antagonistic interactions drive the evolution of ‘decoys’ in both hosts and pathogens. In host–pathogen interactions, the term decoy describes molecules that mimic a component at the host–pathogen interface that is manipulated during infection. Decoys undergo the same manipulation as the component they mimic, but they serve the opposite role, either by preventing manipulation of the component they mimic or by triggering a molecular recognition event. At least three different types of decoy have been defined, described in detail below. However, these different decoy models cause confusion on how they function mechanistically. Here, we discuss the three different types of decoys with examples and classify them according to two distinct mechanisms.

Receptor decoys: Mimics to absorb ligands

Some pathogens use ‘Receptor decoys’ to interfere with host immune signalling (Fig 1A). Examples of Receptor decoys are found in large DNA viruses. Some viruses have acquired a diverse set of Receptor decoys through recombination events with the host [1]. These Receptor decoys typically encode for viral versions of receptor homologs of the host and bind chemokines or cytokines to prevent efficient immune signalling in the host. For example, ectromelia virus (causative of mouse pox) encodes the Type 1-interferon binding protein (T1-IFNbp), a Receptor decoy that is essential for its virulence [2]. T1-IFNbp mimics the interferon receptor and attaches to uninfected cells close to the infection site in liver and spleen. By binding T1-IFN, T1-IFNbp facilitates virus spread and impairs defence signalling [3]. Therefore, this virus-derived Receptor decoy absorbs T1-IFN, a key signal in host immune signalling.

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Fig 1. Three types of decoys act through two distinct mechanisms.

Examples of Receptor (A), Bodyguard (B), and Sensing (C) decoys that act through either Sponge (D) or Bait (E) mechanisms. Avr2, Avirulence gene-2; avrPto, avirulence gene of Pseudomonas syringae pv. tomato; avrPtoB, avirulence gene B of Pseudomonas syringae pv. tomato; CEACAM, epithelial Carcino-embryonic Antigen-related Adhesion Molecules; CERK1, Chitin Elicitor Receptor Kinase-1; Cf-2, Cladosporium fulvum resistance gene-2; ECP6, extracellular Protein-6; GIP1, Glucanase Inhibitor Protein-1; NLR, Nod-like Receptor; OPA, opacity-associated membrane proteins; Pip1, Phytophthora-inhibited protease-1; PopP2, Pseudomonas outer protein P2; Prf, Pseudomonas resistance and fenthion sensitivity; Pto, Resistance to Pseudomonas syringae pv. tomato; Rcr3, Required for Cladosporium resistance-3; RLK, receptor-like kinase; RRS1, Resistance to Ralstonia solanacearum-1; T1-IFNbp, Type-1 interferon binding protein; TALE, Transcription Activator-like Effector; WRKY, Transcription factor with WRKY motif; XEG1, xyloglucan-specific endoglucanase-1; XLP1, XEG1-like protein-1.

https://doi.org/10.1371/journal.ppat.1006761.g001

A similar example of a pathogen-derived Receptor decoy is extracellular Protein-6 (Ecp6), a Lysin Motif (LysM)-containing effector that is secreted by the fungal pathogen Cladosporium fulvum during infection of tomato plants. Ecp6 suppresses chitin recognition and is therefore instrumental for C. fulvum virulence [4]. Chitin is an essential component of fungal cell walls, and many plants can sense fungal chitin through LysM-containing receptors such as Chitin Elicitor Receptor Kinase-1 (CERK1) and its homologs. Interestingly, Ecp6 captures chitin oligomers with high affinity and is thought to outcompete the LysM-based host immune receptor for chitin binding [5]. Therefore, Ecp6 mimics the chitin-binding capacity of the receptor and acts as a Receptor decoy by binding chitin to prevent recognition by the host. Interestingly, LysM-based effectors are widespread amongst fungal plant pathogens, so chitin absorption by LysM effectors appears to be a commonly used decoy strategy [6].

Bodyguard decoys: Protecting secreted virulence factors

Some pathogens employ ‘Bodyguard decoys’ to protect virulence factors [7]. Bodyguard decoys are inactive mimics of secreted virulence factors. They accompany these virulence factors and efficiently bind host-derived defence proteins that aim to suppress these virulence factors (Fig 1B). For instance, soybean secretes inhibitor GmGIP1 that strongly inhibits the xyloglucan-specific endoglucanase PsXEG1 of the soybean oomycete pathogen Phytophthora sojae [8]. PsXEG1 is an important virulence factor that probably acts on the host cell wall during infection. P. sojae, however, protects PsXEG1 by cosecreting the Bodyguard decoy PsXLP1, a truncated paralog of PsXEG1 with no known enzymatic activity [8]. PsXLP1 has a higher binding affinity for GmGIP1 and acts as a Bodyguard decoy by outcompeting the inhibition of PsXEG1.

A similar Bodyguard decoy concept has been proposed for truncated versions of Transcription Activator-like Effectors (TALEs) that are secreted by the bacterial plant pathogen Xanthomonas [7]. TALEs trans-activate host genes in the plant cell nucleus to facilitate bacterial infection and therefore have a major role in virulence. Some host plants carry Nod-like Receptor (NLR) proteins that confer recognition of TALEs and trigger immune responses. Remarkably, a recently discovered class of truncated TALEs named ‘iTALEs’ [9] or ‘truncTALEs’ [10] with N- and C-terminal deletions can suppress TALE recognition by these NLRs, possibly by binding the NLR without activating it. Therefore, these truncated TALEs may act as a Bodyguard decoy to prevent NLR activation through full-length TALEs that act as virulence factors.

Sensing decoys: Mimics of effector targets acting as coreceptors

The decoy concept has also been frequently used to explain the indirect recognition mechanisms through products of disease resistance genes in plants [11]. The usual interpretation is that these resistance genes monitor the modification of a decoy that mimics the target of a pathogen-derived effector. These ‘Sensing decoys’ act as coreceptors with resistance gene products (Fig 1C).

A classic example of a Sensing decoy is the tomato resistance gene product Pto. Pto is a serine/threonine (Ser/Thr) kinase that confers resistance to strains of the bacterial pathogen Pseudomonas syringae secreting the Type-III effectors AvrPto and AvrPtoB [12,13]. AvrPto and AvrPtoB target receptor-like kinases (RLKs) involved in immune signalling by inhibiting or ubiquitinating them, respectively. Pto mimics these RLKs and confers recognition of AvrPto and AvrPtoB together with its binding partner Pseudomonas resistance and fenthion sensitivity (Prf), an NLR that triggers immune signalling. PBS1 is a similar Sensing decoy in the model plant Arabidopsis thaliana [14]. As with Pto, PBS1 is a Ser/Thr kinase that detects AvrPphB, a Type-III effector of P. syringae. AvrPphB is a cysteine protease that cleaves the kinase domain of immune-related RLKs. PBS1 is a Sensing decoy that mimics the target of AvrPphB and confers recognition of this effector by activating its binding partner Resistance to Pseudomonas syringae-5 (RPS5), an NLR that triggers immune signalling [14].

It was recently discovered that many plant NLRs may carry a Sensing decoy within themselves. For instance, the NLR Resistance to Ralstonia solanacearum-1 (RRS1) from A. thaliana carries like a WRKY-DNA–binding domain [15], and the NLRs RGA5 and Pik-1 in rice contain a heavy metal–associated (HMA) domain related to ATX1 (RATX1) [16,17]. These domains seem to mimic targets of effectors and enable pathogen detection. Therefore, they were named ‘Integrated decoys’ [18]. However, given that the specific biochemical activities of the ancestral effector targets and their NLR-integrated counterparts are generally unknown, they could be sensor domains retaining their biochemical activity as an extraneous domain within a classic NLR architecture [19].

Not all Sensing decoys associate with NLRs. A classic example comes from a study of the Cladosporium fulvum resistance gene-2 (Cf-2) resistance gene of tomato, which encodes a transmembrane receptor-like protein. Cf-2 confers recognition of the avirulence 2 (Avr2) effector secreted by the fungal tomato pathogen C. fulvum. Avr2 contributes to virulence by inhibiting Phytophthora-inhibited protease-1 (Pip1) and other extracellular papain-like Cys proteases of tomato. Cf-2 perceives Avr2 through its coreceptor Required for Cladosporium resistance-3 (Rcr3), a paralog of Pip1, which acts as a Sensing decoy to confer Avr2 recognition [20].

Likewise, human epithelial carcinoembryonic antigen-related adhesion molecules 3 (CEACAM3) can be considered to be a Sensing decoy that acts during gonorrhoea infection. To facilitate close attachment to epithelial cells in the human urogenital tract, the bacterial pathogen Neisseria gonorrhoeae expresses opacity-associated (Opa) membrane proteins [21]. Opas interact with a different human CEACAM, and this Opa–CEACAM interaction triggers bacterial engulfment and transcytosis and thereby facilitates infection [22]. However, some Opas also bind to the decoy CEACAM3, and this Opa–CEACAM3 interaction triggers efficient phagocytosis of the bacteria and recruitment and downstream activation of the neutrophils’ antimicrobial responses, including degranulation and oxidative burst [23]. Therefore, CEACAM3 acts as a Sensing decoy that allows the capture and killing of CEACAM-targeting microbes.

The concept of Sensing decoy can be extended beyond proteins. TALEs such as AvrBs3 from X. campestris and AvrHah1 from X. gardneri reprogram the host by binding and activating promoters of upa (up-regulated by AvrBs3) and other genes in the host [24,25]. The promotor of the pepper resistance gene Bs3 (pBs3) mimics the targets of these TALEs and transcriptionally activates the Bs3 gene product, leading to a localised cell death response that stops further pathogen growth. Therefore, pBs3 acts as a nonprotein Sensing decoy to trick AvrBs3 and AvrHah1 into a recognition event [25,26].

Two decoy mechanisms: Sponge and bait

The above examples of Receptor, Bodyguard, and Sensing decoys illustrate that the decoy concept is discussed frequently in host–pathogen interactions. This, however, causes confusion in the field because not all these decoys are mechanistically the same.

Receptor decoys are expected to have a higher affinity and/or abundance when compared to the receptor they mimic, to prevent the ligands from reaching the receptors and inducing immune signalling. Likewise, Bodyguard decoys must have a higher affinity and/or abundance when compared to the acting virulence factor to prevent the virulence factor from being inactivated or recognised. Therefore, both Receptor and Bodyguard decoys act as a sponge to absorb (Fig 1D). The ligand or virulence factor, respectively, is ‘trapped’ because it cannot reach its operative target as it is captured by the Sponge mechanism.

In contrast, all Sensing decoys act like a bait. These baits are not necessarily preventing the interaction of the effector with its operative target. The response to recognition can simply overrule the benefits of the effector manipulating its operative target. Therefore, in the Bait mechanism, the effector is ‘tricked’ by the Sensing decoy that prompts a recognition event (Fig 1E). Indeed, there is no evidence that Sensing decoys like Pto, PBS1, HMA, Rcr3, CEACAM3, and pBs3 prevent the interaction of the sensed effector with its operative target.

Further thoughts

Sponge and Bait mechanisms occur frequently at the host–pathogen interface. By its definition, decoys are thought to have no additional role, e.g., in development, disease or resistance. Hypothetically, however, because of their crucial role, decoys can become an attractive target for manipulation and can evolve into a target. In addition, also outside of that specific host–pathogen interaction, decoys may play a role. Therefore, it is important to use decoy terminology when the decoy acts in conjunction with the component they mimic.

Interestingly, the presented examples indicate a trend: all Sponge mechanisms that we define here are pathogen derived, while Bait mechanisms are host derived. There is, however, no reason to exclude the existence of host-derived Sponge mechanisms. For instance, the absorbance of pathogen-derived toxins to prevent them from reaching their target in the host is likely to occur. Bait mechanisms may only be host-derived because invading pathogens are more likely to sense the host in a direct way, not least because receptors that recognize the host are also under selection pressure and coevolve with the host. Because some pathogenic organisms may become a host themselves, it is conceivable that they may also have decoys that act as a bait.

While both types of decoy mechanisms have been described in the literature, much remains to be discovered. The discovery of more decoy examples will help us to find novel drug targets as well as new possibilities to improve host immunity. The latter is illustrated by a broader resistance spectrum upon decoy engineering of PBS1 in Arabidopsis plants [27].

Acknowledgments

We would like to thank Jiorgos Kourelis, Friederike Grosse-Holz, Daniela Sueldo, Sophien Kamoun, and the anonymous reviewers for their critical reading and suggestions.

References

  1. 1. Felix J, Savvides S N. Mechanisms of immunomodulation by mammalian and viral decoy receptors: insights from structures. Nat. Rev. Immunol. 2017; 17:112–129. http://doi.org/10.1038/nri.2016.134 pmid:28028310
  2. 2. Xu R -H, Cohen M, Tang Y, Lazear E, Whitbeck J C, et al. The orthopoxvirus type I IFN binding protein is essential for virulence and an effective target for vaccination. J. Exp. Med. 2008; 205:981–992. http://doi.org/10.1084/jem.20071854 pmid:18391063
  3. 3. Xu R -H, Rubio D, Roscoe F, Krouse T E, Truckenmiller M E, et al. Antibody inhibition of a viral type 1 interferon decoy receptor cures a viral disease by restoring interferon signaling in the liver. PLoS Pathog. 2012; 8:e1002475. http://doi.org/10.1371/journal.ppat.1002475 pmid:22241999
  4. 4. de Jonge R, van Esse HP, Kombrink A, Shinya T, Desaki Y. et al. Conserved fungal LysM effector Ecp6 prevents chitin-triggered immunity in plants. Science 2010; 329:953–955. http://doi.org/10.1126/science.1190859 pmid:20724636
  5. 5. Sánchez-Vallet A, Saleem-Batcha R, Kombrink A, Hansen G, Valkenburg DJ, et al. Fungal effector Ecp6 outcompetes host immune receptor for chitin binding through intrachain LysM dimerization. eLife 2013; 2:e00790. http://doi.org/10.7554/eLife.00790 pmid:23840930
  6. 6. Kombrink A,Thomma B P H J. LysM effectors: secreted proteins supporting fungal life. PLoS Pathog. 2013; 9:e1003769. http://doi.org/10.1371/journal.ppat.1003769 pmid:24348247
  7. 7. Paulus J K, Kourelis J, van der Hoorn R A L. Bodyguards: pathogen-derived decoys that protect virulence factors. Trends Plant Sci. 2017; 22:355–357. http://doi.org/10.1016/j.tplants.2017.03.004 pmid:28359678
  8. 8. Ma Z, Zhu L, Song T, Wang Y, Zhang Q, et al. A paralogous decoy protects Phytophthora sojae apoplastic effector PsXEG1 from a host inhibitor. Science 2017; 355:710–714. http://doi.org/10.1126/science.aai7919 pmid:28082413
  9. 9. Ji Z, Ji C, Liu B, Zou L, Chen G, et al. Interfering TAL effectors of Xanthomonas oryzae neutralize R-gene-mediated plant disease resistance. Nat. Commun. 2016; 7:13435. http://doi.org/10.1038/ncomms13435 pmid:27811915
  10. 10. Read A C, Rinaldi F C, Hutin M, He Y-Q, Triplett L R, et al. Suppression of Xo1-mediated disease resistance in rice by a truncated, non-DNA-binding TAL effector of Xanthomonas oryzae. Front. Plant Sci. 2016; 7:1516. http://doi.org/10.3389/fpls.2016.01516 pmid:27790231
  11. 11. van der Hoorn R A L, Kamoun S. From guard to decoy: a new model for perception of plant pathogen effectors. Plant Cell 2008; 20:2009–2017. http://doi.org/10.1105/tpc.108.060194 pmid:18723576
  12. 12. Ntoukakis V, Mucyn TS, Gimenez-Ibanez S, Chapman HC, Gutierrez JR, et al. Host inhibition of a bacterial virulence effector triggers immunity to infection. Science 2009; 324:784–787. http://doi.org/10.1126/science.1169430 pmid:19423826
  13. 13. Pedley K F, Martin G B. Molecular basis of Pto-mediated resistance to bacterial speck disease in tomato. Annu. Rev. Phytopathol. 2003; 41:215–243. https://doi.org/10.1146/annurev.phyto.41.121602.143032 pmid:14527329
  14. 14. Qi D, Dubiella U, Kim SH, Sloss DI, Dowen RH, et al. Recognition of the protein kinase AVRPPHB SUSCEPTIBLE1 by the disease resistance protein RESISTANCE TO PSEUDOMONAS SYRINGAE5 is dependent on S-acylation and an exposed loop in AVRPPHB SUSCEPTIBLE1. Plant Physiol. 2014; 164:340–351. http://doi.org/10.1104/pp.113.227686 pmid:24225654
  15. 15. Deslandes L, Olivier J, Theulières F, Hirsch J, Feng D X, et al. Resistance to Ralstonia solanacearum in Arabidopsis thaliana is conferred by the recessive RRS1-R gene, a member of a novel family of resistance genes. Proc. Natl. Acad. Sci. 2002; 99:2404–2409. http://doi.org/10.1073/pnas.032485099 pmid:11842188
  16. 16. Okuyama Y, Kanzaki H, Abe A, Yoshida K, Tamiru M, et al. A multifaceted genomics approach allows the isolation of the rice Pia-blast resistance gene consisting of two adjacent NBS-LRR protein genes. Plant J. Cell Mol. Biol. 2011; 66:467–479. http://doi.org/10.1111/j.1365-313X.2011.04502.x
  17. 17. Cesari S, Thilliez G, Ribot C, Chalvon V, Michel C, et al. The rice resistance protein pair RGA4/RGA5 recognizes the Magnaporthe oryzae effectors AVR-Pia and AVR1-CO39 by direct binding. Plant Cell 2013; 25:1463–1481. http://doi.org/10.1105/tpc.112.107201 pmid:23548743
  18. 18. Cesari S, Bernoux M, Moncuquet P, Kroj T. Dodds P N. A novel conserved mechanism for plant NLR protein pairs: the ‘integrated decoy’ hypothesis. Front. Plant Sci. 2014; 5:606. https://doi.org/10.3389/fpls.2014.00606 pmid:25506347
  19. 19. Wu C-H, Krasileva K V, Banfield M J, Terauchi R, Kamoun S. The “sensor domains” of plant NLR proteins: more than decoys? Front. Plant Sci. 2015; 6:134. https://doi.org/10.3389/fpls.2015.00134 pmid:25798142
  20. 20. Shabab M, Shindo T, Gu C, Kaschani F, Pansuriya T, et al. Fungal effector protein AVR2 targets diversifying defense-related Cys proteases of tomato. Plant Cell 2008; 20:1169–1183. http://doi.org/10.1105/tpc.107.056325 pmid:18451324
  21. 21. Sadarangani M, Pollard A J, Gray-Owen S D. Opa proteins and CEACAMs: pathways of immune engagement for pathogenic Neisseria. FEMS Microbiol. Rev. 2011; 35:498–514. http://doi.org/10.1111/j.1574-6976.2010.00260.x pmid:21204865
  22. 22. Tchoupa A K, Schuhmacher T, Hauck C R. Signaling by epithelial members of the CEACAM family—mucosal docking sites for pathogenic bacteria. Cell Commun. Signal. CCS 2014; 12:27. http://doi.org/10.1186/1478-811X-12-27 pmid:24735478
  23. 23. Sintsova A, Sarantis H, Islam E A, Sun C X, Amin M. et al. Global analysis of neutrophil responses to Neisseria gonorrhoeae reveals a self-propagating inflammatory program. PLoS Pathog. 2014; 10:e1004341. http://doi.org/10.1371/journal.ppat.1004341 pmid:25188454
  24. 24. Kay S, Hahn S, Marois E, Hause G, Bonas U. A Bacterial effector acts as a plant transcription factor and induces a cell size regulator. Science 2007; 318:648–651. http://doi.org/10.1126/science.1144956 pmid:17962565
  25. 25. Schornack S, Minsavage G V, Stall R E, Jones J B, Lahaye T. Characterization of AvrHah1, a novel AvrBs3-like effector from Xanthomonas gardneri with virulence and avirulence activity. New Phytol. 2008; 179:546–556. https://doi.org/10.1111/j.1469-8137.2008.02487.x pmid:19086184
  26. 26. Römer P, Hahn S, Jordan T, Strauss T, Bonas U, Lahaye T, et al. Plant pathogen recognition mediated by promoter activation of the pepper Bs3 resistance gene. Science 2007; 318:645–648. https://doi.org/10.1126/science.1144958 pmid:17962564
  27. 27. Kim S H, Qi D, Ashfield T, Helm M, Innes R W. Using decoys to expand the recognition specificity of a plant disease resistance protein. Science 2016; 351:684–687. https://doi.org/10.1126/science.aad3436 pmid:26912853