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Bacterial effector protein

From Wikipedia, the free encyclopedia

Bacterial effectors are proteins secreted by pathogenic bacteria into the cells of their host, usually using a type 3 secretion system (TTSS/T3SS), a type 4 secretion system (TFSS/T4SS) or a Type VI secretion system (T6SS).[1] Some bacteria inject only a few effectors into their host’s cells while others may inject dozens or even hundreds. Effector proteins may have many different activities, but usually help the pathogen to invade host tissue, suppress its immune system, or otherwise help the pathogen to survive.[2] Effector proteins are usually critical for virulence. For instance, in the causative agent of plague (Yersinia pestis), the loss of the T3SS is sufficient to render the bacteria completely avirulent, even when they are directly introduced into the bloodstream.[3] Gram negative microbes are also suspected to deploy bacterial outer membrane vesicles to translocate effector proteins and virulence factors via a membrane vesicle trafficking secretory pathway, in order to modify their environment or attack/invade target cells, for example, at the host-pathogen interface.

Diversity

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Many pathogenic bacteria are known to have secreted effectors but for most species the exact number is unknown. Once a pathogen genome has been sequenced, effectors can be predicted based on protein sequence similarity, but such predictions are not always precise. More importantly, it is difficult to prove experimentally that a predicted effector is actually secreted into a host cell because the amount of each effector protein is tiny. For instance, Tobe et al. (2006) predicted more than 60 effectors for pathogenic E. coli but could only show for 39 that they are secreted into human Caco-2 cells. Finally, even within the same bacterial species, different strains often have different repertoires of effectors. For instance, the plant pathogen Pseudomonas syringae has 14 effectors in one strain, but more than 150 have been found in multiple different strains.[citation needed]

Species number of effectors reference
Chlamydia (multiple species) 16+ [4]
E. coli EHEC (O157:H7) 40-60 [5]
E. coli (EPEC) >20 [6]
Legionella pneumophila >330 (T4SS) [7][8][9]
Pseudomonas aeruginosa 4 [10]
Pseudomonas syringae 14 (>150 in multiple strains) [11]
Salmonella enterica 60+ [12]
Yersinia (multiple species) 14 [13]

Mechanism of action

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Given the diversity of effectors, they affect a wide variety of intracellular processes. The T3SS effectors of pathogenic E. coli, Shigella, Salmonella, and Yersinia regulate actin dynamics to facilitate their own attachment or invasion, subvert endocytic trafficking, block phagocytosis, modulate apoptotic pathways, and manipulate innate immunity as well as host responses.[14]

Phagocytosis. Phagocytes are immune cells that can recognize and "eat" bacteria. Phagocytes recognize bacteria directly [e.g., through the so-called scavenger receptor A which recognizes bacterial lipopolysaccharide (LPS) [15]] or indirectly through antibodies (IgG) and complement proteins (C3bi) which coat the bacteria and are recognized by the Fcγ receptors and integrinαmβ2 (complement receptor 3). For instance, intracellular Salmonella and Shigella escape phagocytic killing through manipulation of endolysosomal trafficking (see there). Yersinia predominantly survives extracellularly using the translocation of effectors to inhibit cytoskeletal rearrangements and thus phagocytosis. EPEC/EHEC inhibit both transcytosis through M cells and internalization by phagocytes.[16][17] Yersinia inhibits phagocytosis through the concerted actions of several effector proteins, including YopE which acts as a RhoGAP[18] and inhibits Rac-dependent actin polymerization.

Endocytic trafficking. Several bacteria, including Salmonella and Shigella, enter the cell and survive intracellularly by manipulating the endocytic pathway. Once internalized by host cells Salmonella subverts the endolysosome trafficking pathway to create a Salmonella-containing vacuole (SCV), which is essential for its intracellular survival. As the SCVs mature they travel to the microtubule organizing center (MTOC), a perinuclear region adjacent to the Golgi, where they produce Salmonella induced filaments (Sifs) dependent on the T3SS effectors SseF and SseG.[19] By contrast, internalized Shigella avoids the endolysosome system by rapidly lysing its vacuole through the action of the T3SS effectors IpaB and C although the details of this process are poorly understood.[20]

Secretory pathway. Some pathogens, such as EPEC/EHEC disrupt the secretory pathway.[21][22] For instance, their effector EspG can reduce the secretion of interleukin-8 (IL-8),[23] and thus affect the immune system (immunomodulation).[19] EspG functions as a Rab GTPase-activating protein (Rab-GAP),[23] trapping Rab-GTPases in their inactive GDP bound form, and reducing ER–Golgi transport (of IL-8 and other proteins).

Apoptosis (programmed cell death). Apoptosis is usually a mechanism of defense to infection, given that apoptotic cells eventually attract immune cells to remove them and the pathogen. Many pathogenic bacteria have developed mechanisms to prevent apoptosis, not the least to maintain their host environment. For instance, the EPEC/EHEC effectors NleH and NleF block apoptosis.[24][25] Similarly, the Shigella effectors IpgD and OspG (a homolog of NleH) block apoptosis,[24][26] the former by phosphorylating and stabilizing the double minute 2 protein (MDM2) which in turn leads to a block of NF-kB-induced apoptosis.[27] Salmonella inhibits apoptosis and activates pro-survival signals, dependent on the effectors AvrA and SopB, respectively.[28]

Induction of cell death. In contrast to inhibition of apoptosis, several effectors appear to induce programmed cell death. For instance, EHEC effectors EspF, EspH, and Cif induce apoptosis.[29][30][31]

Inflammatory response. Human cells have receptors that recognize pathogen-associated molecular patterns (PAMPs). When bacteria bind to these receptors, they activate signaling cascades such as the NF-kB and MAPK pathways. This leads to expression of cytokines, immunomodulating agents, such as interleukins and interferons which regulate immune response to infection and inflammation. Several bacterial effectors affect NF-kB signaling. For instance, the EPEC/EHEC effectors NleE, NleB, NleC, NleH, and Tir are immunosuppressing effectors that target proteins in the NF-kB signaling pathway. NleC has been shown to cleave the NF-kB p65 subunit (RelA), blocking the production of IL-8 following infection.[32] NleH1, but not NleH2, blocks translocation of NF-kB into the nucleus.[33][34] The Tir effector protein inhibits cytokine production.[35][36] Similarly, YopE, YopP, and YopJ (in Yersinia enterocolitica, Yersinia pestis, and Yersinia pseudotuberculosis respectively) target the NF-kB pathway. YopE inhibits activation of NF-kB, which in part prevents the production of IL-8.[37] YopJ family members are acetyltransferases that modify lysine, serine or threonine residues with an acetyl group, leading to protein aggregation,[38] blockage of phosphorylation[39] or inhibition of ATP binding.[40] In plants, this kind of protein acetylation can be removed through activity of the SOBER1/TIPSY1 deacetylase family.[41][42]

Databases and online resources

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  • EffectiveDB – A database of predicted bacterial effectors. Includes an interactive server to predict effectors.[43]
  • Bacterial Effector Proteins and their domains/motifs (from Paul Dean's lab)
  • T3DB – A database of Type 3 Secretion System (T3SS) proteins [44]
  • T3SE – T3SS Database
  • BEAN 2.0: an integrated web resource for the identification and functional analysis of type III secreted effectors[45]

References

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  1. ^ Ho, Brian T.; Fu, Yang; Dong, Tao G.; Mekalanos, John J. (29 August 2017). "Vibrio cholerae type 6 secretion system effector trafficking in target bacterial cells". Proceedings of the National Academy of Sciences of the United States of America. 114 (35): 9427–9432. doi:10.1073/pnas.1711219114. PMC 5584461. PMID 28808000.
  2. ^ Mattoo, Seema; Lee, Yvonne M; Dixon, Jack E (August 2007). "Interactions of bacterial effector proteins with host proteins". Current Opinion in Immunology. 19 (4): 392–401. doi:10.1016/j.coi.2007.06.005. PMID 17662586.
  3. ^ Viboud, Gloria I.; Bliska, James B. (October 2005). "OUTER PROTEINS: Role in Modulation of Host Cell Signaling Responses and Pathogenesis". Annual Review of Microbiology. 59 (1): 69–89. doi:10.1146/annurev.micro.59.030804.121320. PMID 15847602.
  4. ^ Betts, Helen J; Wolf, Katerina; Fields, Kenneth A (February 2009). "Effector protein modulation of host cells: examples in the Chlamydia spp. arsenal". Current Opinion in Microbiology. 12 (1): 81–87. doi:10.1016/j.mib.2008.11.009. PMID 19138553.
  5. ^ Tobe, Toru; Beatson, Scott A.; Taniguchi, Hisaaki; Abe, Hiroyuki; Bailey, Christopher M.; Fivian, Amanda; Younis, Rasha; Matthews, Sophie; Marches, Olivier; Frankel, Gad; Hayashi, Tetsuya; Pallen, Mark J. (3 October 2006). "An extensive repertoire of type III secretion effectors in Escherichia coli O157 and the role of lambdoid phages in their dissemination". Proceedings of the National Academy of Sciences of the United States of America. 103 (40): 14941–14946. Bibcode:2006PNAS..10314941T. doi:10.1073/pnas.0604891103. PMC 1595455. PMID 16990433.
  6. ^ Dean, Paul; Kenny, Brendan (February 2009). "The effector repertoire of enteropathogenic E. coli: ganging up on the host cell". Current Opinion in Microbiology. 12 (1): 101–109. doi:10.1016/j.mib.2008.11.006. PMC 2697328. PMID 19144561.
  7. ^ Burstein, David; Zusman, Tal; Degtyar, Elena; Viner, Ram; Segal, Gil; Pupko, Tal (10 July 2009). "Genome-Scale Identification of Legionella pneumophila Effectors Using a Machine Learning Approach". PLOS Pathogens. 5 (7): e1000508. doi:10.1371/journal.ppat.1000508. PMC 2701608. PMID 19593377.
  8. ^ Huang, Li; Boyd, Dana; Amyot, Whitney M.; Hempstead, Andrew D.; Luo, Zhao-Qing; O'Connor, Tamara J.; Chen, Cui; Machner, Matthias; Montminy, Timothy; Isberg, Ralph R. (February 2011). "The E Block motif is associated with Legionella pneumophila translocated substrates". Cellular Microbiology. 13 (2): 227–245. doi:10.1111/j.1462-5822.2010.01531.x. PMC 3096851. PMID 20880356.
  9. ^ Zhu, Wenhan; Banga, Simran; Tan, Yunhao; Zheng, Cheng; Stephenson, Robert; Gately, Jonathan; Luo, Zhao-Qing; Kwaik, Yousef Abu (9 March 2011). "Comprehensive Identification of Protein Substrates of the Dot/Icm Type IV Transporter of Legionella pneumophila". PLOS ONE. 6 (3): e17638. Bibcode:2011PLoSO...617638Z. doi:10.1371/journal.pone.0017638. PMC 3052360. PMID 21408005.
  10. ^ Engel, Joanne; Balachandran, Priya (February 2009). "Role of Pseudomonas aeruginosa type III effectors in disease". Current Opinion in Microbiology. 12 (1): 61–66. doi:10.1016/j.mib.2008.12.007. PMID 19168385.
  11. ^ Alfano, James R.; Collmer, Alan (September 2004). "TYPE III SECRETION SYSTEM EFFECTOR PROTEINS: Double Agents in Bacterial Disease and Plant Defense". Annual Review of Phytopathology. 42 (1): 385–414. doi:10.1146/annurev.phyto.42.040103.110731. PMID 15283671.
  12. ^ Van Engelenburg, Schuyler B; Palmer, Amy E (14 March 2010). "Imaging type-III secretion reveals dynamics and spatial segregation of Salmonella effectors". Nature Methods. 7 (4): 325–330. doi:10.1038/nmeth.1437. PMC 2862489. PMID 20228815.
  13. ^ Matsumoto, Hiroyuki; Young, Glenn M (February 2009). "Translocated effectors of Yersinia". Current Opinion in Microbiology. 12 (1): 94–100. doi:10.1016/j.mib.2008.12.005. PMC 2669664. PMID 19185531.
  14. ^ Kleiner, Manuel; Young, Jacque C.; Shah, Manesh; VerBerkmoes, Nathan C.; Dubilier, Nicole; Cavanaugh, Colleen; Moran, Mary Ann (18 June 2013). "Metaproteomics Reveals Abundant Transposase Expression in Mutualistic Endosymbionts". mBio. 4 (3): e00223-13. doi:10.1128/mBio.00223-13. PMC 3684830. PMID 23781067.
  15. ^ Kaufmann, S. H. E.; Peiser, Leanne; Gough, Peter J.; Kodama, Tatsuhiko; Gordon, Siamon (1 April 2000). "Macrophage Class A Scavenger Receptor-Mediated Phagocytosis of Escherichia coli: Role of Cell Heterogeneity, Microbial Strain, and Culture Conditions In Vitro". Infection and Immunity. 68 (4): 1953–1963. doi:10.1128/iai.68.4.1953-1963.2000. PMC 97372. PMID 10722588.
  16. ^ Martinez-Argudo, Isabel; Sands, Caroline; Jepson, Mark A. (June 2007). "Translocation of enteropathogenic Escherichia coli across an in vitro M cell model is regulated by its type III secretion system". Cellular Microbiology. 9 (6): 1538–1546. doi:10.1111/j.1462-5822.2007.00891.x. PMID 17298392. S2CID 36420610.
  17. ^ Goosney, Danika L.; Celli, Jean; Kenny, Brendan; Finlay, B. Brett (February 1999). "Enteropathogenic Escherichia coli Inhibits Phagocytosis". Infection and Immunity. 67 (2): 490–495. doi:10.1128/IAI.67.2.490-495.1999. PMC 96346. PMID 9916050.
  18. ^ Von Pawel-Rammingen, Ulrich; Telepnev, Maxim V.; Schmidt, Gudula; Aktories, Klaus; Wolf-Watz, Hans; Rosqvist, Roland (18 January 2002). "GAP activity of the Yersinia YopE cytotoxin specifically targets the Rho pathway: a mechanism for disruption of actin microfilament structure". Molecular Microbiology. 36 (3): 737–748. doi:10.1046/j.1365-2958.2000.01898.x. PMID 10844661.
  19. ^ a b Raymond, Benoit; Young, Joanna C.; Pallett, Mitchell; Endres, Robert G.; Clements, Abigail; Frankel, Gad (August 2013). "Subversion of trafficking, apoptosis, and innate immunity by type III secretion system effectors". Trends in Microbiology. 21 (8): 430–441. doi:10.1016/j.tim.2013.06.008. PMID 23870533.
  20. ^ Blocker, Ariel; Gounon, Pierre; Larquet, Eric; Niebuhr, Kirsten; Cabiaux, Véronique; Parsot, Claude; Sansonetti, Philippe (1 November 1999). "The Tripartite Type III Secreton of Shigella flexneri Inserts Ipab and Ipac into Host Membranes". Journal of Cell Biology. 147 (3): 683–693. doi:10.1083/jcb.147.3.683. PMC 2151192. PMID 10545510.
  21. ^ Selyunin, Andrey S.; Sutton, Sarah E.; Weigele, Bethany A.; Reddick, L. Evan; Orchard, Robert C.; Bresson, Stefan M.; Tomchick, Diana R.; Alto, Neal M. (19 December 2010). "The assembly of a GTPase–kinase signalling complex by a bacterial catalytic scaffold". Nature. 469 (7328): 107–111. doi:10.1038/nature09593. PMC 3675890. PMID 21170023.
  22. ^ Clements, Abigail; Smollett, Katherine; Lee, Sau Fung; Hartland, Elizabeth L.; Lowe, Martin; Frankel, Gad (September 2011). "EspG of enteropathogenic and enterohemorrhagic E. coli binds the Golgi matrix protein GM130 and disrupts the Golgi structure and function". Cellular Microbiology. 13 (9): 1429–1439. doi:10.1111/j.1462-5822.2011.01631.x. PMID 21740499.
  23. ^ a b Dong, Na; Zhu, Yongqun; Lu, Qiuhe; Hu, Liyan; Zheng, Yuqing; Shao, Feng (August 2012). "Structurally Distinct Bacterial TBC-like GAPs Link Arf GTPase to Rab1 Inactivation to Counteract Host Defenses". Cell. 150 (5): 1029–1041. doi:10.1016/j.cell.2012.06.050. PMID 22939626.
  24. ^ a b Hemrajani, Cordula; Berger, Cedric N.; Robinson, Keith S.; Marchès, Olivier; Mousnier, Aurelie; Frankel, Gad (16 February 2010). "NleH effectors interact with Bax inhibitor-1 to block apoptosis during enteropathogenic Escherichia coli infection". Proceedings of the National Academy of Sciences of the United States of America. 107 (7): 3129–3134. Bibcode:2010PNAS..107.3129H. doi:10.1073/pnas.0911609106. PMC 2840288. PMID 20133763.
  25. ^ Blasche, Sonja; Mörtl, Mario; Steuber, Holger; Siszler, Gabriella; Nisa, Shahista; Schwarz, Frank; Lavrik, Inna; Gronewold, Thomas M. A.; Maskos, Klaus; Donnenberg, Michael S.; Ullmann, Dirk; Uetz, Peter; Kögl, Manfred (14 March 2013). "The E. coli Effector Protein NleF Is a Caspase Inhibitor". PLOS ONE. 8 (3): e58937. Bibcode:2013PLoSO...858937B. doi:10.1371/journal.pone.0058937. PMC 3597564. PMID 23516580.
  26. ^ Clark, Christina S.; Maurelli, Anthony T. (May 2007). "Shigella flexneri Inhibits Staurosporine-Induced Apoptosis in Epithelial Cells". Infection and Immunity. 75 (5): 2531–2539. doi:10.1128/IAI.01866-06. PMC 1865761. PMID 17339354.
  27. ^ Bergounioux, Jean; Elisee, Ruben; Prunier, Anne-Laure; Donnadieu, Françoise; Sperandio, Brice; Sansonetti, Philippe; Arbibe, Laurence (March 2012). "Calpain Activation by the Shigella flexneri Effector VirA Regulates Key Steps in the Formation and Life of the Bacterium's Epithelial Niche". Cell Host & Microbe. 11 (3): 240–252. doi:10.1016/j.chom.2012.01.013. PMID 22423964.
  28. ^ Knodler, Leigh A; Finlay, B Brett; Steele-Mortimer, Olivia (10 January 2005). "The Salmonella Effector Protein SopB Protects Epithelial Cells from Apoptosis by Sustained Activation of Akt". Journal of Biological Chemistry. 280 (10): 9058–9064. doi:10.1074/jbc.M412588200. PMID 15642738.
  29. ^ Nougayrede, Jean-Philippe; Donnenberg, Michael S. (November 2004). "Enteropathogenic Escherichia coli EspF is targeted to mitochondria and is required to initiate the mitochondrial death pathway". Cellular Microbiology. 6 (11): 1097–1111. doi:10.1111/j.1462-5822.2004.00421.x. PMID 15469437.
  30. ^ Samba-Louaka, Ascel; Nougayrède, Jean-Philippe; Watrin, Claude; Oswald, Eric; Taieb, Frédéric (December 2009). "The Enteropathogenic Escherichia coli Effector Cif Induces Delayed Apoptosis in Epithelial Cells". Infection and Immunity. 77 (12): 5471–5477. doi:10.1128/IAI.00860-09. PMC 2786488. PMID 19786559.
  31. ^ Wong, Alexander R. C.; Clements, Abigail; Raymond, Benoit; Crepin, Valerie F.; Frankel, Gad; Bagnoli, Fabio; Rappuoli, Rino (17 January 2012). "The Interplay between the Escherichia coli Rho Guanine Nucleotide Exchange Factor Effectors and the Mammalian RhoGEF Inhibitor EspH". mBio. 3 (1). doi:10.1128/mBio.00250-11. PMC 3374388. PMID 22251971.
  32. ^ Yen, Hilo; Ooka, Tadasuke; Iguchi, Atsushi; Hayashi, Tetsuya; Sugimoto, Nakaba; Tobe, Toru; Van Nhieu, Guy Tran (16 December 2010). "NleC, a Type III Secretion Protease, Compromises NF-κB Activation by Targeting p65/RelA". PLOS Pathogens. 6 (12): e1001231. doi:10.1371/journal.ppat.1001231. PMC 3002990. PMID 21187904.
  33. ^ Pham, Thanh H.; Gao, Xiaofei; Tsai, Karen; Olsen, Rachel; Wan, Fengyi; Hardwidge, Philip R.; McCormick, B. A. (June 2012). "Functional Differences and Interactions between the Escherichia coli Type III Secretion System Effectors NleH1 and NleH2". Infection and Immunity. 80 (6): 2133–2140. doi:10.1128/IAI.06358-11. PMC 3370600. PMID 22451523.
  34. ^ Gao, Xiaofei; Wan, Fengyi; Mateo, Kristina; Callegari, Eduardo; Wang, Dan; Deng, Wanyin; Puente, Jose; Li, Feng; Chaussee, Michael S.; Finlay, B. Brett; Lenardo, Michael J.; Hardwidge, Philip R. (24 December 2009). "Bacterial Effector Binding to Ribosomal Protein S3 Subverts NF-κB Function". PLOS Pathogens. 5 (12): e1000708. doi:10.1371/journal.ppat.1000708. PMC 2791202. PMID 20041225.
  35. ^ Ruchaud-Sparagano, Marie-Hélène; Mühlen, Sabrina; Dean, Paul; Kenny, Brendan (1 December 2011). "The Enteropathogenic E. coli (EPEC) Tir Effector Inhibits NF-κB Activity by Targeting TNFα Receptor-Associated Factors". PLOS Pathogens. 7 (12): e1002414. doi:10.1371/journal.ppat.1002414. PMC 3228809. PMID 22144899.
  36. ^ Yan, Dapeng; Wang, Xingyu; Luo, Lijun; Cao, Xuetao; Ge, Baoxue (23 September 2012). "Inhibition of TLR signaling by a bacterial protein containing immunoreceptor tyrosine-based inhibitory motifs". Nature Immunology. 13 (11): 1063–1071. doi:10.1038/ni.2417. PMID 23001144. S2CID 5226423.
  37. ^ Viboud, Gloria I.; Mejia, Edison; Bliska, James B. (September 2006). "Comparison of YopE and YopT activities in counteracting host signalling responses to Yersinia pseudotuberculosis infection". Cellular Microbiology. 8 (9): 1504–1515. doi:10.1111/j.1462-5822.2006.00729.x. PMID 16922868.
  38. ^ Cheong, Mi Sun; Kirik, Angela; Kim, Jung-Gun; Frame, Kenneth; Kirik, Viktor; Mudgett, Mary Beth; Dangl, Jeffery L. (20 February 2014). "AvrBsT Acetylates Arabidopsis ACIP1, a Protein that Associates with Microtubules and Is Required for Immunity". PLOS Pathogens. 10 (2): e1003952. doi:10.1371/journal.ppat.1003952. PMC 3930583. PMID 24586161.
  39. ^ Mukherjee, Sohini; Keitany, Gladys; Li, Yan; Wang, Yong; Ball, Haydn L.; Goldsmith, Elizabeth J.; Orth, Kim (26 May 2006). "Yersinia YopJ Acetylates and Inhibits Kinase Activation by Blocking Phosphorylation" (PDF). Science. 312 (5777): 1211–1214. Bibcode:2006Sci...312.1211M. doi:10.1126/science.1126867. PMID 16728640. S2CID 13101320. Archived from the original (PDF) on 28 February 2019.
  40. ^ Trosky, Jennifer E.; Li, Yan; Mukherjee, Sohini; Keitany, Gladys; Ball, Haydn; Orth, Kim (1 October 2007). "VopA Inhibits ATP Binding by Acetylating the Catalytic Loop of MAPK Kinases". Journal of Biological Chemistry. 282 (47): 34299–34305. doi:10.1074/jbc.M706970200. PMID 17881352.
  41. ^ Bürger, Marco; Willige, Björn C.; Chory, Joanne (19 December 2017). "A hydrophobic anchor mechanism defines a deacetylase family that suppresses host response against YopJ effectors". Nature Communications. 8 (1): 2201. Bibcode:2017NatCo...8.2201B. doi:10.1038/s41467-017-02347-w. PMC 5736716. PMID 29259199.
  42. ^ Bürger, Marco; Chory, Joanne (5 December 2018). "Structural and chemical biology of deacetylases for carbohydrates, proteins, small molecules and histones". Communications Biology. 1 (1): 217. doi:10.1038/s42003-018-0214-4. PMC 6281622. PMID 30534609.
  43. ^ Jehl, Marc-André; Arnold, Roland; Rattei, Thomas (2011). "Effective—a database of predicted secreted bacterial proteins". Nucleic Acids Research. 39 (Database issue): D591–D595. doi:10.1093/nar/gkq1154. PMC 3013723. PMID 21071416.
  44. ^ Wang, Yejun; Huang, He; Sun, Ming’an; Zhang, Qing; Guo, Dianjing (2012). "T3DB: an integrated database for bacterial type III secretion system". BMC Bioinformatics. 13 (1): 66. doi:10.1186/1471-2105-13-66. PMC 3424820. PMID 22545727.
  45. ^ Dong, Xiaobao; Lu, Xiaotian; Zhang, Ziding (27 June 2015). "BEAN 2.0: an integrated web resource for the identification and functional analysis of type III secreted effectors". Database. 2015: bav064. doi:10.1093/database/bav064. PMC 4483310. PMID 26120140.