Login Register Cart 0
Generic placeholder image

Letters in Drug Design & Discovery

Editor-in-Chief

ISSN (Print): 1570-1808
ISSN (Online): 1875-628X

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

A Novel Design of Multi-epitope Peptide Vaccine Against Pseudomonas aeruginosa

Author(s): Fatemeh Esmaeilzadeh and Shirin Mahmoodi*

Volume 19, Issue 4, 2022

Published on: 13 October, 2021

Page: [304 - 313] Pages: 10

DOI: 10.2174/1570180818666211013110345

Price: $65

Abstract

Background: As an opportunistic pathogen, Pseudomonas aeruginosa causes many different hazardous infections. The high mortality rate resulting from infection with this antibiotic-resistant pathogen has made it a major challenge in clinical treatment; it has been listed as the most harmful bacterium to humans by the WHO. So far, no vaccine has been approved for P. aeruginosa.

Objective: Infections performed by bacterial attachment and colonization with type IV pili (T4P), known as the most essential adhesive vital for adhesion, while pilQ is necessary for the biogenesis of T4P, also outer membrane proteins of a pathogen is also effective in stimulating the immune system; in this regard, pilQ, OprF, and OprI, are excellent candidate antigens for production of an effective vaccine against P. aeruginosa.

Methods: In this research, various bioinformatics methods were employed in order to design a new multiepitope peptide vaccine versus P. aeruginosa. Since T CD4+ cell immunity is important in eradicating P. aeruginosa, OprF, OprI, and pilQ antigens were analyzed to determine Helper T cell Lymphocyte (HTL) epitopes by many different immunoinformatics servers. One of the receptor agonists 2 (TLR2), a segment of the Por B protein from Neisseria meningitides was used as an adjuvant in order to stimulate an effective cellular immune response, and suitable linkers were used to connect all the above mentioned parts. In the vaccine construct, linear B cell epitopes were also identified.

Results: Conforming the bioinformatics forecasts, the designed vaccine possesses high antigenicity and is not allergen.

Conclusion: In this regard, the designed vaccine candidate is strongly believed to possess the potential of inducing cellular and humoral immunity against P. aeruginosa.

Keywords: Bioinformatics, Infection, Pseudomonas aeruginosa, Vaccine, Adjuvant, Linkers, Peptide.

« Previous Next »
Graphical Abstract

[1]
Grimwood, K.; Kyd, J.M.; Owen, S.J.; Massa, H.M.; Cripps, A.W. Vaccination against respiratory Pseudomonas aeruginosa infection. Hum. Vaccin. Immunother., 2015, 11(1), 14-20.
[http://dx.doi.org/10.4161/hv.34296] [PMID: 25483510]
[2]
Blot, S.; Koulenti, D.; Dimopoulos, G.; Martin, C.; Komnos, A.; Krueger, W.A.; Spina, G.; Armaganidis, A.; Rello, J. Prevalence, risk factors, and mortality for ventilator-associated pneumonia in middle-aged, old, and very old critically ill patients. Crit. Care Med., 2014, 42(3), 601-609.
[http://dx.doi.org/10.1097/01.ccm.0000435665.07446.50] [PMID: 24158167]
[3]
Douglas, M.W.; Mulholland, K.; Denyer, V.; Gottlieb, T. Multi-drug resistant Pseudomonas aeruginosa outbreak in a burns unit--an infection control study. Burns, 2001, 27(2), 131-135.
[http://dx.doi.org/10.1016/S0305-4179(00)00084-X] [PMID: 11226649]
[4]
Sun, H-Y.; Fujitani, S.; Quintiliani, R.; Yu, V.L. Pneumonia due to Pseudomonas aeruginosa: Part II: Antimicrobial resistance, pharmacodynamic concepts, and antibiotic therapy. Chest, 2011, 139(5), 1172-1185.
[http://dx.doi.org/10.1378/chest.10-0167] [PMID: 21540216]
[5]
Parkins, M.D.; Gregson, D.B.; Pitout, J.D.; Ross, T.; Laupland, K.B. Population-based study of the epidemiology and the risk factors for Pseudomonas aeruginosa bloodstream infection. Infection, 2010, 38(1), 25-32.
[http://dx.doi.org/10.1007/s15010-009-9145-9] [PMID: 20012908]
[6]
Donta, S.T.; Peduzzi, P.; Cross, A.S.; Sadoff, J.; Haakenson, C.; Cryz, S.J., Jr; Kauffman, C.; Bradley, S.; Gafford, G.; Elliston, D.; Beam, T.R., Jr; John, J.F., Jr; Ribner, B.; Cantey, R.; Welsh, C.H.; Ellison, R.T., III; Young, E.J.; Hamill, R.J.; Leaf, H.; Schein, R.M.; Mulligan, M.; Johnson, C.; Abrutyn, E.; Griffiss, J.M.; Slagle, D. Immunoprophylaxis against klebsiella and pseudomonas aeruginosa infections. J. Infect. Dis., 1996, 174(3), 537-543.
[http://dx.doi.org/10.1093/infdis/174.3.537] [PMID: 8769611]
[7]
Döring, G.; Meisner, C.; Stern, M.; Group, F.V.T.S. A double-blind randomized placebo-controlled phase III study of a Pseudomonas aeruginosa flagella vaccine in cystic fibrosis patients. Proc. Natl. Acad. Sci. USA, 2007, 104(26), 11020-11025.
[http://dx.doi.org/10.1073/pnas.0702403104] [PMID: 17585011]
[8]
Westritschnig, K.; Hochreiter, R.; Wallner, G.; Firbas, C.; Schwameis, M.; Jilma, B. A randomized, placebo-controlled phase I study assessing the safety and immunogenicity of a Pseudomonas aeruginosa hybrid outer membrane protein OprF/I vaccine (IC43) in healthy volunteers. Hum. Vaccin. Immunother., 2014, 10(1), 170-183.
[http://dx.doi.org/10.4161/hv.26565] [PMID: 24064511]
[9]
Lu, Q.; Rouby, J-J.; Laterre, P-F.; Eggimann, P.; Dugard, A.; Giamarellos-Bourboulis, E.J.; Mercier, E.; Garbino, J.; Luyt, C.E.; Chastre, J.; Georgescu-Kyburz, V.; Rudolf, M.P.; Gafner, V.; Lazar, H.; Koch, H.; Perez, A.; Krämer, S.D.; Tamm, M. Pharmacokinetics and safety of panobacumab: Specific adjunctive immunotherapy in critical patients with nosocomial Pseudomonas aeruginosa O11 pneumonia. J. Antimicrob. Chemother., 2011, 66(5), 1110-1116.
[http://dx.doi.org/10.1093/jac/dkr046] [PMID: 21398296]
[10]
François, B.; Luyt, C-E.; Dugard, A.; Wolff, M.; Diehl, J-L.; Jaber, S.; Forel, J.M.; Garot, D.; Kipnis, E.; Mebazaa, A.; Misset, B.; Andremont, A.; Ploy, M.C.; Jacobs, A.; Yarranton, G.; Pearce, T.; Fagon, J.Y.; Chastre, J. Safety and pharmacokinetics of an anti-PcrV PEGylated monoclonal antibody fragment in mechanically ventilated patients colonized with Pseudomonas aeruginosa: A randomized,double-blind, placebo-controlled trial. Crit. Care Med., 2012, 40(8), 2320-2326.
[http://dx.doi.org/10.1097/CCM.0b013e31825334f6] [PMID: 22622405]
[11]
Vincent, J-L. Vaccine development and passive immunization for Pseudomonas aeruginosa in critically ill patients: A clinical update. Future Microbiol., 2014, 9(4), 457-463.
[http://dx.doi.org/10.2217/fmb.14.10] [PMID: 24810345]
[12]
Gellatly, S.L.; Hancock, R.E. Pseudomonas aeruginosa: New insights into pathogenesis and host defenses. Pathog. Dis., 2013, 67(3), 159-173.
[http://dx.doi.org/10.1111/2049-632X.12033] [PMID: 23620179]
[13]
Mosquera-Rendón, J.; Rada-Bravo, A.M.; Cárdenas-Brito, S.; Corredor, M.; Restrepo-Pineda, E.; Benítez-Páez, A. Pangenome-wide and molecular evolution analyses of the Pseudomonas aeruginosa species. BMC Genomics, 2016, 17(1), 45.
[http://dx.doi.org/10.1186/s12864-016-2364-4] [PMID: 26754847]
[14]
Yang, F.; Gu, J.; Yang, L.; Gao, C.; Jing, H.; Wang, Y.; Zeng, H.; Zou, Q.; Lv, F.; Zhang, J. Protective efficacy of the trivalent Pseudomonas aeruginosa vaccine candidate PcrV-OprI-Hcp1 in murine pneumonia and burn models. Sci. Rep., 2017, 7(1), 3957.
[http://dx.doi.org/10.1038/s41598-017-04029-5] [PMID: 28638106]
[15]
Revets, H.; Pynaert, G.; Grooten, J.; De Baetselier, P. Lipoprotein I, a TLR2/4 ligand modulates Th2-driven allergic immune responses. J. Immunol., 2005, 174(2), 1097-1103.
[http://dx.doi.org/10.4049/jimmunol.174.2.1097] [PMID: 15634935]
[16]
Krishnan, S.; Prasadarao, N.V. Outer membrane protein A and OprF: Versatile roles in Gram-negative bacterial infections. FEBS J., 2012, 279(6), 919-931.
[http://dx.doi.org/10.1111/j.1742-4658.2012.08482.x] [PMID: 22240162]
[17]
Bucior, I.; Pielage, J.F.; Engel, J.N. Pseudomonas aeruginosa pili and flagella mediate distinct binding and signaling events at the apical and basolateral surface of airway epithelium. PLoS Pathog., 2012, 8(4), e1002616.
[http://dx.doi.org/10.1371/journal.ppat.1002616] [PMID: 22496644]
[18]
Apostolico, JdS.; Lunardelli, VAS.; Coirada, FC.; Boscardin, SB.; Rosa, DS. Adjuvants: Classification, modus operandi, and licensing. J. Immunol. Res., 2016, 2016, 1459394.
[19]
Smith, K.D.; Andersen-Nissen, E.; Hayashi, F.; Strobe, K.; Bergman, M.A.; Barrett, S.L.R.; Cookson, B.T.; Aderem, A. Toll-like receptor 5 recognizes a conserved site on flagellin required for protofilament formation and bacterial motility. Nat. Immunol., 2003, 4(12), 1247-1253.
[http://dx.doi.org/10.1038/ni1011] [PMID: 14625549]
[20]
Kumar, H.; Kawai, T.; Akira, S. Pathogen recognition by the innate immune system. Int. Rev. Immunol., 2011, 30(1), 16-34.
[http://dx.doi.org/10.3109/08830185.2010.529976] [PMID: 21235323]
[21]
Shahbazi, M.; Haghkhah, M.; Rahbar, M.R.; Nezafat, N.; Ghasemi, Y. In silico sub-unit hexavalent peptide vaccine against an Staphylococcus aureus biofilm-related infection. Int. J. Pept. Res. Ther., 2016, 22(1), 101-117.
[http://dx.doi.org/10.1007/s10989-015-9489-1]
[22]
Zhang, Q.; Wang, P.; Kim, Y.; Haste-Andersen, P.; Beaver, J.; Bourne, P.E.; Bui, H.H.; Buus, S.; Frankild, S.; Greenbaum, J.; Lund, O.; Lundegaard, C.; Nielsen, M.; Ponomarenko, J.; Sette, A.; Zhu, Z.; Peters, B. Immune epitope database analysis resource (IEDB-AR). Nucleic Acids Res., 2008, 36(Web Server issue)(Suppl. 2), W513-8.
[PMID: 18515843]
[23]
Guan, P.; Doytchinova, I.A.; Zygouri, C.; Flower, D.R. MHCPred: A server for quantitative prediction of peptide-MHC binding. Nucleic Acids Res., 2003, 31(13), 3621-3624.
[http://dx.doi.org/10.1093/nar/gkg510] [PMID: 12824380]
[24]
Thomas, B.; Willink, R.; Grice, K.; Twitchett, R.; Purcell, R.; Archbold, N. Unique marine Permian‐Triassic boundary section from Western Australia. Aust. J. Earth Sci., 2004, 51(3), 423-430.
[http://dx.doi.org/10.1111/j.1400-0952.2004.01066.x]
[25]
Magnan, C.N.; Zeller, M.; Kayala, M.A.; Vigil, A.; Randall, A.; Felgner, P.L.; Baldi, P. High-throughput prediction of protein antigenicity using protein microarray data. Bioinformatics, 2010, 26(23), 2936-2943.
[http://dx.doi.org/10.1093/bioinformatics/btq551] [PMID: 20934990]
[26]
Doytchinova, I.A.; Flower, D.R. VaxiJen: A server for prediction of protective antigens, tumour antigens and subunit vaccines. BMC Bioinformatics, 2007, 8(1), 4.
[http://dx.doi.org/10.1186/1471-2105-8-4] [PMID: 17207271]
[27]
Roden, R.B.; Yutzy, W.H., IV; Fallon, R.; Inglis, S.; Lowy, D.R.; Schiller, J.T. Minor capsid protein of human genital papillomaviruses contains subdominant, cross-neutralizing epitopes. Virology, 2000, 270(2), 254-257.
[http://dx.doi.org/10.1006/viro.2000.0272] [PMID: 10792983]
[28]
Gasteiger, E; Hoogland, C; Gattiker, A; Wilkins, MR; Appel, RD Bairoch, A Protein identification and analysis tools on the ExPASy server. The proteomics protocols handbook. 2005, 571-607.
[http://dx.doi.org/10.1385/1-59259-890-0:571]
[29]
Mount, D.W.; Mount, D.W. Bioinformatics: Sequence and genome analysis; Cold spring harbor laboratory press: Cold Spring Harbor, NY, 2001.
[30]
Mahmoodi, S.; Nezafat, N.; Barzegar, A.; Negahdaripour, M.; Nikanfar, A.R.; Zarghami, N.; Ghasemi, Y. Harnessing bioinformatics for designing a novel multiepitope peptide vaccine against breast cancer. Curr. Pharm. Biotechnol., 2016, 17(12), 1100-1114.
[http://dx.doi.org/10.2174/1389201017666160914191106] [PMID: 27633889]
[31]
Hancock, R.E.; Mutharia, L.M.; Chan, L.; Darveau, R.P.; Speert, D.P.; Pier, G.B. Pseudomonas aeruginosa isolates from patients with cystic fibrosis: A class of serum-sensitive, nontypable strains deficient in lipopolysaccharide O side chains. Infect. Immun., 1983, 42(1), 170-177.
[http://dx.doi.org/10.1128/iai.42.1.170-177.1983] [PMID: 6413410]
[32]
Harbarth, S.; Ferrière, K.; Hugonnet, S.; Ricou, B.; Suter, P.; Pittet, D. Epidemiology and prognostic determinants of bloodstream infections in surgical intensive care. Arch. Surg., 2002, 137(12), 1353-1359.
[http://dx.doi.org/10.1001/archsurg.137.12.1353] [PMID: 12470098]
[33]
Davies, M.N.; Flower, D.R. Harnessing bioinformatics to discover new vaccines. Drug Discov. Today, 2007, 12(9-10), 389-395.
[http://dx.doi.org/10.1016/j.drudis.2007.03.010] [PMID: 17467575]
[34]
Mahendran, R.; Jeyabaskar, S.; Sitharaman, G.; Michael, R.D.; Paul, A.V. Computer-aided vaccine designing approach against fish pathogens Edwardsiella tarda and Flavobacterium columnare using bioinformatics softwares. Drug Des. Devel. Ther., 2016, 10, 1703-1714.
[http://dx.doi.org/10.2147/DDDT.S95691] [PMID: 27284239]
[35]
Nezafat, N.; Karimi, Z.; Eslami, M.; Mohkam, M.; Zandian, S.; Ghasemi, Y. Designing an efficient multi-epitope peptide vaccine against Vibrio cholerae via combined immunoinformatics and protein interaction based approaches. Comput. Biol. Chem., 2016, 62, 82-95.
[http://dx.doi.org/10.1016/j.compbiolchem.2016.04.006] [PMID: 27107181]
[36]
Sharma, D.; Patel, S.; Padh, H.; Desai, P. Immunoinformatic identification of potential epitopes against shigellosis. Int. J. Pept. Res. Ther., 2016, 22(4), 481-495.
[http://dx.doi.org/10.1007/s10989-016-9528-6]
[37]
de Groot, E.; Hovingh, G.K.; Wiegman, A.; Duriez, P.; Smit, A.J.; Fruchart, J-C.; Kastelein, J.J. Measurement of arterial wall thickness as a surrogate marker for atherosclerosis. Circulation, 2004, 109(23)(Suppl. 1), III33-III38.
[http://dx.doi.org/10.1161/01.CIR.0000131516.65699.ba] [PMID: 15198964]
[38]
Farhadi, T.; Ovchinnikov, R.S.; Ranjbar, M.M. In silico designing of some agonists of toll-like receptor 5 as a novel vaccine adjuvant candidates. Netw. Model. Anal. Health Inform. Bioinform., 2016, 5(1), 1-10.
[http://dx.doi.org/10.1007/s13721-016-0138-1]
[39]
Liu, X.; Wetzler, L.M.; Massari, P. The PorB porin from commensal Neisseria lactamica induces Th1 and Th2 immune responses to ovalbumin in mice and is a potential immune adjuvant. Vaccine, 2008, 26(6), 786-796.
[http://dx.doi.org/10.1016/j.vaccine.2007.11.080] [PMID: 18191311]
[40]
Duthie, M.S.; Windish, H.P.; Fox, C.B.; Reed, S.G. Use of defined TLR ligands as adjuvants within human vaccines. Immunol. Rev., 2011, 239(1), 178-196.
[http://dx.doi.org/10.1111/j.1600-065X.2010.00978.x] [PMID: 21198672]
[41]
Martinez-Becerra, F.J.; Kissmann, J.M.; Diaz-McNair, J.; Choudhari, S.P.; Quick, A.M.; Mellado-Sanchez, G.; Clements, J.D.; Pasetti, M.F.; Picking, W.L. Broadly protective Shigella vaccine based on type III secretion apparatus proteins. Infect. Immun., 2012, 80(3), 1222-1231.
[http://dx.doi.org/10.1128/IAI.06174-11] [PMID: 22202122]
[42]
Faezi, S.; Nikokar, I.; Elmi, A.; Ghasemi, Y.; Farahbakhsh, M.; Salimi Chirani, A.; Mahdavi, M. Molecular characterization and functional analysis of the PilQ380-706: A novel secretin domain in Pseudomonas aeruginosa. Avicenna J. Med. Biotechnol., 2018, 10(1), 34-40.
[PMID: 29296265]
[43]
Jehl, S.P.; Doling, A.M.; Giddings, K.S.; Phalipon, A.; Sansonetti, P.J.; Goldberg, M.B.; Starnbach, M.N. Antigen-specific CD8(+) T cells fail to respond to Shigella flexneri. Infect. Immun., 2011, 79(5), 2021-2030.
[http://dx.doi.org/10.1128/IAI.00939-10] [PMID: 21357720]
[44]
Rincón, M.; Flavell, R.A. Transcriptional control in the Th1/Th2 decision: T-cell subsets. Curr. Biol., 1997, 7(11), R729-R32.
[http://dx.doi.org/10.1016/S0960-9822(06)00368-X] [PMID: 9382795]
[45]
Agnello, D.; Lankford, C.S.; Bream, J.; Morinobu, A.; Gadina, M.; O’Shea, J.J.; Frucht, D.M. Cytokines and transcription factors that regulate T helper cell differentiation: New players and new insights. J. Clin. Immunol., 2003, 23(3), 147-161.
[http://dx.doi.org/10.1023/A:1023381027062] [PMID: 12797537]
[46]
Matijevic, T.; Pavelic, J. Toll-like receptors: Cost or benefit for cancer? Curr. Pharm. Des., 2010, 16(9), 1081-1090.
[http://dx.doi.org/10.2174/138161210790963779] [PMID: 20030618]
[47]
Conroy, H.; Marshall, N.A.; Mills, K.H. TLR ligand suppression or enhancement of Treg cells? A double-edged sword in immunity to tumours. Oncogene, 2008, 27(2), 168-180.
[http://dx.doi.org/10.1038/sj.onc.1210910] [PMID: 18176598]
[48]
Toussi, D.N.; Massari, P. Immune adjuvant effect of molecularly-defined toll-like receptor ligands. Vaccines (Basel), 2014, 2(2), 323-353.
[http://dx.doi.org/10.3390/vaccines2020323] [PMID: 26344622]
[49]
Basith, S.; Manavalan, B.; Lee, G.; Kim, S.G.; Choi, S. Toll-like receptor modulators: A patent review (2006-2010). Expert Opin. Ther. Pat., 2011, 21(6), 927-944.
[http://dx.doi.org/10.1517/13543776.2011.569494] [PMID: 21406035]
[50]
Kattner, C.; Toussi, D.N.; Zaucha, J.; Wetzler, L.M.; Rüppel, N.; Zachariae, U.; Massari, P.; Tanabe, M. Crystallographic analysis of Neisseria meningitidis PorB extracellular loops potentially implicated in TLR2 recognition. J. Struct. Biol., 2014, 185(3), 440-447.
[http://dx.doi.org/10.1016/j.jsb.2013.12.006] [PMID: 24361688]
[51]
Dosztányi, Z.; Csizmok, V.; Tompa, P.; Simon, I. IUPred: Web server for the prediction of intrinsically unstructured regions of proteins based on estimated energy content. Bioinformatics, 2005, 21(16), 3433-3434.
[http://dx.doi.org/10.1093/bioinformatics/bti541] [PMID: 15955779]
[52]
Le-Barillec, K.; Magalhaes, J.G.; Corcuff, E.; Thuizat, A.; Sansonetti, P.J.; Phalipon, A.; Di Santo, J.P. Roles for T and NK cells in the innate immune response to Shigella flexneri. J. Immunol., 2005, 175(3), 1735-1740.
[http://dx.doi.org/10.4049/jimmunol.175.3.1735] [PMID: 16034114]
[53]
Bai, Y.; Ann, D.K.; Shen, W-C. Recombinant granulocyte colony-stimulating factor-transferrin fusion protein as an oral myelopoietic agent. Proc. Natl. Acad. Sci. USA, 2005, 102(20), 7292-7296.
[http://dx.doi.org/10.1073/pnas.0500062102] [PMID: 15870205]
[54]
Aurora, R.; Creamer, T.P.; Srinivasan, R.; Rose, G.D. Local interactions in protein folding: Lessons from the α-helix. J. Biol. Chem., 1997, 272(3), 1413-1416.
[http://dx.doi.org/10.1074/jbc.272.3.1413] [PMID: 9019474]
[55]
Reche, P.A.; Glutting, J-P.; Reinherz, E.L. Prediction of MHC class I binding peptides using profile motifs. Hum. Immunol., 2002, 63(9), 701-709.
[http://dx.doi.org/10.1016/S0198-8859(02)00432-9] [PMID: 12175724]
[56]
Livingston, B.; Crimi, C.; Newman, M.; Higashimoto, Y.; Appella, E.; Sidney, J.; Sette, A. A rational strategy to design multiepitope immunogens based on multiple Th lymphocyte epitopes. J. Immunol., 2002, 168(11), 5499-5506.
[http://dx.doi.org/10.4049/jimmunol.168.11.5499] [PMID: 12023344]

Rights & Permissions Print Cite
Article Metrics
23
1
© 2024 Bentham Science Publishers | Privacy Policy