Immunoinformatics Evaluation of a Fusion Protein Composed of Leishmania infantum LiHyV and Phlebotomus kandelakii Apyrase as a Vaccine Candidate against Visceral Leishmaniasis
-
Shima Fayaz
,
Fariborz Bahrami
,
Pezhman Fard-Esfahani
,
Parviz Parvizi
,
Golnaz Bahramali
,
Soheila Ajdary
Abstract
Background: Visceral leishmaniasis (VL) is a lethal parasitic disease, transmitted by sand fly vectors. Immunomodulatory properties of sand fly saliva proteins and their protective effects against Leishmania infection in pre-exposed animals suggest that a combination of an antigenic salivary protein along with a Leishmania antigen can be considered for designing a vaccine against leishmaniasis
Methods: Three different fusion forms of L. infantum hypothetical protein (LiHyV) in combination with Phlebotomus kandelakii salivary apyrase (PkanAp) were subjected to in-silico analyses. Major Histocompatibility Complex (MHC) class I and II epitopes in both humans and BALB/c mice were predicted. Antigenicity, immunogenicity, epitope conservancy, toxicity, and population coverage were also evaluated.
Results: Highly antigenic promiscuous epitopes consisting of truncated LiHyV (10-285) and full-length PkanAp (21-329) were identified in human and was named Model 1. This model contained 25 MHC-I and 141 MHC-II antigenic peptides which among them, MPANSDIRI and AQSLFDFSGLALDSN were fully conserved. LALDSNATV, RCSSALVSI, ALVSINVPL, SAVESGALF of MHC-I epitopes, and 28 MHC-II binding epitopes showed 60% conservancy among various clades. A population coverage with a rate of >75% in the Iranian population and >70% in the whole world was also identified.
Conclusion: Based on this in-silico approach, the predicted Model 1 could potentially be used as a vaccine candidate against VL.
1. Asmaa Q, Salwa A-S, Al-Tag M, et al. Par-asitological and biochemical studies on cu-taneous leishmaniasis in Shara’b District, Taiz, Yemen. Ann Clin Microbiol Antimi-crob. 2017;16(1):47.
2. Maroli M, Feliciangeli M, Bichaud L, et al. Phlebotomine sandflies and the spreading of leishmaniases and other diseases of public health concern. Med Vet Entomol. 2013;27(2):123-47.
3. El Hajj R, El Hajj H, Khalifeh I. Fatal vis-ceral leishmaniasis caused by Leishmania in-fantum, Lebanon. Emerg Infect Dis. 2018;24(5):906-7.
4. Mohebali M. Visceral leishmaniasis in Iran: review of the epidemiological and clinical features. Iran J Parasitol. 2013;8(3):348-58.
5. Moafi M, Rezvan H, Sherkat R, et al. Leishmania vaccines entered in clinical trials: A review of literature. Int J Prev Med. 2019;10:95.
6. Duthie MS, Favila M, Hofmeyer KA, et al. Strategic evaluation of vaccine candidate antigens for the prevention of Visceral Leishmaniasis. Vaccine. 2016;34(25):2779-86.
7. Ribeiro PA, Dias DS, Lage DP, et al. Eval-uation of a Leishmania hypothetical protein administered as DNA vaccine or recom-binant protein against Leishmania infantum infection and its immunogenicity in hu-mans. Cell Immunol. 2018;331:67-77.
8. Duarte MC, Lage DP, Martins VT, et al. Recent updates and perspectives on ap-proaches for the development of vaccines against visceral leishmaniasis. Rev Soc Bras Med Trop. 2016;49(4):398-407.
9. Fernandes AP, Coelho EAF, Machado-Coelho GLL, et al. Making an anti-amastigote vaccine for visceral leishmania-sis: rational, update and perspectives. Curr Opin Microbiol. 2012;15(4):476-85.
10. Coelho VT, Oliveira JS, Valadares DG, et al. Identification of proteins in pro-mastigote and amastigote-like Leishmania using an immunoproteomic approach. PLoS Negl Trop Dis. 2012;6(1):e1430.
11. Martins VT, Duarte MC, Chávez-Fumagalli MA, et al. A Leishmania-specific hypothetical protein expressed in both promastigote and amastigote stages of Leishmania infantum employed for the sero-diagnosis of, and as a vaccine candidate against, visceral leishmaniasis. Parasit Vec-tors. 2015;8(1):363.
12. Andrade BdB, De Oliveira C, Brodskyn CI, et al. Role of sand fly saliva in human and experimental leishmaniasis: current in-sights. Scand J Immunol. 2007;66(2‐3):122-7.
13. Abdeladhim M, Kamhawi S, Valenzuela JG. What’s behind a sand fly bite? The profound effect of sand fly saliva on host hemostasis, inflammation and immunity. Infect Genet Evol. 2014;28:691-703.
14. Marzouki S, Ahmed MB, Boussoffara T, et al. Characterization of the antibody re-sponse to the saliva of Phlebotomus papatasi in people living in endemic areas of cuta-neous leishmaniasis. Am J Trop Med Hyg. 2011;84(5):653-61.
15. Vlkova M, Rohousova I, Drahota J, et al. Canine antibody response to Phlebotomus perniciosus bites negatively correlates with the risk of Leishmania infantum transmission. PLoS Negl Trop Dis. 2011;5(10):e1344.
16. Rohousova I, Subrahmanyam S, Volfova V, et al. Salivary gland transcriptomes and proteomes of Phlebotomus tobbi and Phlebotomus sergenti, vectors of leish-maniasis. PLoS Negl Trop Dis. 2012;6(5):e1660.
17. Martín-Martín I, Molina R, Jiménez M. Kinetics of anti-Phlebotomus perniciosus saliva antibodies in experimentally bitten mice and rabbits. PLoS One. 2015;10(11):e0140722.
18. Lestinova T, Rohousova I, Sima M, et al. Insights into the sand fly saliva: Blood-feeding and immune interactions between sand flies, hosts, and Leishmania. PLoS Negl Trop Dis. 2017;11(7):e0005600.
19. Sima M, Ferencova B, Warburg A, et al. Recombinant salivary proteins of Phleboto-mus orientalis are suitable antigens to meas-ure exposure of domestic animals to sand fly bites. PLoS Negl Trop Dis. 2016;10(3):e0004553.
20. Zahra N, Davood K, Morteza A, et al. Epidemiological Aspects of Visceral Leishmaniasis in Larestan and Ghiro-Karzin Counties, Southwest of Iran. Osong Public Health Res Perspect. 2018;9(2):81-5.
21. Duthie MS, Pereira L, Favila M, et al. A defined subunit vaccine that protects against vector-borne visceral leishmaniasis. NPJ Vaccines. 2017;2(1):1-9.
22. Tamura K, Stecher G, Peterson D, et al. MEGA6: molecular evolutionary genetics analysis version 6.0. Mol Biol Evol. 2013;30(12):2725-9.
23. Armenteros JJA, Tsirigos KD, Sønderby CK, et al. SignalP 5.0 improves signal pep-tide predictions using deep neural net-works. Nat Biotechnol. 2019;37(4):420-3.
24. Abedini F, Rahmanian N, Heidari Z, et al. Diversity of HLA class I and class II alleles in Iran populations: Systematic review and Meta-Analaysis. Transpl Immunol. 2021;69:101472.
25. Ebrahimkhani S, Farjadian S, Ebrahimi M. The Royan Public Umbilical Cord Blood Bank: Does It Cover All Ethnic Groups in Iran Based on HLA Diversity? Transfus Med Hemother. 2014;41(2):134-8.
26. Ashouri E, Norman PJ, Guethlein LA, et al. HLA class I variation in Iranian Lur and Kurd populations: high haplotype and al-lotype diversity with an abundance of KIR ligands. HLA. 2016;88(3):87-99.
27. Esmaeili A, Rabe SZT, Mahmoudi M, et al. Frequencies of HLA-A, B and DRB1 al-leles in a large normal population living in the city of Mashhad, Northeastern Iran. Iran J Basic Med Sci. 2017;20(8):940-3.
28. Amirzargar A, Mytilineos J, Farjadian S, et al. Human leukocyte antigen class II allele frequencies and haplotype association in Iranian normal population. Hum Immu-nol. 2001;62(11):1234-8.
29. Mosayebi M, Dalimi Asl A, Moazzeni M, et al. Differential genomics output and susceptibility of Iranian patients with uni-locular hydatidosis. Iran J Parasitol. 2013;8(4):510-5.
30. Doytchinova IA, Flower DR. VaxiJen: a server for prediction of protective anti-gens, tumor antigens and subunit vaccines. BMC Bioinformatics. 2007;8(1):4.
31. Bui HH, Sidney J, Li W, et al. Develop-ment of an epitope conservancy analysis tool to facilitate the design of epitope-based diagnostics and vaccines. BMC Bio-informatics. 2007;8(1):361.
32. Gupta S, Kapoor P, Chaudhary K, et al. In silico approach for predicting toxicity of peptides and proteins. PLoS One. 2013;8(9):e73957.
33. Dimitrov I, Flower DR, Doytchinova I. AllerTOP--a server for in silico prediction of allergens. BMC Bioinformatics. 2013;14 Suppl 6(Suppl 6):S4.
34. WILKINS MR G, Bairoch A, Sanchez J, et al. Protein identification and analysis tools in the ExPASy server. Methods Mol Biol. 1999;112:531-52.
35. Geourjon C, Deleage G. SOPMA: signifi-cant improvements in protein secondary structure prediction by consensus predic-tion from multiple alignments. Comput Appl Biosci. 1995;11(6):681-4.
36. Cuff JA, Clamp ME, Siddiqui AS, et al. JPred: a consensus secondary structure prediction server. Bioinformatics. 1998;14(10):892-3.
37. Ferrè F, Clote P. DiANNA: a web server for disulfide connectivity prediction. Nu-cleic Acids Res. 2005;33(suppl_2):W230-W2.
38. Zhang Y. I-TASSER server for protein 3D structure prediction. BMC Bioinfor-matics. 2008;9(1):40.
39. Wiederstein M, Sippl MJ. ProSA-web: in-teractive web service for the recognition of errors in three-dimensional structures of proteins. Nucleic Acids Res. 2007;35(suppl_2):W407-W10.
40. Ratnapriya S, Sahasrabuddhe AA, Dube A. Visceral leishmaniasis: An overview of vaccine adjuvants and their applications. Vaccine. 2019;37(27):3505-19.
41. Joshi S, Rawat K, Yadav NK, et al. Visceral leishmaniasis: advancements in vaccine development via classical and molecular approaches. Front Immunol. 2014;5:380.
42. Vakili B, Eslami M, Hatam GR, et al. Im-munoinformatics-aided design of a poten-tial multi-epitope peptide vaccine against Leishmania infantum. Int J Biol Macromol. 2018;120:1127-39.
43. Vakili B, Nezafat N, Zare B, et al. A new multi-epitope peptide vaccine induces im-mune responses and protection against Leishmania infantum in BALB/c mice. Med Microbiol Immunol. 2020;209(1):69-79.
44. Tlili A, Marzouki S, Chabaane E, et al. Phlebotomus papatasi yellow-related and apy-rase salivary proteins are candidates for vaccination against human cutaneous leishmaniasis. J Invest Dermatol. 2018;138(3):598-606.
2. Maroli M, Feliciangeli M, Bichaud L, et al. Phlebotomine sandflies and the spreading of leishmaniases and other diseases of public health concern. Med Vet Entomol. 2013;27(2):123-47.
3. El Hajj R, El Hajj H, Khalifeh I. Fatal vis-ceral leishmaniasis caused by Leishmania in-fantum, Lebanon. Emerg Infect Dis. 2018;24(5):906-7.
4. Mohebali M. Visceral leishmaniasis in Iran: review of the epidemiological and clinical features. Iran J Parasitol. 2013;8(3):348-58.
5. Moafi M, Rezvan H, Sherkat R, et al. Leishmania vaccines entered in clinical trials: A review of literature. Int J Prev Med. 2019;10:95.
6. Duthie MS, Favila M, Hofmeyer KA, et al. Strategic evaluation of vaccine candidate antigens for the prevention of Visceral Leishmaniasis. Vaccine. 2016;34(25):2779-86.
7. Ribeiro PA, Dias DS, Lage DP, et al. Eval-uation of a Leishmania hypothetical protein administered as DNA vaccine or recom-binant protein against Leishmania infantum infection and its immunogenicity in hu-mans. Cell Immunol. 2018;331:67-77.
8. Duarte MC, Lage DP, Martins VT, et al. Recent updates and perspectives on ap-proaches for the development of vaccines against visceral leishmaniasis. Rev Soc Bras Med Trop. 2016;49(4):398-407.
9. Fernandes AP, Coelho EAF, Machado-Coelho GLL, et al. Making an anti-amastigote vaccine for visceral leishmania-sis: rational, update and perspectives. Curr Opin Microbiol. 2012;15(4):476-85.
10. Coelho VT, Oliveira JS, Valadares DG, et al. Identification of proteins in pro-mastigote and amastigote-like Leishmania using an immunoproteomic approach. PLoS Negl Trop Dis. 2012;6(1):e1430.
11. Martins VT, Duarte MC, Chávez-Fumagalli MA, et al. A Leishmania-specific hypothetical protein expressed in both promastigote and amastigote stages of Leishmania infantum employed for the sero-diagnosis of, and as a vaccine candidate against, visceral leishmaniasis. Parasit Vec-tors. 2015;8(1):363.
12. Andrade BdB, De Oliveira C, Brodskyn CI, et al. Role of sand fly saliva in human and experimental leishmaniasis: current in-sights. Scand J Immunol. 2007;66(2‐3):122-7.
13. Abdeladhim M, Kamhawi S, Valenzuela JG. What’s behind a sand fly bite? The profound effect of sand fly saliva on host hemostasis, inflammation and immunity. Infect Genet Evol. 2014;28:691-703.
14. Marzouki S, Ahmed MB, Boussoffara T, et al. Characterization of the antibody re-sponse to the saliva of Phlebotomus papatasi in people living in endemic areas of cuta-neous leishmaniasis. Am J Trop Med Hyg. 2011;84(5):653-61.
15. Vlkova M, Rohousova I, Drahota J, et al. Canine antibody response to Phlebotomus perniciosus bites negatively correlates with the risk of Leishmania infantum transmission. PLoS Negl Trop Dis. 2011;5(10):e1344.
16. Rohousova I, Subrahmanyam S, Volfova V, et al. Salivary gland transcriptomes and proteomes of Phlebotomus tobbi and Phlebotomus sergenti, vectors of leish-maniasis. PLoS Negl Trop Dis. 2012;6(5):e1660.
17. Martín-Martín I, Molina R, Jiménez M. Kinetics of anti-Phlebotomus perniciosus saliva antibodies in experimentally bitten mice and rabbits. PLoS One. 2015;10(11):e0140722.
18. Lestinova T, Rohousova I, Sima M, et al. Insights into the sand fly saliva: Blood-feeding and immune interactions between sand flies, hosts, and Leishmania. PLoS Negl Trop Dis. 2017;11(7):e0005600.
19. Sima M, Ferencova B, Warburg A, et al. Recombinant salivary proteins of Phleboto-mus orientalis are suitable antigens to meas-ure exposure of domestic animals to sand fly bites. PLoS Negl Trop Dis. 2016;10(3):e0004553.
20. Zahra N, Davood K, Morteza A, et al. Epidemiological Aspects of Visceral Leishmaniasis in Larestan and Ghiro-Karzin Counties, Southwest of Iran. Osong Public Health Res Perspect. 2018;9(2):81-5.
21. Duthie MS, Pereira L, Favila M, et al. A defined subunit vaccine that protects against vector-borne visceral leishmaniasis. NPJ Vaccines. 2017;2(1):1-9.
22. Tamura K, Stecher G, Peterson D, et al. MEGA6: molecular evolutionary genetics analysis version 6.0. Mol Biol Evol. 2013;30(12):2725-9.
23. Armenteros JJA, Tsirigos KD, Sønderby CK, et al. SignalP 5.0 improves signal pep-tide predictions using deep neural net-works. Nat Biotechnol. 2019;37(4):420-3.
24. Abedini F, Rahmanian N, Heidari Z, et al. Diversity of HLA class I and class II alleles in Iran populations: Systematic review and Meta-Analaysis. Transpl Immunol. 2021;69:101472.
25. Ebrahimkhani S, Farjadian S, Ebrahimi M. The Royan Public Umbilical Cord Blood Bank: Does It Cover All Ethnic Groups in Iran Based on HLA Diversity? Transfus Med Hemother. 2014;41(2):134-8.
26. Ashouri E, Norman PJ, Guethlein LA, et al. HLA class I variation in Iranian Lur and Kurd populations: high haplotype and al-lotype diversity with an abundance of KIR ligands. HLA. 2016;88(3):87-99.
27. Esmaeili A, Rabe SZT, Mahmoudi M, et al. Frequencies of HLA-A, B and DRB1 al-leles in a large normal population living in the city of Mashhad, Northeastern Iran. Iran J Basic Med Sci. 2017;20(8):940-3.
28. Amirzargar A, Mytilineos J, Farjadian S, et al. Human leukocyte antigen class II allele frequencies and haplotype association in Iranian normal population. Hum Immu-nol. 2001;62(11):1234-8.
29. Mosayebi M, Dalimi Asl A, Moazzeni M, et al. Differential genomics output and susceptibility of Iranian patients with uni-locular hydatidosis. Iran J Parasitol. 2013;8(4):510-5.
30. Doytchinova IA, Flower DR. VaxiJen: a server for prediction of protective anti-gens, tumor antigens and subunit vaccines. BMC Bioinformatics. 2007;8(1):4.
31. Bui HH, Sidney J, Li W, et al. Develop-ment of an epitope conservancy analysis tool to facilitate the design of epitope-based diagnostics and vaccines. BMC Bio-informatics. 2007;8(1):361.
32. Gupta S, Kapoor P, Chaudhary K, et al. In silico approach for predicting toxicity of peptides and proteins. PLoS One. 2013;8(9):e73957.
33. Dimitrov I, Flower DR, Doytchinova I. AllerTOP--a server for in silico prediction of allergens. BMC Bioinformatics. 2013;14 Suppl 6(Suppl 6):S4.
34. WILKINS MR G, Bairoch A, Sanchez J, et al. Protein identification and analysis tools in the ExPASy server. Methods Mol Biol. 1999;112:531-52.
35. Geourjon C, Deleage G. SOPMA: signifi-cant improvements in protein secondary structure prediction by consensus predic-tion from multiple alignments. Comput Appl Biosci. 1995;11(6):681-4.
36. Cuff JA, Clamp ME, Siddiqui AS, et al. JPred: a consensus secondary structure prediction server. Bioinformatics. 1998;14(10):892-3.
37. Ferrè F, Clote P. DiANNA: a web server for disulfide connectivity prediction. Nu-cleic Acids Res. 2005;33(suppl_2):W230-W2.
38. Zhang Y. I-TASSER server for protein 3D structure prediction. BMC Bioinfor-matics. 2008;9(1):40.
39. Wiederstein M, Sippl MJ. ProSA-web: in-teractive web service for the recognition of errors in three-dimensional structures of proteins. Nucleic Acids Res. 2007;35(suppl_2):W407-W10.
40. Ratnapriya S, Sahasrabuddhe AA, Dube A. Visceral leishmaniasis: An overview of vaccine adjuvants and their applications. Vaccine. 2019;37(27):3505-19.
41. Joshi S, Rawat K, Yadav NK, et al. Visceral leishmaniasis: advancements in vaccine development via classical and molecular approaches. Front Immunol. 2014;5:380.
42. Vakili B, Eslami M, Hatam GR, et al. Im-munoinformatics-aided design of a poten-tial multi-epitope peptide vaccine against Leishmania infantum. Int J Biol Macromol. 2018;120:1127-39.
43. Vakili B, Nezafat N, Zare B, et al. A new multi-epitope peptide vaccine induces im-mune responses and protection against Leishmania infantum in BALB/c mice. Med Microbiol Immunol. 2020;209(1):69-79.
44. Tlili A, Marzouki S, Chabaane E, et al. Phlebotomus papatasi yellow-related and apy-rase salivary proteins are candidates for vaccination against human cutaneous leishmaniasis. J Invest Dermatol. 2018;138(3):598-606.
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| Issue | Vol 17 No 2 (2022) | |
| Section | Original Article(s) | |
| DOI | https://doi.org/10.18502/ijpa.v17i2.9530 | |
| Keywords | ||
| Immunoinformatics Leishmania infantum Phlebotomus kandelakii Apyrase Vaccine | ||
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How to Cite
1.
Fayaz S, Bahrami F, Fard-Esfahani P, Parvizi P, Bahramali G, Ajdary S. Immunoinformatics Evaluation of a Fusion Protein Composed of Leishmania infantum LiHyV and Phlebotomus kandelakii Apyrase as a Vaccine Candidate against Visceral Leishmaniasis. Iran J Parasitol. 2022;17(2):145-158.
