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Recombinant C-Reactive Protein: A Potential Candidate for the Treatment of Cutaneous Leishmaniasis of BALB/c Mice Caused by Leishmania major

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Abstract

Purpose

Leishmaniasis, a widespread parasitic disease, is a public health concern that is endemic in more than 90 countries. Owing to the drug resistance and also undesirable complications, designing new therapeutic methods are essential. C-reactive protein (CRP) is an acute phase protein of plasma with several immune modulatory functions. This study aimed to evaluate the effect of human recombinant CRP (hrCRP) on treating cutaneous leishmaniasis in mice models.

Methods

hrCRP was expressed in E. coli Rosetta-gami and extracted from the SDS-PAGE gel. Male BALB/c mice were inoculated subcutaneously at the base of their tails by 1 × 105 stationary-phase of Leishmania major promastigotes (MHRO/IR/75/ER) suspended in sterile phosphate buffered saline (PBS). Nodules and subsequently, ulcers developed 14 days post-injection. 1.5 µg of the purified protein was administered on lesions of pre-infected mice by Leishmania major in the intervention group for five consecutive days.

Results

The mean area of the lesions was decreased by about seven folds in the intervention group as compared to the control group after two weeks of the treatment (p = 0.024). The results were verified by the real-time polymerase chain reaction so that the parasite burden was determined 27 times in the control group as compared to the intervention group (p = 0.02). Two weeks after treatment, the conversion of the lesions to scars in the intervention group was observed.

Conclusion

The results indicate a potential therapeutic role for hrCRP in improving cutaneous leishmaniasis due to Leishmania major in mice models. The healing was in a stage-dependent manner.

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Referencess

  1. Aguiar FJ et al (2013) C-reactive protein: clinical applications and proposals for a rational use. Rev Assoc Med Bras (1992) 59:85–92

    Article  Google Scholar 

  2. Ait-Oudhia K, Gazanion E, Vergnes B, Oury B, Sereno D (2011) Leishmania antimony resistance: what we know what we can learn from the field. Parasitol Res 109:1225–1232. https://doi.org/10.1007/s00436-011-2555-5

    Article  PubMed  Google Scholar 

  3. Ansar W, Ghosh S (2013) C-reactive protein and the biology of disease. Immunol Res 56:131–142. https://doi.org/10.1007/s12026-013-8384-0

    Article  CAS  PubMed  Google Scholar 

  4. Antonia AL, Wang L, Ko DC (2018) A real-time PCR assay for quantification of parasite burden in murine models of leishmaniasis. PeerJ 6:e5905

    Article  PubMed  PubMed Central  Google Scholar 

  5. Bíró A et al (2007) Studies on the interactions between C-reactive protein and complement proteins. Immunology 121:40–50

    Article  PubMed  PubMed Central  Google Scholar 

  6. Black S, Kushner I, Samols D (2004) C-reactive protein. J Biol Chem 279:48487–48490

    Article  CAS  PubMed  Google Scholar 

  7. Blackwell JM, Ezekowitz RA, Roberts MB, Channon JY, Sim RB, Gordon S (1985) Macrophage complement and lectin-like receptors bind Leishmania in the absence of serum. J Exp Med 162:324–331. https://doi.org/10.1084/jem.162.1.324

    Article  CAS  PubMed  Google Scholar 

  8. Bodman-Smith KB, Mbuchi M, Culley FJ, Bates PA, Raynes JG (2002) C-reactive protein-mediated phagocytosis of Leishmania donovani promastigotes does not alter parasite survival or macrophage responses. Parasite Immunol 24:447–454

    Article  CAS  PubMed  Google Scholar 

  9. Borghi SM, Fattori V, Conchon-Costa I, Pinge-Filho P, Pavanelli WR, Verri WA Jr (2017) Leishmania infection: painful or painless? Parasitol Res 116:465–475. https://doi.org/10.1007/s00436-016-5340-7

    Article  PubMed  Google Scholar 

  10. Calabro P, Golia E, Yeh ET (2012) Role of C-reactive protein in acute myocardial infarction and stroke: possible therapeutic approaches. Curr Pharm Biotechnol 13:4–16

    Article  CAS  PubMed  Google Scholar 

  11. Cecílio P, Oliveira F, Silva ACd (2018) Vaccines for Human Leishmaniasis: Where Do We Stand and What Is Still Missing? Leishmaniases Reemerg Dis Rijeka IntechOpen. https://doi.org/10.5772/intechopen.75000

    Article  Google Scholar 

  12. Culley FJ, Harris RA, Kaye PM, McAdam KP, Raynes JG (1996) C-reactive protein binds to a novel ligand on Leishmania donovani and increases uptake into human macrophages. J Immunol 156:4691–4696

    CAS  PubMed  Google Scholar 

  13. Culley FJ, Thomson M, Raynes JG (1997) C-reactive protein increases C3 deposition on Leishmania donovani promastigotes in human serum. Biochem Soc Transact 25:286s

    Article  CAS  Google Scholar 

  14. Daigo K, Inforzato A, Barajon I, Garlanda C, Bottazzi B, Meri S, Mantovani A (2016) Pentraxins in the activation and regulation of innate immunity. Immunol Rev 274:202–217

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. De Brito RCF et al (2018) Peptide Vaccines for Leishmaniasis. Front Immunol 9:1043. https://doi.org/10.3389/fimmu.2018.01043

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. de Menezes JP, Guedes CE, Petersen AL, Fraga DB, Veras PS (2015) Advances in development of new treatment for Leishmaniasis. Biomed Res Int 2015:815023. https://doi.org/10.1155/2015/815023

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Devaraj S, Dasu MR, Singh U, Rao LV, Jialal I (2009) C-reactive protein stimulates superoxide anion release and tissue factor activity in vivo. Atherosclerosis 203:67–74. https://doi.org/10.1016/j.atherosclerosis.2008.05.060

    Article  CAS  PubMed  Google Scholar 

  18. Devaraj S, Jialal I (2011) C-reactive protein polarizes human macrophages to an M1 phenotype and inhibits transformation to the M2 phenotype. Arterioscler Thromb Vasc Biol 31:1397–1402

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Ghaffarifar F et al (2013) Enhancement of immune response induced by DNA vaccine cocktail expressing complete LACK and TSA genes against Leishmania major. Apmis 121:290–298

    Article  CAS  PubMed  Google Scholar 

  20. Ghorbani M, Farhoudi R (2018) Leishmaniasis in humans: drug or vaccine therapy? Drug Des Devel Ther 12:25–40. https://doi.org/10.2147/DDDT.S146521

    Article  CAS  PubMed  Google Scholar 

  21. Ho KM, Lipman J (2009) An update on C-reactive protein for intensivists. Anaesth Intensive Care 37:234–241

    Article  CAS  PubMed  Google Scholar 

  22. Kobets T, Badalová J, Grekov I, Havelková H, Svobodová M, Lipoldová M (2010) Leishmania parasite detection and quantification using PCR-ELISA. Nat Protoc 5:1074

    Article  CAS  PubMed  Google Scholar 

  23. Laurenti MD, Orn A, Sinhorini IL, Corbett CE (2004) The role of complement in the early phase of Leishmania (Leishmania) amazonensis infection in BALB/c mice. Braz J Med Biol Res 37:427–434. https://doi.org/10.1590/s0100-879x2004000300021

    Article  CAS  PubMed  Google Scholar 

  24. Liu D, Uzonna JE (2012) The early interaction of Leishmania with macrophages and dendritic cells and its influence on the host immune response. Front Cell Infect Microbiol 2:83

    PubMed  Google Scholar 

  25. Lu J, Marjon KD, Mold C, Du Clos TW, Sun PD (2012) Pentraxins and Fc receptors. Immunol Rev 250:230–238

    Article  PubMed  PubMed Central  Google Scholar 

  26. Moein D, Masoud D, Saeed M, Abbas D (2018) Epidemiological aspects of cutaneous leishmaniasis during 2009–2016 in Kashan city, central Iran. Korean J Parasitol 56:21

    Article  PubMed  PubMed Central  Google Scholar 

  27. Mortazavidehkordi N et al (2018) A lentiviral vaccine expressing KMP11-HASPB fusion protein increases immune response to Leishmania major in BALB/C. Parasitol Res 117:2265–2273. https://doi.org/10.1007/s00436-018-5915-6

    Article  PubMed  Google Scholar 

  28. Mosser DM, Edwards JP (2008) Exploring the full spectrum of macrophage activation. Nat Rev Immunol 8:958–969. https://doi.org/10.1038/nri2448

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Peisajovich A, Marnell L, Mold C, Du Clos TW (2008) C-reactive protein at the interface between innate immunity and inflammation. Expert Rev Clin Immunol 4:379–390

    Article  CAS  PubMed  Google Scholar 

  30. Pepys MB, Hirschfield GM (2003) C-reactive protein: a critical update. J Clin Investig 111:1805–1812. https://doi.org/10.1172/jci18921

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Pilling D, Galvis-Carvajal E, Karhadkar TR, Cox N, Gomer RH (2017) Monocyte differentiation and macrophage priming are regulated differentially by pentraxins and their ligands. BMC Immunol 18:30. https://doi.org/10.1186/s12865-017-0214-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Piscopo TV, Mallia Azzopardi C (2007) Leishmaniasis. Postgrad Med J 83:649–657. https://doi.org/10.1136/pgmj.2006.047340corr1

    Article  PubMed  PubMed Central  Google Scholar 

  33. Ponte-Sucre A et al (2017) Drug resistance and treatment failure in leishmaniasis: a 21st century challenge. PLoS Negl Trop Dis 11:e0006052

    Article  PubMed  PubMed Central  Google Scholar 

  34. Salazar J et al (2014) C-reactive protein: an in-depth look into structure function, and regulation. Int Sch Res Notices 2014:653045. https://doi.org/10.1155/2014/653045

    Article  PubMed  PubMed Central  Google Scholar 

  35. Salazar J et al (2014) C-reactive protein: clinical and epidemiological perspectives. Cardiol Res Pract 2014:605810. https://doi.org/10.1155/2014/605810

    Article  PubMed  PubMed Central  Google Scholar 

  36. Sambrook J, Russell DW (2006) Preparation and transformation of competent E. coli using calcium chloride. CSH Protoc. https://doi.org/10.1101/pdb.prot3932

    Article  PubMed  Google Scholar 

  37. Santos DO et al (2008) Leishmaniasis treatment—a challenge that remains: a review. Parasitol Res 103:1–10. https://doi.org/10.1007/s00436-008-0943-2

    Article  PubMed  Google Scholar 

  38. Scott P, Novais FO (2016) Cutaneous leishmaniasis: immune responses in protection and pathogenesis. Nat Rev Immunol 16:581

    Article  CAS  PubMed  Google Scholar 

  39. Shirzadi MR, Esfahania SB, Mohebalia M, Ershadia MR, Gharachorlo F, Razavia MR, Postigo JA (2015) Epidemiological status of leishmaniasis in the Islamic Republic of Iran, 1983–2012. East Mediterr Health J 21:736–742. https://doi.org/10.26719/2015.21.10.736

    Article  CAS  PubMed  Google Scholar 

  40. Torres-Guerrero E, Quintanilla-Cedillo MR, Ruiz-Esmenjaud J, Arenas R (2017) Leishmaniasis: a review. F1000Research 6:750

    Article  PubMed  PubMed Central  Google Scholar 

  41. Trial J, Potempa LA, Entman ML (2016) The role of C-reactive protein in innate and acquired inflammation: new perspectives. Inflamm Cell Signal 3:e1409

    PubMed  PubMed Central  Google Scholar 

  42. Wilson S (1995) DNA-based methods in the detection of Leishmania parasites: field applications and practicalities. Ann Trop Med Parasitol 89:95–100

    Article  CAS  PubMed  Google Scholar 

  43. Word Health Organization Leishmaniasis epidemiological situation. https://www.who.int/leishmaniasis/burden/en/

  44. Wu Y, Potempa LA, El Kebir D, Filep JG (2015) C-reactive protein and inflammation: conformational changes affect function. Biol Chem 396:1181–1197. https://doi.org/10.1515/hsz-2015-0149

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This work was funded by the Isfahan University of Medical Sciences, Isfahan, Iran (Grant No. 397345 dated 2018).

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Correspondence to Hossein Khanahmad.

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The authors declare that they have no conflict of interest.

Ethical approval

Animal maintenance and injections were performed in the animal facility of Medicine School, Isfahan University of Medical Sciences, Isfahan, Iran, according to the university guidelines for animal care (IR.MUI.MED.REC.1397.365).

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Zahedi, S.N., Hejazi, S.H., Boshtam, M. et al. Recombinant C-Reactive Protein: A Potential Candidate for the Treatment of Cutaneous Leishmaniasis of BALB/c Mice Caused by Leishmania major. Acta Parasit. 66, 53–59 (2021). https://doi.org/10.1007/s11686-020-00251-w

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