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Mitogen-Activated Protein Kinase and Aquaglyceroporin Gene Expression in Treatment Failure Leishmania major

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Abstract

Purpose

Leishmaniasis comprises various clinical forms mainly including cutaneous, muco-cutaneous, and visceral leishmaniasis; caused by Leishmania species. Antimoniate is the first-line treatment but some cases showed no response to treatment in the worldwide. In this study, mitogen-activated protein kinase (MAPK) and aquaglyceroporin 1 (AQP1) gene expressions were assessed in treatment failure clinical isolates of Leishmania major. Also, molecular and phylogenic analyses of the mentioned isolates were performed.

Methods

Samples were obtained from the patients with suspicious CL referred to the laboratory of Diagnosis Center, Gorgan Province, Iran, from October 2016 to December 2019. Detection and identification of the parasite was performed. The genes expressions of MAPK1 and AQP1 were done using SYBR Green real-time PCR. The AQP1 gene from the isolates with treatment failure was sequenced and analyzed using BLAST and multiple alignments. The phylogenic analysis was done using MEGA7. The statistical analysis was done using SPSS 16.0 by non-parametric MannWhitney U test.

Results

All clinical isolates were detected L. major. The mean AQP1 and MAPK1 gene expressions in treatment failure isolates were 58.71 and 6.139 fold less than the ones in treatment response isolates, respectively. Based on the AQP1 gene sequence, a nucleotide change of aspartic acid with asparagine at the site 234 was observed. Phylogenic tree analysis showed three groups with the minimum dissimilarity of 0.008 between TF isolates with the standard L. major strains.

Conclusion

We showed that MAPK1 and AQP1 may have critical roles in response to antimoniate in clinical isolates L. major in this study.

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Availability of data and materials

All data generated or analyzed during this study are available by the corresponding author.

Code availability

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References

  1. Alvar J, Aparicio P, Aseffa A, Den Boer M, Cañavate C, Dedet JP, Gradoni L, Ter Horst R, López-Vélez R, Moreno J (2008) The relationship between leishmaniasis and AIDS: the second 10 years. Clin Microbiol Rev 21:334–359. https://doi.org/10.1128/CMR.00061-07

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Alvar J, Vélez ID, Bern C, Herrero M, Desjeux P, Cano J, Jannin J, den Boer J, WHO Leishmaniasis Control Team (2012) Leishmaniasis worldwide and global estimates of its incidence. PLoS ONE 7:e35671. https://doi.org/10.1371/journal.pone.0035671

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Torres-Guerrero E, Quintanilla-Cedillo MR, Ruiz-Esmenjaud J, Arenas R (2017) Leishmaniasis: a review. F1000Rres 6:750–750. https://doi.org/10.12688/f1000research.11120.1

    Article  Google Scholar 

  4. Hejazi H, Eslami G, Dalimi A (2004) The parasiticidal effect of electricity on Leishmania major, both in vitro and in vivo. Ann Trop Med Parasitol 98:37–42. https://doi.org/10.1179/136485913X13789813917661

    Article  CAS  PubMed  Google Scholar 

  5. Machado-Silva A, Guimarães PP, Tavares CA, Sinisterra RD (2015) New perspectives for leishmaniasis chemotherapy over current anti-leishmanial drugs: a patent landscape. Expert Opin Ther Pat 25:247–260. https://doi.org/10.1517/13543776.2014.993969

    Article  CAS  PubMed  Google Scholar 

  6. Abtahi M, Eslami G, Cavallero S, Vakili M, Hosseini SS, Ahmadian S, Boozhmehrani MJ, Khamesipour A (2020) Relationship of Leishmania RNA Virus (LRV) and treatment failure in clinical isolates of Leishmania major. BMC Res Notes 13:126. https://doi.org/10.1186/s13104-020-04973-y

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Alijani Y, Hosseini SS, Ahmadian S, Boughattas S, Eslami G, Naderian S, Ajamein V (2019) Molecular analysis of Aquaglyceroporin 1 gene in non-healing clinical isolates obtained from patients with cutaneous Leishmaniasis from Central of Iran. J Arthropod Borne Dis 13:145–152. https://doi.org/10.18502/jad.v13i2.1240

    Article  PubMed  PubMed Central  Google Scholar 

  8. Eslami G, Hatefi S, Ramezani V, Tohidfar M, Churkina TV, Orlov YL, Hosseini SS, Boozhmehrani MJ, Vakili M (2021) Molecular characteristic of treatment failure clinical isolates of Leishmania major. PeerJ 9:e10969. https://doi.org/10.7717/peerj.10969

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Hindley A, Kolch W (2002) Extracellular signal regulated kinase (ERK)/mitogen activated protein kinase (MAPK)-independent functions of Raf kinases. J Cell Sci 115(8):1575–1581. https://doi.org/10.1242/jcs.115.8.1575

    Article  CAS  PubMed  Google Scholar 

  10. Mandal G, Sharma M, Kruse M, Sander-Juelch C, Munro LA, Wang Y, Vilg JV, Tamás MJ, Bhattacharjee H, Wiese M, Mukhopadhyay R (2012) Modulation of Leishmania major aquaglyceroporin activity by a mitogen-activated protein kinase. Mol Microbiol 85:1204–1218. https://doi.org/10.1111/j.1365-2958.2012.08169.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Figarella K, Uzcategui NL, Zhou Y, Lefurgey A, Ouellette M, Bhattacharjee H, Mukhopadhyay R (2007) Biochemical characterization of Leishmania major aquaglyceroporin LmAQP1: possible role in volume regulation and osmotaxis. Mol Microbiol 65:1006–1017. https://doi.org/10.1111/j.1365-2958.2007.05845.x

    Article  CAS  PubMed  Google Scholar 

  12. Marquis N, Gourbal B, Rosen BP, Mukhopadhyay R, Ouellette M (2005) Modulation in aquaglyceroporin AQP1 gene transcript levels in drug-resistant Leishmania. Mol Microbiol 57:1690–1699. https://doi.org/10.1111/j.1365-2958.2005.04782.x

    Article  CAS  PubMed  Google Scholar 

  13. Martínez DY, Llanos-Cuentas A, Dujardin JC, Polman K, Adaui V, Boelaert M, Verdonck K (2020) A case-control study on the association between intestinal helminth infections and treatment failure in patients with cutaneous leishmaniasis. Open Forum Infect Dis 7:ofaa155. https://doi.org/10.1093/ofid/ofaa155

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Eslami G, Salehi R, Khosravi S, Doudi M (2012) Genetic analysis of clinical isolates of Leishmania major from Isfahan, Iran. J Vector Borne Dis 49:168–174

    CAS  PubMed  Google Scholar 

  15. Eslami G, Zarchi MV, Moradi A, Hejazi SH, Sohrevardi SM, Vakili M, Khamesipour A (2016) Aquaglyceroporin1 gene expression in antimony resistance and susceptible Leishmania major isolates. J Vector Borne Dis 53:370–374

    CAS  PubMed  Google Scholar 

  16. Hoffert JD, Leitch V, Agre P, King LS (2000) Hypertonic induction of aquaporin-5 expression through an ERK-dependent pathway. J Biol Chem 275:9070–9077. https://doi.org/10.1074/jbc.275.12.9070

    Article  CAS  PubMed  Google Scholar 

  17. Arima H, Yamamoto N, Sobue K, Umenishi F, Tada T, Katsuya H, Asai K (2003) Hyperosmolar mannitol simulates expression of aquaporins 4 and 9 through a p38 mitogen-activated protein kinase-dependent pathway in rat astrocytes. J Biol Chem 278:44525–44534. https://doi.org/10.1074/jbc.M304368200

    Article  CAS  PubMed  Google Scholar 

  18. Thorsen M, Di Y, Tängemo C, Morillas M, Ahmadpour D, Van der Does C, Wagner A, Johansson E, Boman J, Posas F, Wysocki R, Tamás MJ (2006) The MAPK Hog1p modulates Fps1p-dependent arsenite uptake and tolerance in yeast. Mol Biol Cell 17:4400–4410. https://doi.org/10.1091/mbc.E06-04-0315

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Uzcategui NL, Zhou Y, Figarella K, Ye J, Mukhopadhyay R, Bhattacharjee H (2008) Alteration in glycerol and metalloid permeability by a single mutation in the extracellular C-loop of Leishmania major aquaglyceroporin LmAQP1. Mol Microbiol 70:1477–1486. https://doi.org/10.1111/j.1365-2958.2008.06494.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Ishibashi K, Morishita Y, Tanaka Y (2017) The evolutionary aspects of aquaporin family. Adv Exp Med Biol 969:35–50. https://doi.org/10.1007/978-94-024-1057-0_2

    Article  CAS  PubMed  Google Scholar 

  21. Wree D, Wu B, Zeuthen T, Beitz E (2011) Requirement for asparagine in the aquaporin NPA sequence signature motifs for cation exclusion. FEBS J 278:740–748. https://doi.org/10.1111/j.1742-4658.2010.07993.x

    Article  CAS  PubMed  Google Scholar 

  22. Wu B, Steinbronn C, Alsterfjord M, Zeuthen T, Beitz E (2009) Concerted action of two cation filters in the aquaporin water channel. EMBO J 28:2188–2194. https://doi.org/10.1038/emboj.2009.182

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Ishibashi K, Koike S, Kondo S, Hara S, Tanaka Y (2009) The role of a group III AQP, AQP11 in intracellular organelle homeostasis. J Med Investig 56(Suppl):312–317. https://doi.org/10.2152/jmi.56.312

    Article  Google Scholar 

  24. Kaur P, Anand A, Bhat A, Maras JS, Goyal N (2021) Comparative phosphoproteomic analysis unravels MAPK1 regulated phosphoproteins in Leishmaniadonovani. J Proteom 240:104189. https://doi.org/10.1016/j.jprot.2021.104189

    Article  CAS  Google Scholar 

  25. Raj S, Saha G, Sasidharan S, Dubey VK, Saudagar P (2019) Biochemical characterization and chemical validation of Leishmania MAP Kinase-3 as a potential drug target. Sci Rep 9:16209. https://doi.org/10.1038/s41598-019-52774-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Baker N, Catta-Preta CMC, Neish R, Sadlova J, Powell B, Alves-Ferreira EVC, Geoghegan V, Carnielli JBT, Newling K, Hughes C, Vojtkova B, Anand J, Mihut A, Walrad PB, Wilson LG, Pitchford JW, Volf P, Mottram JC (2021) Systematic functional analysis of Leishmania protein kinases identifies regulators of differentiation or survival. Nat Commun 12:1244. https://doi.org/10.1038/s41467-021-21360-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This research was done by Research Center of Food Hygiene and Safety, Shahid Sadoughi University of Medical Sciences, Yazd, Iran. We sincerely thank the technical supports of the staff of Research Center of Food Hygiene and Safety, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.

Funding

This research was financially supported by Shahid Sadoughi University of Medical Sciences, Yazd, Iran.

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Contributions

Data collection, doing the experiments (RS); study design, supervising the method, critical revising the manuscript: (GE); statistical analysis: (MV). All authors read the manuscript.

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Correspondence to Gilda Eslami.

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There is no conflict of interest.

Ethical approval

This study was approved by Ethics ID of IR.SSU.MEDICINE.REC.1395.335 by the Ethical Committee of Shahid Sadoughi University of Medical Sciences, Yazd, Iran. All patients wrote and signed the informed consent form prior to including in this study.

Consent to participate

The informed consent was written and completed by each patient participating in this study before recording the information and sampling based on Helsinki declaration.

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The consent form was completed with the patients.

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Somee, R., Eslami, G. & Vakili, M. Mitogen-Activated Protein Kinase and Aquaglyceroporin Gene Expression in Treatment Failure Leishmania major. Acta Parasit. 67, 309–315 (2022). https://doi.org/10.1007/s11686-021-00463-8

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