Research article

Enhancing the efficacy of anti-malarial drugs with immune boosters: A mathematical model

  • Received: 17 August 2023 Revised: 01 December 2023 Accepted: 04 December 2023 Published: 20 December 2023
  • This paper presents a mathematical model of severe malarial anemia (SMA), which is a complication of malaria and is a major contributor to malaria-related deaths. SMA is characterized by a decrease in hemoglobin levels in the blood due to the suppression of red blood cell (RBC) recruitment by the protein macrophage migration inhibitory factor (MIF). Plasmodium falciparum, which is a malaria-causing parasite, secretes a specific form of MIF called plasmodium falciparum macrophage migration inhibitory factor (PFMIF), which affects immune cells. Artesunate, which is the primary treatment for SMA, reduces the parasite level but does not increase hemoglobin levels and can sometimes lead to hemolytic anemia, which requires a blood transfusion. To address this issue, the experimental drug Epoxyazadiradione (Epoxy) was explored as a potential treatment for SMA. Epoxy inhibits both MIF and PFMIF interactions with immune cells and has the potential to increase hemoglobin levels in SMA patients. Our model simulations support previous findings that the appropriate combination of Artesunate with Epoxy can reduce parasite load while preventing anemia by maintaining hemoglobin levels at an adequate level. Additionally, we explored the impact of immune boosters on the anti-malarial drugs Artesunate and Epoxy and discovered that an insufficient amount of drugs is ineffective, while an excessive amount may not be beneficial.

    Citation: Dorcas Mulenga, Winnie Anoumedem, Blessing O. Emerinini, Nourridine Siewe. Enhancing the efficacy of anti-malarial drugs with immune boosters: A mathematical model[J]. AIMS Allergy and Immunology, 2023, 7(4): 281-303. doi: 10.3934/Allergy.2023019

    Related Papers:

  • This paper presents a mathematical model of severe malarial anemia (SMA), which is a complication of malaria and is a major contributor to malaria-related deaths. SMA is characterized by a decrease in hemoglobin levels in the blood due to the suppression of red blood cell (RBC) recruitment by the protein macrophage migration inhibitory factor (MIF). Plasmodium falciparum, which is a malaria-causing parasite, secretes a specific form of MIF called plasmodium falciparum macrophage migration inhibitory factor (PFMIF), which affects immune cells. Artesunate, which is the primary treatment for SMA, reduces the parasite level but does not increase hemoglobin levels and can sometimes lead to hemolytic anemia, which requires a blood transfusion. To address this issue, the experimental drug Epoxyazadiradione (Epoxy) was explored as a potential treatment for SMA. Epoxy inhibits both MIF and PFMIF interactions with immune cells and has the potential to increase hemoglobin levels in SMA patients. Our model simulations support previous findings that the appropriate combination of Artesunate with Epoxy can reduce parasite load while preventing anemia by maintaining hemoglobin levels at an adequate level. Additionally, we explored the impact of immune boosters on the anti-malarial drugs Artesunate and Epoxy and discovered that an insufficient amount of drugs is ineffective, while an excessive amount may not be beneficial.



    加载中

    Acknowledgments



    This research was supported by the African Institute for Mathematical Sciences (AIMS)-Cameroon, and the School of Mathematics and Statistics at Rochester Institute of Technology.

    Conflict of interest



    The authors declare that they have no known competing interests that could have appeared to influence the work reported in this paper.

    [1] Snow RW, Korenromp EL, Gouws E (2004) Pediatric mortality in Africa: plasmodium falciparum malaria as a cause or risk?. Am J Trop Med Hyg 71: 16-24. https://doi.org/10.4269/ajtmh.2004.71.16
    [2] Ross A, Maire N, Molineaux L, et al. (2006) An epidemiologic model of severe morbidity and mortality caused by Plasmodium falciparum. Am J Trop Med Hyg 75: 63-73. https://doi.org/10.4269/ajtmh.2006.75.63
    [3] Graumans W, Jacobs E, Bousema T, et al. (2020) When is a Plasmodium-infected mosquito an infectious mosquito?. Trends Parasitol 36: 705-716. https://doi.org/10.1016/j.pt.2020.05.011
    [4] Beier JC (1998) Malaria parasite development in mosquitoes. Annu Rev Entomol 43: 519-543. https://doi.org/10.1146/annurev.ento.43.1.519
    [5] Kafsack BF, Rovira-Graells N, Clark TG, et al. (2014) A transcriptional switch underlies commitment to sexual development in malaria parasites. Nature 507: 248-252. https://doi.org/10.1038/nature12920
    [6] Fernández-Grandon GM, Gezan SA, Armour JA, et al. (2015) Heritability of attractiveness to mosquitoes. PloS One 10: e0122716. https://doi.org/10.1371/journal.pone.0122716
    [7] Delves M, Plouffe D, Scheurer C, et al. (2012) The activities of current antimalarial drugs on the life cycle stages of Plasmodium: a comparative study with human and rodent parasites. PLoS Med 9: e1001169. https://doi.org/10.1371/journal.pmed.1001169
    [8] Kappe SH, Kaiser K, Matuschewski K (2003) The Plasmodium sporozoite journey: a rite of passage. Trends Parasitol 19: 135-143. https://doi.org/10.1016/S1471-4922(03)00007-2
    [9] Nureye D, Assefa S (2020) Old and recent advances in life cycle, pathogenesis, diagnosis, prevention, and treatment of malaria including perspectives in Ethiopia. Sci World J 2020: 1-17. https://doi.org/10.1155/2020/1295381
    [10] Centers for Disease Control and Prevention, The history of malaria, an ancient disease. CDC (2010) . Available from: https://stacks.cdc.gov/view/cdc/135582
    [11] McDevitt MA, Xie J, Ganapathy-Kanniappan S, et al. (2006) A critical role for the host mediator macrophage migration inhibitory factor in the pathogenesis of malarial anemia. J Exp Med 203: 1185-1196. https://doi.org/10.1084/jem.20052398
    [12] Sun T, Holowka T, Song Y, et al. (2012) A Plasmodium-encoded cytokine suppresses T-cell immunity during malaria. P Natl Acad Sci USA 109: E2117-E2126. https://doi.org/10.1073/pnas.1206573109
    [13] Wynn AA, Myint O, Zin T (2016) Host and parasite immunopathogenesis of malaria. Survival 34: 35.
    [14] Cordery DV (2007) Characterisation of macrophage migration inhibitory factor homologues in plasmodium species [PhD's thesis]. United Kingdom: Open University.
    [15] Rosenthal PJ (2008) Artesunate for the treatment of severe falciparum malaria. N Engl J Med 358: 1829-1836. https://doi.org/10.1056/NEJMct0709050
    [16] Burri C, Ferrari G, Ntuku HM, et al. (2014) Delayed anemia after treatment with injectable artesunate in the Democratic Republic of the Congo: a manageable issue. Am J Trop Med Hyg 91: 821. https://doi.org/10.4269/ajtmh.14-0149
    [17] Alam A, Haldar S, Thulasiram HV, et al. (2012) Novel anti-inflammatory activity of epoxyazadiradione against macrophage migration inhibitory factor: inhibition of tautomerase and proinflammatory activities of macrophage migration inhibitory factor. J Biol Chem 287: 24844-24861. https://doi.org/10.1074/jbc.M112.341321
    [18] Olotu A, Urbano V, Hamad A, et al. (2018) Advancing global health through development and clinical trials partnerships: A randomized, placebo-controlled, double-blind assessment of safety, tolerability, and immunogenicity of PfSPZ vaccine for malaria in healthy equatoguinean men. Am J Trop Med Hyg 98: 308. https://doi.org/10.4269/ajtmh.17-0449
    [19] Gupta S, Snow RW, Donnelly CA, et al. (1999) Immunity to non-cerebral severe malaria is acquired after one or two infections. Nat Med 5: 340-343. https://doi.org/10.1038/6560
    [20] Frosch AE, John CC (2012) Immunomodulation in Plasmodium falciparum malaria: experiments in nature and their conflicting implications for potential therapeutic agents. Expert Rev Anti Infect Ther 10: 1343-1356. https://doi.org/10.1586/eri.12.118
    [21] Siewe N, Friedman A (2020) Increase hemoglobin level in severe malarial anemia while controlling parasitemia: A mathematical model. Math Biosci 326: 108374. https://doi.org/10.1016/j.mbs.2020.108374
    [22] Cooper B (2011) The origins of bone marrow as the seedbed of our blood: from antiquity to the time of Osler. Bayl Univ Med Cent 24: 115-118. https://doi.org/10.1080/08998280.2011.11928697
    [23] Cowman AF, Tonkin CJ, Tham WH, et al. (2017) The molecular basis of erythrocyte invasion by malaria parasites. Cell Host Microbe 22: 232-245. https://doi.org/10.1016/j.chom.2017.07.003
    [24] Cowman AF, Crabb BS (2006) Invasion of red blood cells by malaria parasites. Cell 124: 755-766. https://doi.org/10.1016/j.cell.2006.02.006
    [25] Birkle T, Brown G (2021) I'm infected, eat me! Innate immunity mediated by live, infected cells signaling to be phagocytosed. Infect Immun 89: e00476-20. https://doi.org/10.1128/IAI.00476-20
    [26] Alzoubi K, Calabrò S, Bissinger R, et al. (2014) Stimulation of suicidal erythrocyte death by artesunate. Cell Physiol Biochem 34: 2232-2244. https://doi.org/10.1159/000369666
    [27] Fernandes P, Loubens M, Le Borgne R, et al. (2022) The AMA1-RON complex drives Plasmodium sporozoite invasion in the mosquito and mammalian hosts. PLoS Pathog 18: e1010643. https://doi.org/10.1371/journal.ppat.1010643
    [28] Aggarwal R, Chamoli A, Rawat M, et al. (2023) A review on malaria, its control and management. AJPSci . https://doi.org/10.52711/2231-5659.2023.00027
    [29] Antonelli LR, Junqueira C, Vinetz JM, et al. (2020) The immunology of Plasmodium vivax malaria. Immunol Rev 293: 163-189. https://doi.org/10.1111/imr.12816
    [30] Elmore S (2007) Apoptosis: a review of programmed cell death. Toxicol Pathol 35: 495-516. https://doi.org/10.1080/01926230701320337
    [31] Junqueira C, Polidoro RB, Castro G, et al. (2021) γδ T cells suppress Plasmodium falciparum blood-stage infection by direct killing and phagocytosis. Nat Immunol 22: 347-357. https://doi.org/10.1038/s41590-020-00847-4
    [32] Kumar R, Loughland JR, Ng SS, et al. (2020) The regulation of CD4+ T cells during malaria. Immunol Rev 293: 70-87. https://doi.org/10.1111/imr.12804
    [33] Alimonti JB, Ball TB, Fowke KR (2003) Mechanisms of CD4+ T lymphocyte cell death in human immunodeficiency virus infection and AIDS. J Gen Virol 84: 1649-1661. https://doi.org/10.1099/vir.0.19110-0
    [34] Calandra T, Spiegel LA, Metz CN, et al. (1998) Macrophage migration inhibitory factor is a critical mediator of the activation of immune cells by exotoxins of Gram-positive bacteria. P Natl Acad Sci USA 95: 11383-11388. https://doi.org/10.1073/pnas.95.19.11383
    [35] Tarasuk M, Poungpair O, Ungsupravate D, et al. (2014) Human single-chain variable fragment antibody inhibits macrophage migration inhibitory factor tautomerase activity. Int J Mol Med 33: 515-522. https://doi.org/10.3892/ijmm.2014.1622
    [36] Augustijn KD, Kleemann R, Thompson J, et al. (2007) Functional characterization of the Plasmodium falciparum and P. berghei homologues of macrophage migration inhibitory factor. Infect Immun 75: 1116-1128. https://doi.org/10.1128/IAI.00902-06
    [37] Schipper S, Springer E, Hahn J, et al. (2022) Characterization of Plasmodium falciparum macrophage migration inhibitory factor homologue and its cysteine deficient mutants. Parasitol Int 87: 102513. https://doi.org/10.1016/j.parint.2021.102513
    [38] Brundha M, Pathmashri V, Sundari S (2019) Quantitative changes of red blood cells in cancer patients under palliative radiotherapy-a retrospective study. Res J Pharm Technol 12: 687-692. https://doi.org/10.5958/0974-360X.2019.00122.7
    [39] Stadler AM, Digel I, Artmann GM, et al. (2008) Hemoglobin dynamics in red blood cells: correlation to body temperature. Biophys J 95: 5449-5461. https://doi.org/10.1529/biophysj.108.138040
    [40] Siewe N, Yakubu AA, Satoskar AR, et al. (2016) Immune response to infection by leishmania: A mathematical model. Math Biosci 276: 28-43. https://doi.org/10.1016/j.mbs.2016.02.015
    [41] Ludwig H, Strasser K (2001) Symptomatology of anemia. Semin Oncol 28: 7-14. https://doi.org/10.1016/S0093-7754(01)90206-4
    [42] Otto JM, Montgomery HE, Richards T (2013) Haemoglobin concentration and mass as determinants of exercise performance and of surgical outcome. Extrem Physiol Med 2: 1-8. https://doi.org/10.1186/2046-7648-2-33
    [43] Kariyeva GK, Magtymova A, Sharman A (2000) Turkmenistan demographic and health survey: Anemia. DHS 12: 141-147.
    [44] Ruwizhi N, Maseko RB, Aderibigbe BA (2022) Recent advances in the therapeutic efficacy of artesunate. Pharmaceutics 14: 504. https://doi.org/10.3390/pharmaceutics14030504
    [45] Eltahir HG, Bilal JA, Ali EA, et al. (2017) No reduction in hemoglobin level in severe plasmodium falciparum malaria treated with artesunate in central Sudan. J Trop Pediatr 63: 18-22. https://doi.org/10.1093/tropej/fmw041
    [46] Rehman K, Lötsch F, Kremsner PG, et al. (2014) Haemolysis associated with the treatment of malaria with artemisinin derivatives: a systematic review of current evidence. Int J Infect Dis 29: 268-273. https://doi.org/10.1016/j.ijid.2014.09.007
    [47] El-Moamly AA, El-Sweify MA (2023) Malaria vaccines: the 60-year journey of hope and final success—lessons learned and future prospects. Trop Med Health 51: 29. https://doi.org/10.1186/s41182-023-00516-w
    [48] O'Flaherty K, Maguire J, Simpson JA, et al. (2017) Immunity as a predictor of anti-malarial treatment failure: a systematic review. Malar J 16: 1-11. https://doi.org/10.1186/s12936-017-1815-y
    [49] Doolan DL, Dobano C, Baird JK (2009) Acquired immunity to malaria. Clin Microbiol Rev 22: 13-36. https://doi.org/10.1128/CMR.00025-08
    [50] Siewe N, Yakubu AA, Satoskar AR, et al. (2017) Granuloma formation in leishmaniasis: A mathematical model. J Theor Biol 412: 48-60. https://doi.org/10.1016/j.jtbi.2016.10.004
    [51] Siewe N, Friedman A (2022) Cancer therapy with immune checkpoint inhibitor and CSF-1 blockade: A mathematical model. J Theor Biol 556: 111297. https://doi.org/10.1016/j.jtbi.2022.111297
    [52] Siewe N, Friedman A (2022) Combination therapy for mCRPC with immune checkpoint inhibitors, ADT and vaccine: A mathematical model. PLoS One 17: e0262453. https://doi.org/10.1371/journal.pone.0262453
    [53] Siewe N, Friedman A (2023) Breast cancer exosomal microRNAs facilitate pre-metastatic niche formation in the bone: A mathematical model. Bull Math Biol 85: 12. https://doi.org/10.1007/s11538-022-01117-0
    [54] Siewe N, Friedman A (2022) Optimal timing of steroid initiation in response to CTLA-4 antibody in metastatic cancer: A mathematical model. PLoS One 17: e0277248. https://doi.org/10.1371/journal.pone.0277248
    [55] Friedman A, Siewe N (2020) Overcoming drug resistance to BRAF inhibitor. Bull Math Biol 82: 1-31. https://doi.org/10.1007/s11538-019-00691-0
    [56] Siewe N, Friedman A (2021) TGF-β inhibition can overcome cancer primary resistance to PD-1 blockade: a mathematical model. PLoS One 16: 1-16. https://doi.org/10.1371/journal.pone.0252620
    [57] Friedman A, Siewe N (2018) Chronic hepatitis B virus and liver fibrosis: A mathematical model. PLoS One 13: 1-23. https://doi.org/10.1371/journal.pone.0195037
    [58] Mulder C, Hendriks AJ (2014) Half-saturation constants in functional responses. Glob Ecol Conserv 2: 161-169. https://doi.org/10.1016/j.gecco.2014.09.006
    [59] Kamangira B, Nyamugure P, Magombedze G (2014) A theoretical mathematical assessment of the effectiveness of coartemether in the treatment of Plasmodium falciparum malaria infection. Math Biosci 256: 28-41. https://doi.org/10.1016/j.mbs.2014.07.010
    [60] Quinlivan EP (2008) Calculation of steady state conditions and elimination kinetics of red blood cell folate in women of childbearing age after daily supplementation with various forms and doses of folate. Am J Clin Nutr 87: 1537-1538. https://doi.org/10.1093/ajcn/87.5.1537
    [61] Boyle MJ, Wilson DW, Richards JS, et al. (2010) Isolation of viable Plasmodium falciparum merozoites to define erythrocyte invasion events and advance vaccine and drug development. P Natl Acad Sci USA 107: 14378-14383. https://doi.org/10.1073/pnas.1009198107
    [62] Li Q, Weina P (2010) Artesunate: the best drug in the treatment of severe and complicated malaria. Pharmaceuticals 3: 2322-2332. https://doi.org/10.3390/ph3072322
    [63] Zoller T, Junghanss T, Kapaun A, et al. (2011) Intravenous artesunate for severe malaria in travelers, Europe. J Clin Invest 17: 771-777. https://doi.org/10.3201/eid1705.101229
    [64] (2000) World Health OrganizationManagement of Severe Malaria: a Practical Handbook.World Health Organization.
  • Reader Comments
  • © 2023 the Author(s), licensee AIMS Press. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0)
通讯作者: 陈斌, bchen63@163.com
  • 1. 

    沈阳化工大学材料科学与工程学院 沈阳 110142

  1. 本站搜索
  2. 百度学术搜索
  3. 万方数据库搜索
  4. CNKI搜索

Metrics

Article views(642) PDF downloads(59) Cited by(0)

Article outline

Figures and Tables

Figures(5)  /  Tables(2)

/

DownLoad:  Full-Size Img  PowerPoint
Return
Return

Catalog