Plasmodium Falciparum: A Pathogenesis and Therapeutic Challenges in Combating Fatal Malaria: A Subject Review
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Plasmodium falciparum is the most lethal malaria parasite worldwide with characteristic mature gametocytes of the crescentic form and intricate capacity by sequestration in the microvasculature of host. Its life cycle is a complex change between the Anopheles mosquito and human host with a silent hepatic phase followed by an erythrocytic pathogenic one that occurs every 48 hours. Avoidance of the host’s immune response is effected by the rapid shift of expression from one PfEMP1 variant to another through antigenic variation on the surface of infected erythrocytes, mediated by 'patching' and 'segmental gene conversion'. Although Iraq has achieved an elimination status with no autochthonous transmission, the risk of re-importation and resurgence are high because of imported cases from neighboring endemic countries (Iran) and it is also under threat of vector expansion as a result of climatic changes. New management has shifted to rapid diagnostic tests and the Artemisinin-based Combination Therapies (ACTs) As well as the elimination by 2030, it faces biological and ecological issues.
1. World Health Organization. World malaria report 2023. Geneva: World Health Organization; 2023.
2. Ashley EA, Pyae Phyo A, Woodrow CJ. Malaria. Lancet. 2018 Apr 21;391(10130):1608-1621.
3. Cowman AF, Healer J, Marapana D, Marsh K. Malaria: Biology and Disease. Cell. 2016 Oct 20;167(3):610-624.
4. White NJ. Malaria. In: Manson's Tropical Infectious Diseases. 24th ed. Philadelphia: Elsevier; 2023. p. 532-600.
5. Miller LH, Baruch DI, Marsh K, Doumbo OK. The pathogenic basis of malaria. Nature. 2002 Feb 7;415(6872):673-9.
6. Wahlgren M, Goel S, Akhouri RR. Variant surface antigens of Plasmodium falciparum and their roles in severe malaria. Nat Rev Microbiol. 2017 Aug;15(8):479-491.
7. Deitsch KW, Hviid L. Establishing a model for the pathogenesis of severe Plasmodium falciparum malaria. Trends Parasitol. 2021;37(12):1043-1052.
8. Haeggström M, Deitsch K, Hviid L, Jensen AT, Miller LH. The Role of PfEMP1 in Cytoadherence and Sequestration. Frontiers in Cellular and Infection Microbiology. 2020;10:145.
9. Phillips MA, Burrows JN, Manyando C, et al. Malaria. Nature Reviews Disease Primers. 2017;3:17050.
10. Menard D, Ariey F. Plasmodium falciparum resistance to artemisinin: Current status and future challenges. Med Sci (Paris). 2015;31(11):980-6.
11. Haldar K, Bhattacharjee S, Safeukui I. Drug resistance in Plasmodium falciparum malaria. Nat Rev Microbiol. 2018;16(3):156-170.
12. White NJ. Antimalarial drug resistance. J Clin Invest. 2004;113(8):1084-1092.
13. Ministry of Health, Iraq. National Malaria Elimination Program: Annual Epidemiological Report. Baghdad: MOH Press; 2022.
14. Rasheed HI, Hasan HF, Ahmed NA. Molecular Characterization of Human Cryptosporidium Isolates from in Kirkuk, Iraq. Iraqi Journal of Science. 2025 Apr;66(4):1516–1524.
15. WHO Regional Office for the Eastern Mediterranean. Malaria elimination in the Eastern Mediterranean Region: Progress and challenges. Cairo: WHO-EMRO; 2021.
16. Hama AA, Al-Zubaidi F, Al-Azawi A. Distribution and bionomics of Anopheles mosquitoes in Iraq. International Journal of Entomology Research. 2018;3(2):124-129.
17. Bourgard C, Albrecht L, Kayano ACAV, Sunnerhagen P. Plasmodium vivax biology: insights provided by genomics, transcriptomics and proteomics. Front Cell Infect Microbiol. 2018;8:34.
18. Kappe SH, Vaughan AM, Boddey JA, Cowman AF. That was then but this is now: malaria research in the post-genomic era. Science. 2010;328(5980):862-6.
19. Frischknecht F, Mueller AK. The Cell Biology of Malaria Invasion: Gametes to Sporozoites. Cold Spring Harb Perspect Med. 2017;7(2):a025510.
20. Pradel G. Proteins of the malaria parasite sexual stages: expression, function and immunity. Cell Microbiol. 2007;9(9):2113-24.
21. Bennink S, Kiesow MJ, Pradel G. The development of malaria parasites in the mammalian host. Int J Med Microbiol. 2016;306(5):300-11.
22. Enomoto M, Kawazu S-I, Kawai S, Furuyama W. Blockage of spontaneous Ca²⁺ oscillation causes cell death in intraerythrocytic Plasmodium falciparum. PLoS One. 2012;7(7):e39499.
23. Tilley L, Dixon MW, Kirk K. The Plasmodium falciparum-infected red blood cell: Structural and functional changes. Int J Parasitol. 2011;41(1):5-22.
24. Cowman AF, Crabb BS. Invasion of red blood cells by malaria parasites. Cell. 2006;124(4):755-66.
25. Goldberg DE. Hemoglobin degradation. Curr Top Microbiol Immunol. 2005;295:275-91.
26. Gravenor MB, Kwiatkowski D. Analysis of the 48-hour cycle of Plasmodium falciparum in vivo. Parasitology. 1998;117 ( Pt 4):311-6.
27. Josling GA, Llinás M. Sexual commitment in Plasmodium falciparum: a molecular pivot. Trends Parasitol. 2015;31(12):603-10.
28. Dixon MW, et al. Shape-shifting gametocytes: how and why does P. falciparum go banana-shaped? Trends Parasitol. 2012;28(11):471-8.
29. Aly AS, Vaughan AM, Kappe SH. Malaria parasite development in the mosquito and infection of the mammalian host. Annu Rev Microbiol. 2009;63:195-221.
30. Turner L, Lavstsen T, Berger SS, et al. Severe malaria is associated with parasite binding to endothelial protein C receptor. Nature. 2013;498(7455):502-5.
31. Avril M, Bernabeu M, Benjamin M, et al. Interaction between endothelial protein C receptor and intercellular adhesion molecule 1 mediates P. falciparum cytoadherence. Science. 2012;338(6112):1230-3.
32. Rowe JA, Claessens A, Corrigan RA, Arman M. Adhesion of Plasmodium falciparum-infected red blood cells to human cells: molecular mechanisms and therapeutic implications. Expert Rev Mol Med. 2009;11:e16.
33. Guizot-Noël A, et al. The var genes of Plasmodium falciparum: a central role in virulence and immune evasion. Trends Parasitol. 2021;37(12):1043-52.
34. Moody A. Rapid diagnostic tests for malaria. Clin Microbiol Rev. 2002;15(1):66-78.
35. Okell LC, et al. Factors determining the occurrence of submicroscopic malaria infections and their relevance for control. Nature Communications. 2012;3(1):1237.
36. Dondorp AM, et al. Artesunate versus quinine for treatment of severe falciparum malaria: a randomised trial. The Lancet. 2005;366(9490):717-25.
37. Cheng Q, et al. Plasmodium falciparum parasites lacking histidine-rich protein 2 and 3: a review and recommendations for surveillance. BMJ Global Health. 2020;5(11):e003357.
38. Uwimana A, et al. Emergence and clonal expansion of in vitro artemisinin-resistant Plasmodium falciparum in Rwanda. Nature Medicine. 2020;26(10):1602-1608.
39. Hancock PA, et al. The evolution of insecticide resistance in Anopheles mosquitoes. Science. 2020;368(6492):748-751.
40. Ryan SJ, et al. Global expansion of human malaria transmission risk under climate change. Nature Communications. 2023;14(1):1-12.
41. Sinka ME, et al. Anopheles stephensi in Africa: a silent threat to its urban populations. BMJ Global Health. 2020;5(10):e003279.
42. Kyrou K, et al. A site-specific gene drive system across the entire population of Anopheles gambiae. Nature Biotechnology. 2018;36(11):1062-1066.
43. Saleh AH, Abbood HAR. The role of silver (Ag) nanoparticles synthesis by Penicillium spp against the toxicity of Echinococcus granulosus in adult albino male rats. Medico Legal Update. 2020;20(1):532–537.
44. Dalmat R, et al. Artificial intelligence for malaria elimination: a review. Malaria Journal. 2019;18(1):165.
45. Jacobson JO, et al. Genomic surveillance for malaria elimination. Trends in Parasitology. 2021;37(10):855-866.
