Molecular Machinery of Malaria Infection: Insights into Host-parasite Interactions and Therapeutic Targets

PDF Review History

Published: 2024-04-04

Page: 79-95

Temesgen Mitiku *

Department of Medical Biotechnology, Dambi Dollo University, Dambi Dollo, Ethiopia.

Betelhem Abebe

Department of Biotechnology, University of Gondar, Gondar, Ethiopia.

*Author to whom correspondence should be addressed.


Malaria continues to be a main global health issues, with millions of people affected each year. Understanding the molecular machinery behind malaria infection is crucial for the development of effective therapeutic interventions. This review aims to discuss the lifecycle of the malaria parasite, highlighting the molecular mechanisms of invasion, immune evasion, and sequestration. Furthermore, we delve into the intricate signaling pathways and molecular factors that contribute to malaria-induced immune dysregulation and disease progression. Finally, we explore potential therapeutic targets, including drug resistance mechanisms and novel strategies for intervention. By unraveling the molecular machinery of malaria infection, we hope to provide valuable insights for the development of targeted therapies and the eventual eradication of this devastating disease.

Keywords: Malaria, molecular mechanisms, host-parasite interactions, pathogenesis

How to Cite

Mitiku , T., & Abebe , B. (2024). Molecular Machinery of Malaria Infection: Insights into Host-parasite Interactions and Therapeutic Targets. Asian Journal of Research in Biosciences, 6(1), 79–95. Retrieved from


Download data is not yet available.


Zareen S, et al. Malaria is still a life threatening disease review. J. Entomol. Zool. Stud. 2016;105:105-112.

Lee WC, et al. Plasmodium knowlesi: The game changer for malaria eradication. Malaria Journal. 2022;21(1):1-24.

Joste V, et al. Plasmodium ovale wallikeri and p. ovale curtisi infections and diagnostic approaches to imported Malaria, France, 2013–2018. Emerging Infectious Diseases. 2021;27(2):372.

Kinoshita T, et al. first malaria in pregnancy followed in philippine real-world setting: Proof-of-concept of probabilistic record linkage between disease surveillance and hospital administrative data. Tropical Medicine and Health. 2024; 52(1):17.

Organization WH. World malaria report 2022: World Health Organization; 2022.

Venkatesan P. The 2023 who world Malaria report. The Lancet Microbe; 2024.

Mwakalinga SB, et al. Expression of a type B RIFIN in plasmodium falciparum merozoites and gametes. Malaria Journal. 2012;11:1-12.

Organization WH. Global technical strategy for malaria 2016-2030. world health organization; 2015.

Qiu D, et al. A G358S mutation in the Plasmodium falciparum Na+ pump PfATP4 confers clinically-relevant resistance to cipargamin. Nature Communications. 2022;13(1):5746.

Achan J, et al. Quinine, an old anti-malarial drug in a modern world: Role in the treatment of Malaria. Malaria Journal. 2011;10(1):1-12.

Nosten F, White NJ. Artemisinin-based combination treatment of falciparum malaria. Defining and Defeating the Intolerable Burden of Malaria III: Progress and Perspectives: Supplement to Volume 77 (6) of American Journal of Tropical Medicine and Hygiene; 2007.

Balikagala B, et al. Evidence of artemisinin-resistant malaria in Africa. New England Journal of Medicine. 2021; 385(13):1163-1171.

Hamilton WL, et al. Evolution and expansion of multidrug-resistant malaria in southeast Asia: A genomic epidemiology study. The Lancet Infectious Diseases. 2019;19(9):943-951.

Stokes BH, Ward KE, Fidock DA. Evidence of artemisinin-resistant malaria in Africa. The New England Journal of Medicine. 2022;386(14):1385.

Ariey F, et al. A molecular marker of artemisinin-resistant Plasmodium falciparum malaria. Nature. 2014; 505(7481):50-55.

Kavishe RA, et al. Surveillance of artemether-lumefantrine associated Plasmodium falciparum multidrug resistance protein-1 gene polymorphisms in Tanzania. Malaria Journal. 2014;13(1): 1-6.

Zaw MT, Lin Z, Emran NA. Importance of kelch 13 C580Y mutation in the studies of artemisinin resistance in Plasmodium falciparum in Greater Mekong Subregion. Journal of Microbiology, Immunology and Infection. 2020;53(5):676-681.

Duraisingh MT, Cowman AF. Contribution of the pfmdr1 gene to antimalarial drug-resistance. Acta Tropica. 2005;94(3): 181-190.

Sanchez CP, et al. Polymorphisms within PfMDR1 alter the substrate specificity for anti‐malarial drugs in Plasmodium falciparum. Molecular Microbiology. 2008; 70(4):786-798.

Bray PG, et al. Defining the role of PfCRT in Plasmodium falciparum chloroquine resistance. Molecular Microbiology. 2005; 56(2):323-333.

Ecker A, et al. PfCRT and its role in antimalarial drug resistance. Trends in Parasitology. 2012.28(11):504-514.

Bhattacharjee S, et al. Mechanism of immune evasion in mosquito-borne diseases. Pathogens. 2023;12(5):635.

Bennink S, Kiesow MJ, Pradel G. The development of malaria parasites in the mosquito midgut. Cellular Microbiology. 2016;18(7):905-918.

Smith RC, Barillas-Mury C. Plasmodium oocysts: Overlooked targets of mosquito immunity. Trends in Parasitology. 2016; 32(12):979-990.

Balaji S, Deshmukh R, Trivedi V. Severe malaria: Biology, clinical manifestation, pathogenesis and consequences. Journal of Vector Borne Diseases. 2020;57(1):1-1.

White NJ. Determinants of relapse periodicity in Plasmodium vivax malaria. Malaria Journal. 2011;10(1):1-36.

Zuccala ES, Baum J. Cytoskeletal and membrane remodelling during malaria parasite invasion of the human erythrocyte. British Journal of Haematology. 2011; 154(6):680-689.

Zhong D, et al. Molecular approaches to determine the multiplicity of Plasmodium infections. Malaria Journal. 2018;17: 1-9.

Abukari Z, et al. The diversity, multiplicity of infection and population structure of P. falciparum parasites circulating in asymptomatic carriers living in high and low malaria transmission settings of Ghana. Genes. 2019;10(6):434.

Sondo P, et al. Genetically diverse Plasmodium falciparum infections, within-host competition and symptomatic malaria in humans. Scientific Reports. 2019; 9(1):127.

Srimath-Tirumula-Peddinti RCPK, Neelapu NRR, Sidagam N. Association of climatic variability, vector population and malarial disease in district of Visakhapatnam, India: A modeling and prediction analysis. Plos One. 2015;10(6):e0128377.

Mayengue PI, et al. Genetic polymorphism of merozoite surface protein-1 and merozoite surface protein-2 in Plasmodium falciparum isolates from Brazzaville, Republic of Congo. Malaria Journal. 2011; 10:1-7.

Mwingira F, et al. Plasmodium falciparum msp1, msp2 and glurp allele frequency and diversity in sub-Saharan Africa. Malaria Journal. 2011;10:1-10.

Karl S, et al. Spatial effects on the multiplicity of Plasmodium falciparum infections. Plos One. 2016;11(10): e0164054.

Organization WH. Methods and techniques for clinical trials on antimalarial drug efficacy: Genotyping to identify parasite populations: Informal consultation organized by the Medicines for Malaria Venture and cosponsored by the World Health Organization, 29-31 May 2007, Amsterdam, The Netherlands. World Health Organization; 2008.

Botwe AK, et al. Dynamics in multiplicity of Plasmodium falciparum infection among children with asymptomatic malaria in central Ghana. BMC Genetics. 2017;18: 1-9.

Saha P, Ganguly S, Maji AK. Genetic diversity and multiplicity of infection of Plasmodium falciparum isolates from Kolkata, West Bengal, India. Infection, Genetics and Evolution. 2016;43: 239-244.

Healer J, et al. Independent translocation of two micronemal proteins in developing Plasmodium falciparum merozoites. Infection and Immunity. 2002;70(10): 5751-5758.

Kremer K, et al. An overexpression screen of Toxoplasma gondii Rab-GTPases reveals distinct transport routes to the micronemes. Plos Pathogens. 2013;9(3): e1003213.

Yeoh S, et al. Subcellular discharge of a serine protease mediates release of invasive malaria parasites from host erythrocytes. Cell. 2007;131(6):1072-1083.

Paul AS, Egan ES, Duraisingh MT. Host–parasite interactions that guide red blood cell invasion by malaria parasites. Current Opinion in Hematology. 2015;22(3):220-226.

Das S et al. Processing of Plasmodium falciparum merozoite surface protein MSP1 activates a spectrin-binding function enabling parasite egress from RBCs. Cell Host and Microbe. 2015;18(4):433-444.

Baumgartner M. Enforcing host cell polarity: An apicomplexan parasite strategy towards dissemination. Current Opinion in Microbiology. 2011;14(4):436-444.

Kobayashi K, et al. Plasmodium falciparum BAEBL binds to heparan sulfate proteoglycans on the human erythrocyte surface. Journal of Biological Chemistry. 2010;285(3):1716-1725.

Nguyen TV, et al. Characterization of immunoglobulin G antibodies to Plasmodium falciparum sporozoite surface antigen MB 2 in malaria exposed individuals. Malaria Journal. 2009;8:1-12.

Puentes A, et al. Identifying Plasmodium falciparum merozoite surface protein-10 human erythrocyte specific binding regions. Biochimie. 2005;87(5):461-472.

Singh SK, et al. Structural basis for Duffy recognition by the Malaria parasite Duffy-binding-like domain. Nature. 2006; 439(7077):741-744.

Awah NW, et al. Mechanisms of malarial anaemia: Potential involvement of the Plasmodium falciparum low molecular weight rhoptry-associated proteins. Acta Tropica. 2009;112(3):295-302.

Arévalo-Pinzón G, et al. Synthetic peptides from two Pf sporozoite invasion-associated proteins specifically interact with HeLa and HepG2 cells. Peptides. 2011;32(9): 1902-1908.

Risco-Castillo V, et al. Malaria sporozoites traverse host cells within transient vacuoles. Cell Host and Microbe. 2015; 18(5):593-603.

Cirimotich CM, et al. Mosquito immune defenses against Plasmodium infection. Developmental and Comparative Immunology. 2010;34(4):387-395.

Patarroyo ME, Alba MP, Curtidor H. Biological and structural characteristics of the binding peptides from the sporozoite proteins essential for cell traversal (SPECT)-1 and-2. Peptides. 2011;32(1): 154-160.

Sinnis P, Zavala F. The skin: Where Malaria infection and the host immune response begin. In Seminars in Immunopathology. Springer; 2012.

Müller H, et al. Thrombospondin related anonymous protein (TRAP) of Plasmodium falciparum binds specifically to sulfated glycoconjugates and to HepG2 hepatoma cells suggesting a role for this molecule in sporozoite invasion of hepatocytes. The EMBO Journal. 1993;12(7): 2881-2889.

Wilson KL, Xiang SD, Plebanski M. A model to study the impact of polymorphism driven liver-stage immune evasion by malaria parasites, to help design effective cross-reactive vaccines. Frontiers in Microbiology. 2016;7:180272.

Liehl P, et al. Innate immunity induced by Plasmodium liver infection inhibits malaria reinfections. Infection and Immunity. 2015; 83(3):1172-1180.

Liehl P, et al. Host-cell sensors for Plasmodium activate innate immunity against liver-stage infection. Nature Medicine. 2014;20(1):47-53.

Hisaeda H, Yasutomo K, Himeno K. Malaria: Immune evasion by parasites. The International Journal of Biochemistry and Cell Biology. 2005;37(4):700-706.

Spottiswoode N, Duffy PE, Drakesmith H. Iron, anemia and hepcidin in malaria. Frontiers in Pharmacology. 2014;5:89777.

Tavares J, et al. Role of host cell traversal by the malaria sporozoite during liver infection. Journal of Experimental Medicine. 2013;210(5):905-915.

Meslin B, et al. Features of apoptosis in Plasmodium falciparum erythrocytic stage through a putative role of PfMCA1 metacaspase-like protein. The Journal of Infectious Diseases. 2007;195(12): 1852-1859.

Cha SJ, et al. CD68 acts as a major gateway for malaria sporozoite liver infection. Journal of Experimental Medicine. 2015;212(9):1391-1403.

Klotz C, Frevert U. Plasmodium yoelii sporozoites modulate cytokine profile and induce apoptosis in murine kupffer cells. International Journal for Parasitology. 2008;38(14):1639-1650.

Ikarashi M, et al. Distinct development and functions of resident and recruited liver Kupffer cells/macrophages. Journal of Leukocyte Biology. 2013;94(6):1325-1336.

Steers N, et al. The immune status of Kupffer cells profoundly influences their responses to infectious Plasmodium berghei sporozoites. European Journal of Immunology. 2005;35(8):2335-2346.

Itoe MA, et al. Host cell phosphatidylcholine is a key mediator of malaria parasite survival during liver stage infection. Cell Host and Microbe. 2014; 16(6):778-786.

Ding Y, et al. The Plasmodium circumsporozoite protein, a novel NF-κB inhibitor, suppresses the growth of SW480. Pathology and Oncology Research. 2012; 18:895-902.

Pamplona A, et al. Heme oxygenase-1 and carbon monoxide suppress the pathogenesis of experimental cerebral malaria. Nature Medicine. 2007;13(6): 703-710.

Hanson KK, et al. Torins are potent antimalarials that block replenishment of Plasmodium liver stage parasitophorous vacuole membrane proteins. Proceedings of the National Academy of Sciences. 2013;110(30):E2838-E2847.

Thieleke‐Matos C, et al. Host cell autophagy contributes to Plasmodium liver development. Cellular Microbiology. 2016; 18(3):437-450.

Sturm A, et al. Manipulation of host hepatocytes by the Malaria parasite for delivery into liver sinusoids. Science. 2006; 313(5791):1287-1290.

Garg S, et al. Calcium-dependent permeabilization of erythrocytes by a perforin-like protein during egress of malaria parasites. Nature Communications. 2013;4(1):1736.

Bowen DG, Walker CM. Mutational escape from CD8+ T cell immunity: HCV evolution, from chimpanzees to man. The Journal of Experimental Medicine. 2005;201(11): 1709.

Moll K, et al. Evasion of immunity to Plasmodium falciparum: Rosettes of blood group A impair recognition of PfEMP1. Plos One. 2015;10(12):e0145120.

Escalante AA, Lal AA, Ayala FJ. Genetic polymorphism and natural selection in the malaria parasite Plasmodium falciparum. Genetics. 1998;149(1):189-202.

Kraemer SM, Smith JD. A family affair: Var genes, PfEMP1 binding, and malaria disease. Current Opinion in Microbiology. 2006;9(4):374-380.

Helmby H, et al. Rosetting Plasmodium falciparum-infected erythrocytes express unique strain-specific antigens on their surface. Infection and Immunity. 1993; 61(1):284-288.

Patel A, et al. Cyclic AMP signalling controls key components of malaria parasite host cell invasion machinery. Plos Biology. 2019;17(5):e3000264.

Flueck C, et al. Phosphodiesterase beta is the master regulator of cAMP signalling during malaria parasite invasion. Plos Biology. 2019;17(2):e3000154.

Ravnskjaer K, Madiraju A, Montminy M. Role of the cAMP pathway in glucose and lipid metabolism. Metabolic Control. 2016; 29-49.

Saran S, et al. cAMP signaling in dictyostelium. Journal of Muscle Research and Cell Motility. 2002;23: 793-802.

Ono T, et al. Adenylyl cyclase α and cAMP signaling mediate Plasmodium sporozoite apical regulated exocytosis and hepatocyte infection. Plos Pathogens. 2008;4(2): e1000008.

Zhang M, et al. Uncovering the essential genes of the human malaria parasite Plasmodium falciparum by saturation mutagenesis. Science. 2018;360(6388): eaap7847.

Bushell E, et al. Functional profiling of a Plasmodium genome reveals an abundance of essential genes. Cell. 2017; 170(2):260-272. e8.

Lakshmanan V, et al. Cyclic GMP balance is critical for malaria parasite transmission from the mosquito to the mammalian host. MBio. 2015;6(2):10.1128/mbio. 02330-14.

Howard BL, et al. Identification of potent phosphodiesterase inhibitors that demonstrate cyclic nucleotide-dependent functions in apicomplexan parasites. ACS Chemical Biology. 2015;10(4):1145-1154.

Wentzinger L, et al. Cyclic nucleotide-specific phosphodiesterases of Plasmodium falciparum: PfPDEα, a non-essential cGMP-specific PDE that is an integral membrane protein. International Journal for Parasitology. 2008;38(14): 1625-1637.

Taylor SS, et al. Assembly of allosteric macromolecular switches: Lessons from PKA. Nature reviews Molecular Cell Biology. 2012;13(10):646-658.

Dawn A, et al. The central role of cAMP in regulating Plasmodium falciparum merozoite invasion of human erythrocytes. Plos Pathogens. 2014;10(12): e1004520.

Koussis K, et al. Simultaneous multiple allelic replacement in the malaria parasite enables dissection of PKG function. Life Science Alliance. 2020;3(4).

Perrin AJ, et al. The actinomyosin motor drives malaria parasite red blood cell invasion but not egress. MBio. 2018;9(4):e00905-18.

Lasonder E, et al. Extensive differential protein phosphorylation as intraerythrocytic Plasmodium falciparum schizonts develop into extracellular invasive merozoites. Proteomics. 2015;15(15):2716-2729.

Knuepfer E, et al. Generating conditional gene knockouts in Plasmodium–a toolkit to produce stable DiCre recombinase-expressing parasite lines using CRISPR/Cas9. Scientific Reports. 2017; 7(1):3881.

Burrows JN, et al. Antimalarial drug discovery–the path towards eradication. Parasitology. 2014;141(1):128-139.

Gachelin G, et al. Evaluating Cinchona bark and quinine for treating and preventing malaria. Journal of the Royal Society of Medicine. 2017;110(1): 31-40.

Hokkanen M. Quinine, malarial fevers and mobility: A biography of a ‘European fetish’, c. 1859–c. 1940, in Medicine, mobility and the empire. Manchester University Press. 2017;186-217.

Siddiqui FA, Liang X, Cui L. Plasmodium falciparum resistance to ACTs: Emergence, mechanisms, and outlook. International Journal for Parasitology: Drugs and Drug Resistance. 2021;16: 102-118.

Straimer J, et al. K13-propeller mutations confer artemisinin resistance in Plasmodium falciparum clinical isolates. Science. 2015;347(6220):428-431.

Solomon VR, Lee H. Chloroquine and its analogs: A new promise of an old drug for effective and safe cancer therapies. European Journal of Pharmacology. 2009;625(1-3):220-233.

Yang T, et al. Decreased K13 abundance reduces hemoglobin catabolism and proteotoxic stress, underpinning artemisinin resistance. Cell Reports. 2019; 29(9):2917-2928. e5.

Birnbaum J, et al. A Kelch13-defined endocytosis pathway mediates artemisinin resistance in malaria parasites. Science. 2020;367(6473):51-59.

Reyser T, et al. Identification of compounds active against quiescent artemisinin- resistant Plasmodium falciparum parasites via the quiescent-stage survival assay (QSA). Journal of Antimicrobial Chemotherapy. 2020;75(10): 2826-2834.

Rts S. Clinical Trials Partnership. Efficacy and safety of the RTS, S/AS01 malaria vaccine during 18 months after vaccination: A phase 3 randomized, controlled trial in children and young infants at 11 African sites. Plos Med. 2014;11(7):e1001685.

Rts S. Efficacy and safety of RTS, S/AS01 malaria vaccine with or without a booster dose in infants and children in Africa: Final results of a phase 3, individually randomised, controlled trial. Lancet. 2015; 386(9988):31-45.

White MT, et al. Immunogenicity of the RTS, S/AS01 malaria vaccine and implications for duration of vaccine efficacy: Secondary analysis of data from a phase 3 randomised controlled trial. The Lancet Infectious Diseases. 2015;15(12): 1450-1458.

Seder RA, et al. Protection against Malaria by intravenous immunization with a nonreplicating sporozoite vaccine. Science. 2013;341(6152):1359-1365.

Ishizuka AS, et al. Protection against malaria at 1 year and immune correlates following PfSPZ vaccination. Nature Medicine. 2016;22(6):614-623.

Epstein J, et al. Live attenuated malaria vaccine designed to protect through hepatic CD8+ T cell immunity. Science. 2011;334(6055):475-480.

Lyke KE, et al. Attenuated PfSPZ Vaccine induces strain-transcending T cells and durable protection against heterologous controlled human malaria infection. Proceedings of the National Academy of Sciences. 2017;114(10):2711-2716.

Charoenvit Y, et al. Inability of malaria vaccine to induce antibodies to a protective epitope within its sequence. Science. 1991;251(4994):668-671.

Mordmüller B, et al. Sterile protection against human malaria by chemoattenuated PfSPZ vaccine. Nature. 2017;542(7642):445-449.

Zaidi I, et al. γδ T cells are required for the induction of sterile immunity during irradiated sporozoite vaccinations. The Journal of Immunology. 2017;199(11): 3781-3788.

Paget-McNicol S, Saul A. Mutation rates in the dihydrofolate reductase gene of Plasmodium falciparum. Parasitology. 2001;122(5):497-505.

Müller O. Malaria in Africa: Challenges for control and elimination in the 21st century. (No Title); 2011.

Newton PN, et al. Poor quality vital anti-malarials in Africa-an urgent neglected public health priority. Malaria Journal. 2011;10(1):1-22.

Hall KA, et al. Characterization of counterfeit artesunate antimalarial tablets from southeast Asia. American Journal of Tropical Medicine and Hygiene. 2006; 75(5):804-811.

Bloland PB, WH. Organization, drug resistance in malaria. World Health Organization; 2001.

Barnes KI, et al. World antimalarial resistance network (WARN) IV: Clinical pharmacology. Malaria Journal. 2007;6: 1-8.

Barnes KI, Watkins WM, White NJ. Antimalarial dosing regimens and drug resistance. Trends in Parasitology. 2008;24(3):127-134.

Yeung S, et al. Antimalarial drug resistance, artemisinin-based combination therapy, and the contribution of modeling to elucidating policy choices. The American Journal of Tropical Medicine and Hygiene. 2004;71(2 Supp):179-186.

White N. Antimalarial drug resistance and combination chemotherapy. Philosophical Transactions of the Royal Society of London. Series B: Biological Sciences. 1999;354(1384):739-749.

Uwimana A, et al. Association of Plasmodium falciparum kelch13 R561H genotypes with delayed parasite clearance in Rwanda: An open-label, single-arm, multicentre, therapeutic efficacy study. The Lancet Infectious Diseases. 2021;21(8): 1120-1128.

Conrad MD, Rosenthal PJ. Antimalarial drug resistance in Africa: The calm before the storm? The Lancet Infectious Diseases. 2019;19(10):e338-e351.

Sigala PA, Goldberg DE. The peculiarities and paradoxes of Plasmodium heme metabolism. Annual Review of Microbiology. 2014;68:259-278.

Djimdé A, et al. A molecular marker for chloroquine-resistant falciparum Malaria. New England Journal of Medicine. 2001; 344(4):257-263.

Nkrumah LJ, et al. Probing the multifactorial basis of Plasmodium falciparum quinine resistance: evidence for a strain-specific contribution of the sodium-proton exchanger PfNHE. Molecular and Biochemical Parasitology. 2009;165(2): 122- 131.

Petersen I, et al. Balancing drug resistance and growth rates via compensatory mutations in the P lasmodium falciparum chloroquine resistance transporter. Molecular Microbiology. 2015;97(2): 381-395.