Adapt or Die: Targeting Unique Transmission-Stage Biology for Malaria Elimination

Overview

Journal Front Cell Infect Microbiol

Specialties Cell Biology
Infectious Diseases
Microbiology

Date 2022 Jun 27

PMID 35755845

Authors

Mariette E van der Watt

Janette Reader

Lyn-Marie Birkholtz

Affiliations

Soon will be listed here.

Abstract

parasites have a complex life cycle that includes development in the human host as well as the vector. Successful transmission of the parasite between its host and vector therefore requires the parasite to balance its investments in asexual replication and sexual reproduction, varying the frequency of sexual commitment to persist within the human host and generate future opportunities for transmission. The transmission window is extended further by the ability of stage V gametocytes to circulate in peripheral blood for weeks, whereas immature stage I to IV gametocytes sequester in the bone marrow and spleen until final maturation. Due to the low gametocyte numbers in blood circulation and with the ease of targeting such life cycle bottlenecks, transmission represents an efficient target for therapeutic intervention. The biological process of transmission is a multistage, multifaceted process and the past decade has seen a much deeper understanding of the molecular mechanisms and regulators involved. Clearly, specific and divergent processes are used during transmission compared to asexual proliferation, which both poses challenges but also opportunities for discovery of transmission-blocking antimalarials. This review therefore presents an update of our molecular understanding of gametocyte and gamete biology as well as the status of transmission-blocking activities of current antimalarials and lead development compounds. By defining the biological components associated with transmission, considerations for the development of new transmission-blocking drugs to target such untapped but unique biology is suggested as an important, main driver for transmission-blocking drug discovery.

Citing Articles

Eliminating malaria transmission requires targeting immature and mature gametocytes through lipoidal uptake of antimalarials.

Naude M, van Heerden A, Reader J, van der Watt M, Niemand J, Joubert D Nat Commun. 2024; 15(1):9896.

PMID: 39548094 PMC: 11568134. DOI: 10.1038/s41467-024-54144-x.

Plant-based nanoparticles targeting malaria management.

Lokole P, Byamungu G, Mutwale P, Ngombe N, Mudogo C, Krause R Front Pharmacol. 2024; 15:1440116.

PMID: 39185312 PMC: 11341498. DOI: 10.3389/fphar.2024.1440116.

The Tuberculosis Drug Candidate SQ109 and Its Analogs Have Multistage Activity against .

Watson S, van der Watt M, Theron A, Reader J, Tshabalala S, Erlank E ACS Infect Dis. 2024; 10(9):3358-3367.

PMID: 39143042 PMC: 11406516. DOI: 10.1021/acsinfecdis.4c00461.

Transmission-Blocking Strategies for Malaria Eradication: Recent Advances in Small-Molecule Drug Development.

Appetecchia F, Fabbrizi E, Fiorentino F, Consalvi S, Biava M, Poce G Pharmaceuticals (Basel). 2024; 17(7).

PMID: 39065810 PMC: 11279868. DOI: 10.3390/ph17070962.

2,8-Disubstituted-1,5-naphthyridines as Dual Inhibitors of Phosphatidylinositol-4-kinase and Hemozoin Formation with Efficacy.

Dziwornu G, Seanego D, Fienberg S, Clements M, Ferreira J, Sypu V J Med Chem. 2024; 67(13):11401-11420.

PMID: 38918002 PMC: 11247499. DOI: 10.1021/acs.jmedchem.4c01154.

References

Garg A, Lukk T, Kumar V, Choi J, Augagneur Y, Voelker D . Structure, function and inhibition of the phosphoethanolamine methyltransferases of the human malaria parasites Plasmodium vivax and Plasmodium knowlesi. Sci Rep. 2015; 5:9064. PMC: 4357015. DOI: 10.1038/srep09064. View

Hart K, Oberstaller J, Walker M, Minns A, Kennedy M, Padykula I . Plasmodium male gametocyte development and transmission are critically regulated by the two putative deadenylases of the CAF1/CCR4/NOT complex. PLoS Pathog. 2019; 15(1):e1007164. PMC: 6355032. DOI: 10.1371/journal.ppat.1007164. View

Eksi S, Morahan B, Haile Y, Furuya T, Jiang H, Ali O . Plasmodium falciparum gametocyte development 1 (Pfgdv1) and gametocytogenesis early gene identification and commitment to sexual development. PLoS Pathog. 2012; 8(10):e1002964. PMC: 3475683. DOI: 10.1371/journal.ppat.1002964. View

Alano P, Read D, Bruce M, Aikawa M, Kaido T, Tegoshi T . COS cell expression cloning of Pfg377, a Plasmodium falciparum gametocyte antigen associated with osmiophilic bodies. Mol Biochem Parasitol. 1995; 74(2):143-56. DOI: 10.1016/0166-6851(95)02491-3. View

Dearnley M, Yeoman J, Hanssen E, Kenny S, Turnbull L, Whitchurch C . Origin, composition, organization and function of the inner membrane complex of Plasmodium falciparum gametocytes. J Cell Sci. 2012; 125(Pt 8):2053-63. DOI: 10.1242/jcs.099002. View

Giannangelo C, Siddiqui G, De Paoli A, Anderson B, Edgington-Mitchell L, Charman S . System-wide biochemical analysis reveals ozonide antimalarials initially act by disrupting Plasmodium falciparum haemoglobin digestion. PLoS Pathog. 2020; 16(6):e1008485. PMC: 7347234. DOI: 10.1371/journal.ppat.1008485. View

Baker D, Matralis A, Osborne S, Large J, Penzo M . Targeting the Malaria Parasite cGMP-Dependent Protein Kinase to Develop New Drugs. Front Microbiol. 2021; 11:602803. PMC: 7773720. DOI: 10.3389/fmicb.2020.602803. View

Sinha A, Hughes K, Modrzynska K, Otto T, Pfander C, Dickens N . A cascade of DNA-binding proteins for sexual commitment and development in Plasmodium. Nature. 2014; 507(7491):253-257. PMC: 4105895. DOI: 10.1038/nature12970. View

Delves M . Plasmodium cell biology should inform strategies used in the development of antimalarial transmission-blocking drugs. Future Med Chem. 2012; 4(18):2251-63. DOI: 10.4155/fmc.12.182. View

10.

Witola W, El Bissati K, Pessi G, Xie C, Roepe P, Ben Mamoun C . Disruption of the Plasmodium falciparum PfPMT gene results in a complete loss of phosphatidylcholine biosynthesis via the serine-decarboxylase-phosphoethanolamine-methyltransferase pathway and severe growth and survival defects. J Biol Chem. 2008; 283(41):27636-27643. PMC: 2562060. DOI: 10.1074/jbc.M804360200. View

11.

Furuya T, Mu J, Hayton K, Liu A, Duan J, Nkrumah L . Disruption of a Plasmodium falciparum gene linked to male sexual development causes early arrest in gametocytogenesis. Proc Natl Acad Sci U S A. 2005; 102(46):16813-8. PMC: 1277966. DOI: 10.1073/pnas.0501858102. View

12.

Vallone A, DAlessandro S, Brogi S, Brindisi M, Chemi G, Alfano G . Antimalarial agents against both sexual and asexual parasites stages: structure-activity relationships and biological studies of the Malaria Box compound 1-[5-(4-bromo-2-chlorophenyl)furan-2-yl]-N-[(piperidin-4-yl)methyl]methanamine (MMV019918) and.... Eur J Med Chem. 2018; 150:698-718. PMC: 5902032. DOI: 10.1016/j.ejmech.2018.03.024. View

13.

Talman A, Paul R, Sokhna C, Domarle O, Ariey F, Trape J . Influence of chemotherapy on the Plasmodium gametocyte sex ratio of mice and humans. Am J Trop Med Hyg. 2005; 71(6):739-44. View

14.

Bobenchik A, Witola W, Augagneur Y, Nic Lochlainn L, Garg A, Pachikara N . Plasmodium falciparum phosphoethanolamine methyltransferase is essential for malaria transmission. Proc Natl Acad Sci U S A. 2013; 110(45):18262-7. PMC: 3831454. DOI: 10.1073/pnas.1313965110. View

15.

TRAGER W, Gill G, Lawrence C, Nagel R . Plasmodium falciparum: enhanced gametocyte formation in vitro in reticulocyte-rich blood. Exp Parasitol. 1999; 91(2):115-8. DOI: 10.1006/expr.1998.4347. View

16.

Poran A, Notzel C, Aly O, Mencia-Trinchant N, Harris C, Guzman M . Single-cell RNA sequencing reveals a signature of sexual commitment in malaria parasites. Nature. 2017; 551(7678):95-99. PMC: 6055935. DOI: 10.1038/nature24280. View

17.

Paquet T, Le Manach C, Gonzalez Cabrera D, Younis Y, Henrich P, Abraham T . Antimalarial efficacy of MMV390048, an inhibitor of phosphatidylinositol 4-kinase. Sci Transl Med. 2017; 9(387). PMC: 5731459. DOI: 10.1126/scitranslmed.aad9735. View

18.

Bouyer G, Barbieri D, Dupuy F, Marteau A, Sissoko A, NDri M . Plasmodium falciparum sexual parasites regulate infected erythrocyte permeability. Commun Biol. 2020; 3(1):726. PMC: 7708629. DOI: 10.1038/s42003-020-01454-7. View

19.

Tiburcio M, Dixon M, Looker O, Younis S, Tilley L, Alano P . Specific expression and export of the Plasmodium falciparum Gametocyte EXported Protein-5 marks the gametocyte ring stage. Malar J. 2015; 14:334. PMC: 4552133. DOI: 10.1186/s12936-015-0853-6. View

20.

Ridgway M, Cihalova D, Brown S, Tran P, Mitchell T, Maier A . Analysis of sex-specific lipid metabolism of Plasmodium falciparum points to the importance of sphingomyelin for gametocytogenesis. J Cell Sci. 2021; 135(5). DOI: 10.1242/jcs.259592. View