VAR2CSA-Mediated Host Defense Evasion of Infected Erythrocytes in Placental Malaria

Overview

Journal Front Immunol

Specialty Allergy & Immunology

Date 2021 Feb 26

PMID 33633743

Citations 5

Authors

Alice Tomlinson

Jean-Philippe Semblat

Benoit Gamain

Arnaud Chene

Affiliations

Soon will be listed here.

Abstract

Over 30 million women living in endemic areas are at risk of developing malaria during pregnancy every year. Placental malaria is characterized by massive accumulation of infected erythrocytes in the intervillous space of the placenta, accompanied by infiltration of immune cells, particularly monocytes. The consequent local inflammation and the obstruction of the maternofetal exchanges can lead to severe clinical outcomes for both mother and child. Even if protection against the disease can gradually be acquired following successive pregnancies, the malaria parasite has developed a large panel of evasion mechanisms to escape from host defense mechanisms and manipulate the immune system to its advantage. Infected erythrocytes isolated from placentas of women suffering from placental malaria present a unique phenotype and express the pregnancy-specific variant VAR2CSA of the Erythrocyte Membrane Protein (PfEMP1) family at their surface. The polymorphic VAR2CSA protein is able to mediate the interaction of infected erythrocytes with a variety of host cells including placental syncytiotrophoblasts and leukocytes but also with components of the immune system such as non-specific IgM. This review summarizes the described VAR2CSA-mediated host defense evasion mechanisms employed by the parasite during placental malaria to ensure its survival and persistence.

Citing Articles

Evasive mechanisms of human VSG and PfEMP1 antigens with link to Vaccine scenario: a review.

Obi O, Obiezue R, Eze D, Adebote D J Parasit Dis. 2025; 49(1):13-28.

PMID: 39975623 PMC: 11833005. DOI: 10.1007/s12639-024-01740-9.

Multi-System Dysregulation in Placental Malaria Contributes to Adverse Perinatal Outcomes in Mice.

Ekregbesi P, Seibert B, Parish M, Flores-Garcia Y, Creisher P, Hoffmann J bioRxiv. 2025; .

PMID: 39868257 PMC: 11761038. DOI: 10.1101/2025.01.15.633265.

Casein Kinases 2-dependent phosphorylation of the placental ligand VAR2CSA regulates Plasmodium falciparum-infected erythrocytes cytoadhesion.

Dorin-Semblat D, Semblat J, Hamelin R, Srivastava A, Tetard M, Matesic G PLoS Pathog. 2025; 21(1):e1012861.

PMID: 39804934 PMC: 11761665. DOI: 10.1371/journal.ppat.1012861.

Structure-guided design of VAR2CSA-based immunogens and a cocktail strategy for a placental malaria vaccine.

Ma R, Salinas N, Orr-Gonzalez S, Richardson B, Ouahes T, Torano H PLoS Pathog. 2024; 20(3):e1011879.

PMID: 38437239 PMC: 10939253. DOI: 10.1371/journal.ppat.1011879.

The Need for Novel Asexual Blood-Stage Malaria Vaccine Candidates for .

Takashima E, Otsuki H, Morita M, Ito D, Nagaoka H, Yuguchi T Biomolecules. 2024; 14(1).

PMID: 38254700 PMC: 10813614. DOI: 10.3390/biom14010100.

References

Maubert B, Guilbert L, Deloron P . Cytoadherence of Plasmodium falciparum to intercellular adhesion molecule 1 and chondroitin-4-sulfate expressed by the syncytiotrophoblast in the human placenta. Infect Immun. 1997; 65(4):1251-7. PMC: 175125. DOI: 10.1128/iai.65.4.1251-1257.1997. View

Ndam N, Bischoff E, Proux C, Lavstsen T, Salanti A, Guitard J . Plasmodium falciparum transcriptome analysis reveals pregnancy malaria associated gene expression. PLoS One. 2008; 3(3):e1855. PMC: 2267001. DOI: 10.1371/journal.pone.0001855. View

Subramani R, Quadt K, Jeppesen A, Hempel C, Petersen J, Hassenkam T . Plasmodium falciparum-infected erythrocyte knob density is linked to the PfEMP1 variant expressed. mBio. 2015; 6(5):e01456-15. PMC: 4611047. DOI: 10.1128/mBio.01456-15. View

Bostrom S, Ibitokou S, Oesterholt M, Schmiegelow C, Persson J, Minja D . Biomarkers of Plasmodium falciparum infection during pregnancy in women living in northeastern Tanzania. PLoS One. 2012; 7(11):e48763. PMC: 3498253. DOI: 10.1371/journal.pone.0048763. View

Moormann A, Sullivan A, Rochford R, Chensue S, Bock P, Nyirenda T . Malaria and pregnancy: placental cytokine expression and its relationship to intrauterine growth retardation. J Infect Dis. 1999; 180(6):1987-93. DOI: 10.1086/315135. View

Patel J, Hathaway N, Parobek C, Thwai K, Madanitsa M, Khairallah C . Increased risk of low birth weight in women with placental malaria associated with P. falciparum VAR2CSA clade. Sci Rep. 2017; 7(1):7768. PMC: 5554196. DOI: 10.1038/s41598-017-04737-y. View

Ismail M, Ordi J, Menendez C, Ventura P, Aponte J, Kahigwa E . Placental pathology in malaria: a histological, immunohistochemical, and quantitative study. Hum Pathol. 2000; 31(1):85-93. DOI: 10.1016/s0046-8177(00)80203-8. View

Dorin-Semblat D, Tetard M, Claes A, Semblat J, Dechavanne S, Fourati Z . Phosphorylation of the VAR2CSA extracellular region is associated with enhanced adhesive properties to the placental receptor CSA. PLoS Biol. 2019; 17(6):e3000308. PMC: 6586358. DOI: 10.1371/journal.pbio.3000308. View

Nielsen M, Resende M, de Jongh W, Ditlev S, Mordmuller B, Houard S . The Influence of Sub-Unit Composition and Expression System on the Functional Antibody Response in the Development of a VAR2CSA Based Plasmodium falciparum Placental Malaria Vaccine. PLoS One. 2015; 10(9):e0135406. PMC: 4556615. DOI: 10.1371/journal.pone.0135406. View

10.

Yockey L, Iwasaki A . Interferons and Proinflammatory Cytokines in Pregnancy and Fetal Development. Immunity. 2018; 49(3):397-412. PMC: 6152841. DOI: 10.1016/j.immuni.2018.07.017. View

11.

Bertin G, Sabbagh A, Guillonneau F, Jafari-Guemouri S, Ezinmegnon S, Federici C . Differential protein expression profiles between Plasmodium falciparum parasites isolated from subjects presenting with pregnancy-associated malaria and uncomplicated malaria in Benin. J Infect Dis. 2013; 208(12):1987-97. DOI: 10.1093/infdis/jit377. View

12.

Walter P, Garin Y, Blot P . Placental pathologic changes in malaria. A histologic and ultrastructural study. Am J Pathol. 1982; 109(3):330-42. PMC: 1916118. View

13.

Gustafsson C, Mjosberg J, Matussek A, Geffers R, Matthiesen L, Berg G . Gene expression profiling of human decidual macrophages: evidence for immunosuppressive phenotype. PLoS One. 2008; 3(4):e2078. PMC: 2323105. DOI: 10.1371/journal.pone.0002078. View

14.

Doritchamou J, Sabbagh A, Jespersen J, Renard E, Salanti A, Nielsen M . Identification of a Major Dimorphic Region in the Functionally Critical N-Terminal ID1 Domain of VAR2CSA. PLoS One. 2015; 10(9):e0137695. PMC: 4579133. DOI: 10.1371/journal.pone.0137695. View

15.

Gysin J, Pouvelle B, Fievet N, Scherf A, Lepolard C . Ex vivo desequestration of Plasmodium falciparum-infected erythrocytes from human placenta by chondroitin sulfate A. Infect Immun. 1999; 67(12):6596-602. PMC: 97072. DOI: 10.1128/IAI.67.12.6596-6602.1999. View

16.

Silver K, Conroy A, Leke R, Leke R, Gwanmesia P, Molyneux M . Circulating soluble endoglin levels in pregnant women in Cameroon and Malawi--associations with placental malaria and fetal growth restriction. PLoS One. 2011; 6(9):e24985. PMC: 3178568. DOI: 10.1371/journal.pone.0024985. View

17.

Donati D, Mok B, Chene A, Xu H, Thangarajh M, Glas R . Increased B cell survival and preferential activation of the memory compartment by a malaria polyclonal B cell activator. J Immunol. 2006; 177(5):3035-44. DOI: 10.4049/jimmunol.177.5.3035. View

18.

Burton G, Fowden A . The placenta: a multifaceted, transient organ. Philos Trans R Soc Lond B Biol Sci. 2015; 370(1663):20140066. PMC: 4305167. DOI: 10.1098/rstb.2014.0066. View

19.

Barfod L, Dalgaard M, Pleman S, Ofori M, Pleass R, Hviid L . Evasion of immunity to Plasmodium falciparum malaria by IgM masking of protective IgG epitopes in infected erythrocyte surface-exposed PfEMP1. Proc Natl Acad Sci U S A. 2011; 108(30):12485-90. PMC: 3145728. DOI: 10.1073/pnas.1103708108. View

20.

Fried M, Hixson K, Anderson L, Ogata Y, Mutabingwa T, Duffy P . The distinct proteome of placental malaria parasites. Mol Biochem Parasitol. 2007; 155(1):57-65. DOI: 10.1016/j.molbiopara.2007.05.010. View