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Structural insights into global mutations in the ligand-binding domain of VAR2CSA and its implications on placental malaria vaccine

September 1, 2021 - 15:45 -- Open Access
Gill J, Chakraborti S, Bharti P, Sharma A
Int J Infect Dis. 2021 Aug 24:S1201-9712(21)00687-1

Placental malaria is a public health burden particularly in Africa as it causes severe symptoms and results in stillbirths or maternal deaths. Plasmodium falciparum protein VAR2CSA drives placental malaria (PM) in pregnant women by adhering to chondroitin sulfate A (CSA) on the placenta. VAR2CSA is a primary vaccine candidate for PM with two vaccines based on it already under clinical trials.

Developing a multivariate prediction model of antibody features associated with protection of malaria-infected pregnant women from placental malaria

June 30, 2021 - 09:30 -- Open Access
Aitken EH, Damelang T, Rogerson SJ, et al.
Elife. 2021 Jun 29;10:e65776

Plasmodium falciparum causes placental malaria, which results in adverse outcomes for mother and child. P. falciparum-infected erythrocytes that express the parasite protein VAR2CSA on their surface can bind to placental chondroitin sulfate A. It has been hypothesized that naturally acquired antibodies towards VAR2CSA protect against placental infection, but it has proven difficult to identify robust antibody correlates of protection from disease. The objective of this study was to develop a prediction model using antibody features that could identify women protected from placental malaria.

NOT Open Access | Platelet Membrane-Coated and VAR2CSA Malaria Protein-Functionalized Nanoparticles for Targeted Treatment of Primary and Metastatic Cancer

June 1, 2021 - 12:21 -- NOT Open Access
Zhou M, Lai W, Li G, Wang F, Liu W, Liao J, Yang H, Liu Y, Zhang Q, Tang Q, Hu C, Huang J, Zhang R
ACS Appl Mater Interfaces. 2021 May 26

Metastasis is the main cause of death in cancer patients. The efficacy of pharmacological therapy for cancer is limited by the heterogeneous nature of cancer cells and the lack of knowledge of microenvironments in metastasis. Evidence has shown that activated platelets possess both tumor-homing and metastasis-targeting properties via intrinsic cell adhesion molecules on platelets, and malaria protein VAR2CSA is able to specifically bind to oncofetal chondroitin sulfate, which is overexpressed on cancer cells with both epithelial and mesenchymal phenotypes.

Cryo-EM reveals the architecture of placental malaria VAR2CSA and provides molecular insight into chondroitin sulfate binding

May 25, 2021 - 14:39 -- Open Access
Wang K, Dagil R, Salanti A, et al.
Nat Commun. 2021 May 19;12(1):2956

Placental malaria can have severe consequences for both mother and child and effective vaccines are lacking. Parasite-infected red blood cells sequester in the placenta through interaction between parasite-expressed protein VAR2CSA and the glycosaminoglycan chondroitin sulfate A (CS) abundantly present in the intervillous space. Here, we report cryo-EM structures of the VAR2CSA ectodomain at up to 3.1 Å resolution revealing an overall V-shaped architecture and a complex domain organization.

Development of a bispecific immune engager using a recombinant malaria protein

April 7, 2021 - 12:15 -- Open Access
Nordmaj MA, Roberts ME, Salanti A, et al.
Cell Death Dis. 2021 Apr 6;12(4):353

As an immune evasion and survival strategy, the Plasmodium falciparum malaria parasite has evolved a protein named VAR2CSA. This protein mediates sequestration of infected red blood cells in the placenta through the interaction with a unique carbohydrate abundantly and exclusively present in the placenta. Cancer cells were found to share the same expression of this distinct carbohydrate, termed oncofetal chondroitin sulfate on their surface.

NOT Open Access | Progress and new horizons toward a VAR2CSA-based placental malaria vaccine

February 8, 2021 - 10:47 -- NOT Open Access
Doritchamou JYA, Suurbaar J, Tuikue Ndam N
Expert Rev Vaccines. 2021 Feb 4:1-12

Several malaria vaccines are under various phases of development with some promising results. In placental malaria (PM) a deliberately anti-disease approach is considered as many studies have underlined the key role of VAR2CSA protein, which therefore represents the leading vaccine candidate. However, evidence indicates that VAR2CSA antigenic polymorphism remains an obstacle to overcome.

Structural basis for placental malaria mediated by Plasmodium falciparum VAR2CSA

January 20, 2021 - 07:28 -- Open Access
Ma R, Lian T, Huang R, Renn JP, Petersen JD, Zimmerberg J, Duffy PE, Tolia NH
Nat Microbiol. 2021 Jan 15

Plasmodium falciparum VAR2CSA binds to chondroitin sulfate A (CSA) on the surface of the syncytiotrophoblast during placental malaria. This interaction facilitates placental sequestration of malaria parasites resulting in severe health outcomes for both the mother and her offspring. Furthermore, CSA is presented by diverse cancer cells and specific targeting of cells by VAR2CSA may become a viable approach for cancer treatment. In the present study, we determined the cryo-electron microscopy structures of the full-length ectodomain of VAR2CSA from P. falciparum strain NF54 in complex with CSA, and VAR2CSA from a second P. falciparum strain FCR3.

VAR2CSA Antibodies in Non-Pregnant Populations

January 7, 2021 - 09:08 -- Open Access
Gnidehou S, Yanow SK
Trends Parasitol. 2021 Jan;37(1):65-76

The Plasmodium falciparum protein VAR2CSA is a critical mediator of placental malaria, and VAR2CSA antibodies (IgGs) are important to protect pregnant women. Although infrequently detected outside pregnancy, VAR2CSA IgGs were reported in men and children from Colombia and Brazil and in select African populations.

Not Open Access | Molecular architecture and domain arrangement of the placental malaria protein VAR2CSA suggests a model for carbohydrate binding

December 30, 2020 - 14:19 -- NOT Open Access
Bewley MC, Gautam L, Jagadeeshaprasad MG, Gowda DC, Flanagan JM
J Biol Chem. 2020 Dec 25;295(52):18589-18603

VAR2CSA is the placental-malaria-specific member of the antigenically variant Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) family. It is expressed on the surface of Plasmodium falciparum-infected host red blood cells and binds to specific chondroitin-4-sulfate chains of the placental proteoglycan receptor. The functional ∼310 kDa ectodomain of VAR2CSA is a multidomain protein that requires a minimum 12-mer chondroitin-4-sulfate molecule for specific, high affinity receptor binding. However, it is not known how the individual domains are organized and interact to create the receptor-binding surface, limiting efforts to exploit its potential as an effective vaccine or drug target.

An affinity chromatography and glycoproteomics workflow to profile the chondroitin sulfate proteoglycans that interact with malarial VAR2CSA in the placenta and in cancer

December 15, 2020 - 15:57 -- Open Access
Toledo AG, Pihl J, Spliid CB, Persson A, Nilsson J, Pereira MA, Gustavsson T, Choudhary S, Zarni Oo H, Black PC, Daugaard M, Esko JD, Larson G, Salanti A, Clausen TM
Glycobiology. 2020 Dec 9;30(12):989-1002

Chondroitin sulfate (CS) is the placental receptor for the VAR2CSA malaria protein, expressed at the surface of infected erythrocytes during Plasmodium falciparum infection. Infected cells adhere to syncytiotrophoblasts or get trapped within the intervillous space by binding to a determinant in a 4-O-sulfated CS chains. However, the exact structure of these glycan sequences remains unclear.

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