Placental Malaria: Tackling variants with antibodies
Malaria is a serious, potentially life-threatening disease spread by mosquitoes. Pregnant women are especially at risk, as high densities of the parasite that causes malaria can accumulate in the placenta. This can trigger damaging inflammation in the placenta, which could affect the growth and development of the unborn baby, and even lead to a higher risk of infant death (Walker et al., 2014).
The malaria parasites that infect pregnant women are unique in displaying a protein called VAR2CSA on their surface. When VAR2CSA binds to CSA, a molecule on the surface of placenta cells, it leads to placental malaria. Over successive pregnancies, the body develops immunity against placental malaria by generating antibodies targeting VAR2CSA, and preventing it from attaching to CSA (Salanti et al., 2004). This suggests that VAR2CSA vaccines, which mimic the body’s natural defence mechanisms, may be able to provide some protection against placental malaria.
However, the sequences of the gene that codes for VAR2CSA vary between the different parasite strains (Benavente et al., 2018). Two trial vaccines have so far been developed based on sub-parts of the protein, using different variants of VAR2CSA that included an important CSA-binding domain. And although each vaccine candidate worked well against the variant of the protein used, there was little evidence of protection against other variants (Mordmüller et al., 2019; Sirima et al., 2020). Now, in eLife, Patrick Duffy and colleagues at the US National Institute of Allergy and Infectious Diseases – including Justin Doritchamou as first author – investigated whether an antibody could recognise different versions of the full-length VAR2CSA protein from different parasites (Doritchamou et al., 2022).
Doritchamou et al. first mixed five variants of the VAR2CSA protein (one at a time) with a pooled plasma sample from women who were immune to placental malaria. Each time they mixed a single VAR2CSA variant with the plasma, antibodies that bound to that variant were purified out of the pool and quantified. This revealed that most antibodies had bound to the first two variants, suggesting that antibodies towards the latter variants had already been depleted from the pool because they also recognised the earlier variants.
To confirm that antibodies were cross-protective, the researchers then took the antibodies they had purified using one particular VAR2CSA variant and tested their ability to recognise other variants. This revealed that the antibodies that attached to the first VAR2CSA variant were able to recognise all other tested variants. Cross-recognition was seen using purified proteins or using infected red blood cells expressing the variant.
The fact that naturally acquired antibodies against one version of full-length VAR2CSA also react with other variants implies that exposure to a small number of VAR2CSA variants might be enough to provide protection (Figure 1). This finding differs from the group’s previous results using just domains of VAR2CSA, where antibodies for a specific domain from one variant did not bind to other variants (Doritchamou et al., 2016). This suggests that the important antibody target on the protein may only form when the whole protein folds together. However, VAR2CSA is a large molecule and synthesising the amount of complete protein needed for a vaccine would be challenging, especially if multiple variants are required.
Additionally, naturally occurring antibodies, which lack an attached sugar called fucose, may be more protective than antibodies induced by a placental malaria vaccine, which have this sugar (Larsen et al., 2021). The reasons for this difference are unclear. Perhaps vaccine formulations that better mimic natural antigen presentation, such as providing the full-length protein, would lead to highly active antibodies without fucose, which would be highly desirable.
There is also the question of when is the best time to administer a vaccine. Ideally, immunisation would start in young, adolescent girls, a strategy commonly used for HPV vaccines to prevent cervical cancer. Such a vaccine roll-out would require detailed and ongoing consultation in communities where the vaccine might be used, but saving the lives of young mothers and their babies should be worth every effort.
References
-
VAR2CSA domain-specific analysis of naturally acquired functional antibodies to Plasmodium falciparum placental malariaThe Journal of Infectious Diseases 214:577–586.https://doi.org/10.1093/infdis/jiw197
-
Evidence for the involvement of VAR2CSA in pregnancy-associated malariaThe Journal of Experimental Medicine 200:1197–1203.https://doi.org/10.1084/jem.20041579
Article and author information
Author details
Publication history
- Version of Record published: March 28, 2022 (version 1)
Copyright
© 2022, Aitken and Rogerson
This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 787
- views
-
- 91
- downloads
-
- 1
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Further reading
-
- Evolutionary Biology
- Immunology and Inflammation
CD4+ T cell activation is driven by five-module receptor complexes. The T cell receptor (TCR) is the receptor module that binds composite surfaces of peptide antigens embedded within MHCII molecules (pMHCII). It associates with three signaling modules (CD3γε, CD3δε, and CD3ζζ) to form TCR-CD3 complexes. CD4 is the coreceptor module. It reciprocally associates with TCR-CD3-pMHCII assemblies on the outside of a CD4+ T cells and with the Src kinase, LCK, on the inside. Previously, we reported that the CD4 transmembrane GGXXG and cytoplasmic juxtamembrane (C/F)CV+C motifs found in eutherian (placental mammal) CD4 have constituent residues that evolved under purifying selection (Lee et al., 2022). Expressing mutants of these motifs together in T cell hybridomas increased CD4-LCK association but reduced CD3ζ, ZAP70, and PLCγ1 phosphorylation levels, as well as IL-2 production, in response to agonist pMHCII. Because these mutants preferentially localized CD4-LCK pairs to non-raft membrane fractions, one explanation for our results was that they impaired proximal signaling by sequestering LCK away from TCR-CD3. An alternative hypothesis is that the mutations directly impacted signaling because the motifs normally play an LCK-independent role in signaling. The goal of this study was to discriminate between these possibilities. Using T cell hybridomas, our results indicate that: intracellular CD4-LCK interactions are not necessary for pMHCII-specific signal initiation; the GGXXG and (C/F)CV+C motifs are key determinants of CD4-mediated pMHCII-specific signal amplification; the GGXXG and (C/F)CV+C motifs exert their functions independently of direct CD4-LCK association. These data provide a mechanistic explanation for why residues within these motifs are under purifying selection in jawed vertebrates. The results are also important to consider for biomimetic engineering of synthetic receptors.
-
- Genetics and Genomics
- Immunology and Inflammation
Transposable elements (TEs) are repetitive sequences representing ~45% of the human and mouse genomes and are highly expressed by medullary thymic epithelial cells (mTECs). In this study, we investigated the role of TEs on T-cell development in the thymus. We performed multiomic analyses of TEs in human and mouse thymic cells to elucidate their role in T-cell development. We report that TE expression in the human thymus is high and shows extensive age- and cell lineage-related variations. TE expression correlates with multiple transcription factors in all cell types of the human thymus. Two cell types express particularly broad TE repertoires: mTECs and plasmacytoid dendritic cells (pDCs). In mTECs, transcriptomic data suggest that TEs interact with transcription factors essential for mTEC development and function (e.g., PAX1 and REL), and immunopeptidomic data showed that TEs generate MHC-I-associated peptides implicated in thymocyte education. Notably, AIRE, FEZF2, and CHD4 regulate small yet non-redundant sets of TEs in murine mTECs. Human thymic pDCs homogenously express large numbers of TEs that likely form dsRNA, which can activate innate immune receptors, potentially explaining why thymic pDCs constitutively secrete IFN ɑ/β. This study highlights the diversity of interactions between TEs and the adaptive immune system. TEs are genetic parasites, and the two thymic cell types most affected by TEs (mTEcs and pDCs) are essential to establishing central T-cell tolerance. Therefore, we propose that orchestrating TE expression in thymic cells is critical to prevent autoimmunity in vertebrates.