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
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
-
- 882
- views
-
- 105
- 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
-
- Immunology and Inflammation
Here, we sequenced rearranged TCRβ and TCRα chain sequences in CD4+CD8+ double positive (DP), CD4+CD8- single positive (SP4) and CD4-CD8+ (SP8) thymocyte populations from the foetus and young adult mouse. We found that life-stage had a greater impact on TCRβ and TCRα gene segment usage than cell-type. Foetal repertoires showed bias towards 3’TRAV and 5’TRAJ rearrangements in all populations, whereas adult repertoires used more 5’TRAV gene segments, suggesting that progressive TCRα rearrangements occur less frequently in foetal DP cells. When we synchronised young adult DP thymocyte differentiation by hydrocortisone treatment the new recovering DP thymocyte population showed more foetal-like 3’TRAV and 5’TRAJ gene segment usage. In foetus we identified less influence of MHC-restriction on α-chain and β-chain combinatorial VxJ usage and CDR1xCDR2 (V region) usage in SP compared to adult, indicating weaker impact of MHC-restriction on the foetal TCR repertoire. The foetal TCRβ repertoire was less diverse, less evenly distributed, with fewer non-template insertions, and all foetal populations contained more clonotypic expansions than adult. The differences between the foetal and adult thymus TCR repertoires are consistent with the foetal thymus producing αβT-cells with properties and functions that are distinct from adult T-cells: their repertoire is less governed by MHC-restriction, with preference for particular gene segment usage, less diverse with more clonotypic expansions, and more closely encoded by genomic sequence.
-
- Immunology and Inflammation
Airway macrophages (AM) are the predominant immune cell in the lung and play a crucial role in preventing infection, making them a target for host directed therapy. Macrophage effector functions are associated with cellular metabolism. A knowledge gap remains in understanding metabolic reprogramming and functional plasticity of distinct human macrophage subpopulations, especially in lung resident AM. We examined tissue-resident AM and monocyte-derived macrophages (MDM; as a model of blood derived macrophages) in their resting state and after priming with IFN-γ or IL-4 to model the Th1/Th2 axis in the lung. Human macrophages, regardless of origin, had a strong induction of glycolysis in response to IFN-γ or upon stimulation. IFN-γ significantly enhanced cellular energetics in both AM and MDM by upregulating both glycolysis and oxidative phosphorylation. Upon stimulation, AM do not decrease oxidative phosphorylation unlike MDM which shift to ‘Warburg’-like metabolism. IFN-γ priming promoted cytokine secretion in AM. Blocking glycolysis with 2-deoxyglucose significantly reduced IFN-γ driven cytokine production in AM, indicating that IFN-γ induces functional plasticity in human AM, which is mechanistically mediated by glycolysis. Directly comparing responses between macrophages, AM were more responsive to IFN-γ priming and dependent on glycolysis for cytokine secretion than MDM. Interestingly, TNF production was under the control of glycolysis in AM and not in MDM. MDM exhibited glycolysis-dependent upregulation of HLA-DR and CD40, whereas IFN-γ upregulated HLA-DR and CD40 on AM independently of glycolysis. These data indicate that human AM are functionally plastic and respond to IFN-γ in a manner distinct from MDM. These data provide evidence that human AM are a tractable target for inhalable immunomodulatory therapies for respiratory diseases.