Developing a multivariate prediction model of antibody features associated with protection of malaria-infected pregnant women from placental malaria
Abstract
Background: 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 which could identify women protected from placental malaria.
Methods: We used a systems serology approach with elastic net-regularized logistic regression, Partial Least Squares Discriminant Analysis and a case control study design to identify naturally acquired antibody features mid pregnancy that were associated with protection from placental malaria at delivery in a cohort of 77 pregnant women from Madang, Papua New Guinea.
Results: The machine learning techniques selected six out of 169 measured antibody features towards VAR2CSA that could predict (with 86% accuracy) whether a woman would subsequently have active placental malaria infection at delivery. Selected features included previously described associations with inhibition of placental binding and/or opsonic phagocytosis of infected erythrocytes, and network analysis indicated that there are not one but multiple pathways to protection from placental malaria.
Conclusions: We have identified candidate antibody features which could accurately identify malaria-infected women as protected from placental infection. It is likely that there are multiple pathways to protection against placental malaria.
Funding: This study was supported by the National Health and Medical Research Council (No. APP1143946, GNT1145303, APP1092789, APP1140509 and APP1104975).
Data availability
All antibody feature data has been deposited in datadryad.
-
Antibody features towards VAR2CSA and CSA binding infected erythrocytes in a cohort of pregnant women from PNGDryad Digital Repository, doi.org/10.5061/dryad.wpzgmsbkx.
Article and author information
Author details
Funding
National Health and Medical Research Council (APP1143946)
- Elizabeth H Aitken
- Amy Chung
- Stephen J Rogerson
National Health and Medical Research Council (GNT1145303)
- P Mark Hogarth
- Bruce D Wines
National Health and Medical Research Council (APP1092789)
- Stephen J Rogerson
National Health and Medical Research Council (APP1140509)
- Amy Chung
University of Melbourne
- Amaya Ortega-Pajares
Australian Society for Parasitology
- Elizabeth H Aitken
National Health and Medical Research Council (APP1104975)
- Julie A Simpson
Bill and Melinda Gates Foundation (46099)
- Stephen J Rogerson
Miller Foundation Australia
- Amaya Ortega-Pajares
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Human subjects: Collection and use of plasma samples from women in PNG was approved by the PNG Institute of Medical Research Institutional Review Board, the PNG Medical Research Advisory Council and the Melbourne Health Human Research Ethics Committee. All participants provided informed written consent. The use of blood products from donors in Melbourne for isolation of primary cells, culture of parasites and leukocytes and for use as negative controls was approved by the Melbourne Health Human Research Ethics committee and the University of Melbourne Human Research Ethics committee.
Reviewing Editor
- Urszula Krzych, Walter Reed Army Institute of Research, United States
Version history
- Received: December 15, 2020
- Accepted: June 16, 2021
- Accepted Manuscript published: June 29, 2021 (version 1)
- Version of Record published: June 29, 2021 (version 2)
- Version of Record updated: August 16, 2021 (version 3)
Copyright
© 2021, Aitken et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 1,418
- Page views
-
- 171
- Downloads
-
- 12
- Citations
Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.
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
-
- Genetics and Genomics
- Immunology and Inflammation
Age-associated DNA methylation in blood cells convey information on health status. However, the mechanisms that drive these changes in circulating cells and their relationships to gene regulation are unknown. We identified age-associated DNA methylation sites in six purified blood-borne immune cell types (naive B, naive CD4+ and CD8+ T cells, granulocytes, monocytes, and NK cells) collected from healthy individuals interspersed over a wide age range. Of the thousands of age-associated sites, only 350 sites were differentially methylated in the same direction in all cell types and validated in an independent longitudinal cohort. Genes close to age-associated hypomethylated sites were enriched for collagen biosynthesis and complement cascade pathways, while genes close to hypermethylated sites mapped to neuronal pathways. In silico analyses showed that in most cell types, the age-associated hypo- and hypermethylated sites were enriched for ARNT (HIF1β) and REST transcription factor (TF) motifs, respectively, which are both master regulators of hypoxia response. To conclude, despite spatial heterogeneity, there is a commonality in the putative regulatory role with respect to TF motifs and histone modifications at and around these sites. These features suggest that DNA methylation changes in healthy aging may be adaptive responses to fluctuations of oxygen availability.
-
- Immunology and Inflammation
- Neuroscience
Infection with Influenza A virus (IAV) causes the well-known symptoms of the flu, including fever, loss of appetite, and excessive sleepiness. These responses, mediated by the brain, will normally disappear once the virus is cleared from the system, but a severe respiratory virus infection may cause long-lasting neurological disturbances. These include encephalitis lethargica and narcolepsy. The mechanisms behind such long lasting changes are unknown. The hypothalamus is a central regulator of the homeostatic response during a viral challenge. To gain insight into the neuronal and non-neuronal molecular changes during an IAV infection, we intranasally infected mice with an H1N1 virus and extracted the brain at different time points. Using single-nucleus RNA sequencing (snRNA-seq) of the hypothalamus, we identify transcriptional effects in all identified cell populations. The snRNA-seq data showed the most pronounced transcriptional response at 3 days past infection, with a strong downregulation of genes across all cell types. General immune processes were mainly impacted in microglia, the brain resident immune cells, where we found increased numbers of cells expressing pro-inflammatory gene networks. In addition, we found that most neuronal cell populations downregulated genes contributing to the energy homeostasis in mitochondria and protein translation in the cytosol, indicating potential reduced cellular and neuronal activity. This might be a preventive mechanism in neuronal cells to avoid intracellular viral replication and attack by phagocytosing cells. The change of microglia gene activity suggest that this is complemented by a shift in microglia activity to provide increased surveillance of their surroundings.