Developing a multivariate prediction model of antibody features associated with protection of malaria-infected pregnant women from placental malaria
- The University of Melbourne, Australia
- Royal Darwin Hospital, Australia
- Walter and Eliza Hall Institute of Medical Research, Australia
- University of Copenhagen, Denmark
- Seattle Children's Research Institute, United States
- Burnet Institute, Australia
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
Stephen J Rogerson
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
Publication 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
-
- 1,033
- Page views
-
- 115
- Downloads
-
- 7
- Citations
Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
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)
Developing a multivariate prediction model of antibody features associated with protection of malaria-infected pregnant women from placental malaria
eLife 10:e65776.
https://doi.org/10.7554/eLife.65776
Further reading
-
- Immunology and Inflammation
Knockout (KO) mouse models play critical roles in elucidating biological processes behind disease-associated or disease-resistant traits. As a presumed consequence of gene KO, mice display certain phenotypes. Based on insight into the molecular role of said gene in a biological process, it is inferred that the particular biological process causally underlies the trait. This approach has been crucial towards understanding the basis of pathological and/or advantageous traits associated with Mertk KO mice. Mertk KO mice suffer from severe, early-onset retinal degeneration. MERTK, expressed in retinal pigment epithelia, is a receptor tyrosine kinase with a critical role in phagocytosis of apoptotic cells or cellular debris. Therefore, early-onset, severe retinal degeneration was described to be a direct consequence of failed MERTK-mediated phagocytosis of photoreceptor outer segments by retinal pigment epithelia. Here we report that the loss of Mertk alone is not sufficient for retinal degeneration. The widely used Mertk KO mouse carries multiple coincidental changes in its genome that affect the expression of a number of genes, including the Mertk paralog Tyro3. Retinal degeneration manifests only when the function of Tyro3 is concomitantly lost. Furthermore, Mertk KO mice display improved anti-tumor immunity. MERTK is expressed in macrophages. Therefore, enhanced anti-tumor immunity was inferred to result from the failure of macrophages to dispose of cancer cell corpses, resulting in a pro-inflammatory tumor microenvironment. The resistance against two syngeneic mouse tumor models observed in Mertk KO mice is not, however, phenocopied by the loss of Mertk alone. Neither Tyro3, nor macrophage phagocytosis by alternate genetic redundancy, account for the absence of anti-tumor immunity. Collectively, our results indicate that context-dependent epistasis of independent modifier alleles determines Mertk KO traits.
-
- Immunology and Inflammation
There is a growing appreciation that a tight relationship exists between cholesterol homeostasis and immunity in leukocytes, however, this relationship has not been deeply explored in the vascular endothelium. Endothelial cells (ECs) rapidly respond to extrinsic signals, such as tissue damage or microbial infection, by upregulating factors to activate and recruit circulating leukocytes to the site of injury and aberrant activation of ECs leads to inflammatory based diseases, such as multiple sclerosis and atherosclerosis. Here, we studied the role of cholesterol and a key transcription regulator of cholesterol homeostasis, SREBP2, in the EC responses to inflammatory stress. Treatment of primary human ECs with pro-inflammatory cytokines upregulated SREBP2 cleavage and cholesterol biosynthetic gene expression within the late phase of the acute inflammatory response. Furthermore, SREBP2 activation was dependent on NF-kB DNA binding and canonical SCAP-SREBP2 processing. Mechanistically, inflammatory activation of SREBP was mediated by a reduction in accessible cholesterol, leading to heightened sterol sensing and downstream SREBP2 cleavage. Detailed analysis of NF-kB inducible genes that may impact sterol sensing resulted in the identification of a novel RELA-inducible target, STARD10, that mediates accessible cholesterol homeostasis in ECs. Thus, this study provides an in-depth characterization of the relationship between cholesterol homeostasis and the acute inflammatory response in EC.
