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.
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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.
Reviewing Editor
- Urszula Krzych, Walter Reed Army Institute of Research, United States
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.
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.
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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
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- Cell Biology
- Immunology and Inflammation
Cytokine polyfunctionality is a well-established concept in immune cells, especially T cells, and their ability to concurrently produce multiple cytokines has been associated with better immunological disease control and subsequent effectiveness during infection and disease. To date, only little is known about the secretion dynamics of those cells, masked by the widespread deployment of mainly time-integrated endpoint measurement techniques that do not easily differentiate between concurrent and sequential secretion. Here, we employed a single-cell microfluidic platform capable of resolving the secretion dynamics of individual PBMCs. To study the dynamics of poly-cytokine secretion, as well as the dynamics of concurrent and sequential polyfunctionality, we analyzed the response at different time points after ex vivo activation. First, we observed the simultaneous secretion of cytokines over the measurement time for most stimulants in a subpopulation of cells only. Second, polyfunctionality generally decreased with prolonged stimulation times and revealed no correlation with the concentration of secreted cytokines in response to stimulation. However, we observed a general trend towards higher cytokine secretion in polyfunctional cells, with their secretion dynamics being distinctly different from mono-cytokine-secreting cells. This study provided insights into the distinct secretion behavior of heterogenous cell populations after stimulation with well-described agents and such a system could provide a better understanding of various immune dynamics in therapy and disease.
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- Immunology and Inflammation
- Medicine
Background:
Prinflammatory extracellular chromatin from neutrophil extracellular traps (NETs) and other cellular sources is found in COVID-19 patients and may promote pathology. We determined whether pulmonary administration of the endonuclease dornase alfa reduced systemic inflammation by clearing extracellular chromatin.
Methods:
Eligible patients were randomized (3:1) to the best available care including dexamethasone (R-BAC) or to BAC with twice-daily nebulized dornase alfa (R-BAC + DA) for seven days or until discharge. A 2:1 ratio of matched contemporary controls (CC-BAC) provided additional comparators. The primary endpoint was the improvement in C-reactive protein (CRP) over time, analyzed using a repeated-measures mixed model, adjusted for baseline factors.
Results:
We recruited 39 evaluable participants: 30 randomized to dornase alfa (R-BAC +DA), 9 randomized to BAC (R-BAC), and included 60 CC-BAC participants. Dornase alfa was well tolerated and reduced CRP by 33% compared to the combined BAC groups (T-BAC). Least squares (LS) mean post-dexamethasone CRP fell from 101.9 mg/L to 23.23 mg/L in R-BAC +DA participants versus a 99.5 mg/L to 34.82 mg/L reduction in the T-BAC group at 7 days; p=0.01. The anti-inflammatory effect of dornase alfa was further confirmed with subgroup and sensitivity analyses on randomised participants only, mitigating potential biases associated with the use of CC-BAC participants. Dornase alfa increased live discharge rates by 63% (HR 1.63, 95% CI 1.01–2.61, p=0.03), increased lymphocyte counts (LS mean: 1.08 vs 0.87, p=0.02) and reduced circulating cf-DNA and the coagulopathy marker D-dimer (LS mean: 570.78 vs 1656.96 μg/mL, p=0.004).
Conclusions:
Dornase alfa reduces pathogenic inflammation in COVID-19 pneumonia, demonstrating the benefit of cost-effective therapies that target extracellular chromatin.
Funding:
LifeArc, Breathing Matters, The Francis Crick Institute (CRUK, Medical Research Council, Wellcome Trust).
Clinical trial number:
