Proteome-wide antigenic profiling in Ugandan cohorts identifies associations between age, exposure intensity, and responses to repeat-containing antigens in Plasmodium falciparum
- University of California, San Francisco, United States
- Chan Zuckerberg Initiative, United States
- University of California, Berkeley, United States
- Infectious Diseases Research Collaboration, Uganda
- London School of Hygiene and Tropical Medicine, United Kingdom
Abstract
Protection against Plasmodium falciparum, which is primarily antibody-mediated, requires recurrent exposure to develop. The study of both naturally acquired limited immunity and vaccine induced protection against malaria remains critical for ongoing eradication efforts. Towards this goal, we deployed a customized P. falciparum PhIP-seq T7 phage display library containing 238,068 tiled 62-amino acid peptides, covering all known coding regions, including antigenic variants, to systematically profile antibody targets in 198 Ugandan children and adults from high and moderate transmission settings. Repeat elements - short amino acid sequences repeated within a protein - were significantly enriched in antibody targets. While breadth of responses to repeat-containing peptides was twofold higher in children living in the high versus moderate exposure setting, no such differences were observed for peptides without repeats, suggesting that antibody responses to repeat-containing regions may be more exposure dependent and/or less durable in children than responses to regions without repeats. Additionally, short motifs associated with seroreactivity were extensively shared among hundreds of antigens, potentially representing cross-reactive epitopes. PfEMP1 shared motifs with the greatest number of other antigens, partly driven by the diversity of PfEMP1 sequences. These data suggest that the large number of repeat elements and potential cross-reactive epitopes found within antigenic regions of P. falciparum could contribute to the inefficient nature of malaria immunity.
Data availability
All data generated or analyzed during this study are included in the manuscript, supporting files and in the Dryad repository with the doi:doi.org/10.7272/Q69S1P9G
Article and author information
Author details
Isabel Rodriguez-Barraquer
Funding
Chan Zuckerberg Biohub
- Joseph L DeRisi
Chan Zuckerberg Biohub (Investigator program)
- Bryan Greenhouse
National Institutes of Health (A1089674 (East Africa ICEMR))
- Bryan Greenhouse
National Institutes of Health (AI119019)
- Bryan Greenhouse
National Institutes of Health (AI144048)
- Bryan Greenhouse
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: The study protocol was reviewed and approved by the Makerere University School of Medicine Research and Ethics Committee (Identification numbers 2011-149 and 2011-167), the London School of Hygiene and Tropical Medicine Ethics Committee (Identification numbers 5943 and 5944), the University of California, San Francisco, Committee on Human Research (Identification numbers 11-05539 and 11-05995) and the Uganda National Council for Science and Technology (Identification numbers HS-978 and HS-1019). Written informed consent was obtained from all participants in the study. For children, this was obtained from the parents or guardians. The US control samples were from New York Blood Center and these samples came from volunteer blood donors who consented as follows, "I authorize NYBC to use or transfer my blood or portions of it for any purpose it deems appropriate, including transfusion, research, or commercial purposes."
Version history
- Preprint posted: June 26, 2022 (view preprint)
- Received: June 26, 2022
- Accepted: February 14, 2023
- Accepted Manuscript published: February 15, 2023 (version 1)
- Version of Record published: March 10, 2023 (version 2)
Copyright
© 2023, Raghavan 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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Proteome-wide antigenic profiling in Ugandan cohorts identifies associations between age, exposure intensity, and responses to repeat-containing antigens in Plasmodium falciparum
eLife 12:e81401.
https://doi.org/10.7554/eLife.81401
Further reading
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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:
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Trained immunity is the long-term functional reprogramming of innate immune cells, which results in altered responses toward a secondary challenge. Despite indoxyl sulfate (IS) being a potent stimulus associated with chronic kidney disease (CKD)-related inflammation, its impact on trained immunity has not been explored. Here, we demonstrate that IS induces trained immunity in monocytes via epigenetic and metabolic reprogramming, resulting in augmented cytokine production. Mechanistically, the aryl hydrocarbon receptor (AhR) contributes to IS-trained immunity by enhancing the expression of arachidonic acid (AA) metabolism-related genes such as arachidonate 5-lipoxygenase (ALOX5) and ALOX5 activating protein (ALOX5AP). Inhibition of AhR during IS training suppresses the induction of IS-trained immunity. Monocytes from end-stage renal disease (ESRD) patients have increased ALOX5 expression and after 6 days training, they exhibit enhanced TNF-α and IL-6 production to lipopolysaccharide (LPS). Furthermore, healthy control-derived monocytes trained with uremic sera from ESRD patients exhibit increased production of TNF-α and IL-6. Consistently, IS-trained mice and their splenic myeloid cells had increased production of TNF-α after in vivo and ex vivo LPS stimulation compared to that of control mice. These results provide insight into the role of IS in the induction of trained immunity, which is critical during inflammatory immune responses in CKD patients.
