Proteome-wide antigenic profiling in Ugandan cohorts identifies associations between age, exposure intensity, and responses to repeat-containing antigens in Plasmodium falciparum

  1. Madhura Raghavan
  2. Katrina L Kalantar
  3. Elias Duarte
  4. Noam Teyssier
  5. Saki Takahashi
  6. Andrew F Kung
  7. Jayant V Rajan
  8. John Rek
  9. Kevin KA Tetteh
  10. Chris Drakeley
  11. Isaac Ssewanyana
  12. Isabel Rodriguez-Barraquer
  13. Bryan Greenhouse  Is a corresponding author
  14. Joseph L DeRisi  Is a corresponding author
  1. University of California, San Francisco, United States
  2. Chan Zuckerberg Initiative, United States
  3. University of California, Berkeley, United States
  4. Infectious Diseases Research Collaboration, Uganda
  5. 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

The following data sets were generated

Article and author information

Author details

  1. Madhura Raghavan

    University of California, San Francisco, San Francisco, United States
    Competing interests
    No competing interests declared.
  2. Katrina L Kalantar

    Chan Zuckerberg Initiative, Redwood City, United States
    Competing interests
    No competing interests declared.
  3. Elias Duarte

    University of California, Berkeley, Berkeley, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2541-5504
  4. Noam Teyssier

    University of California, San Francisco, San Francisco, United States
    Competing interests
    No competing interests declared.
  5. Saki Takahashi

    University of California, San Francisco, San Francisco, United States
    Competing interests
    No competing interests declared.
  6. Andrew F Kung

    University of California, San Francisco, San Francisco, United States
    Competing interests
    No competing interests declared.
  7. Jayant V Rajan

    University of California, San Francisco, San Francisco, United States
    Competing interests
    No competing interests declared.
  8. John Rek

    Infectious Diseases Research Collaboration, Kampala, Uganda
    Competing interests
    No competing interests declared.
  9. Kevin KA Tetteh

    London School of Hygiene and Tropical Medicine, London, United Kingdom
    Competing interests
    No competing interests declared.
  10. Chris Drakeley

    London School of Hygiene and Tropical Medicine, London, United Kingdom
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4863-075X
  11. Isaac Ssewanyana

    Infectious Diseases Research Collaboration, Kampala, Uganda
    Competing interests
    No competing interests declared.
  12. Isabel Rodriguez-Barraquer

    University of California, San Francisco, San Francisco, United States
    Competing interests
    Isabel Rodriguez-Barraquer, Reviewing editor, eLife.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6784-1021
  13. Bryan Greenhouse

    University of California, San Francisco, San Francisco, United States
    For correspondence
    bryan.greenhouse@ucsf.edu
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0287-9111
  14. Joseph L DeRisi

    University of California, San Francisco, San Francisco, United States
    For correspondence
    joe@derisilab.ucsf.edu
    Competing interests
    Joseph L DeRisi, Paid scientific advisor for Allen & Co. Paid scientific advisor for the Public Health Company, Inc. and holds stock options. Founder and holding stock options in VeriPhi Health, Inc...
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4611-9205

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.

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."

Reviewing Editor

  1. Urszula Krzych, Walter Reed Army Institute of Research, United States

Version history

  1. Preprint posted: June 26, 2022 (view preprint)
  2. Received: June 26, 2022
  3. Accepted: February 14, 2023
  4. Accepted Manuscript published: February 15, 2023 (version 1)
  5. 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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  1. Madhura Raghavan
  2. Katrina L Kalantar
  3. Elias Duarte
  4. Noam Teyssier
  5. Saki Takahashi
  6. Andrew F Kung
  7. Jayant V Rajan
  8. John Rek
  9. Kevin KA Tetteh
  10. Chris Drakeley
  11. Isaac Ssewanyana
  12. Isabel Rodriguez-Barraquer
  13. Bryan Greenhouse
  14. Joseph L DeRisi
(2023)
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

Share this article

https://doi.org/10.7554/eLife.81401

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