Common host variation drives malaria parasite fitness in healthy human red cells

  1. Emily R Ebel
  2. Frans A Kuypers
  3. Carrie Lin
  4. Dmitri A Petrov  Is a corresponding author
  5. Elizabeth S Egan  Is a corresponding author
  1. Stanford University, United States
  2. Children's Hospital Oakland Research Institute, United States
  3. Stanford University School of Medicine, United States

Abstract

The replication of Plasmodium falciparum parasites within red blood cells (RBCs) causes severe disease in humans, especially in Africa. Deleterious alleles like hemoglobin S are well-known to confer strong resistance to malaria, but the effects of common RBC variation are largely undetermined. Here we collected fresh blood samples from 121 healthy donors, most with African ancestry, and performed exome sequencing, detailed RBC phenotyping, and parasite fitness assays. Over one third of healthy donors unknowingly carried alleles for G6PD deficiency or hemoglobinopathies, which were associated with characteristic RBC phenotypes. Among non-carriers alone, variation in RBC hydration, membrane deformability, and volume was strongly associated with P. falciparum growth rate. Common genetic variants in PIEZO1, SPTA1/SPTB, and several P. falciparum invasion receptors were also associated with parasite growth rate. Interestingly, we observed little or negative evidence for divergent selection on non-pathogenic RBC variation between Africans and Europeans. These findings suggest a model in which globally widespread variation in a moderate number of genes and phenotypes modulates P. falciparum fitness in RBCs.

Data availability

All data generated or analyzed during this study are included in the manuscript and supporting files. Source data files have been provided for Figures 1, 4, and 5 and other raw data and normalization scripts are available at https://github.com/emily-ebel/RBC

The following data sets were generated

Article and author information

Author details

  1. Emily R Ebel

    Biology, Stanford University, Stanford, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3244-4250
  2. Frans A Kuypers

    Children's Hospital Oakland Research Institute, Oakland, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Carrie Lin

    Stanford University School of Medicine, Stanford, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Dmitri A Petrov

    Department of Biology, Stanford University, Stanford, United States
    For correspondence
    dpetrov@stanford.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3664-9130
  5. Elizabeth S Egan

    Stanford University School of Medicine, Stanford, United States
    For correspondence
    eegan@stanford.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2112-7700

Funding

Stanford Maternal and Child Health Research Institute (N/A)

  • Elizabeth S Egan

Stanford University School of Medicine Office of Faculty Development and Diversity (N/A)

  • Elizabeth S Egan

Stanford Center for Computational, Evolutionary, and Human Genomics (N/A)

  • Emily R Ebel

National Institute of General Medical Sciences (5R35GM118165-05)

  • Dmitri A Petrov

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Jenny Tung, Duke University, United States

Ethics

Human subjects: Written informed consent and consent to publish was obtained from each subject and/or their parent as part of a protocol approved by the Stanford University Institutional Review Board (#40479).

Version history

  1. Preprint posted: October 9, 2020 (view preprint)
  2. Received: April 27, 2021
  3. Accepted: September 22, 2021
  4. Accepted Manuscript published: September 23, 2021 (version 1)
  5. Version of Record published: October 7, 2021 (version 2)

Copyright

© 2021, Ebel 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. Emily R Ebel
  2. Frans A Kuypers
  3. Carrie Lin
  4. Dmitri A Petrov
  5. Elizabeth S Egan
(2021)
Common host variation drives malaria parasite fitness in healthy human red cells
eLife 10:e69808.
https://doi.org/10.7554/eLife.69808

Share this article

https://doi.org/10.7554/eLife.69808

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