A coordinated transcriptional switching network mediates antigenic variation of human malaria parasites

Abstract

Malaria parasites avoid immune clearance through their ability to systematically alter antigens exposed on the surface of infected red blood cells. This is accomplished by tightly regulated transcriptional control of individual members of a large, multicopy gene family called var and is the key to both the virulence and chronic nature of malaria infections. Expression of var genes is mutually exclusive and controlled epigenetically, however how large populations of parasites coordinate var gene switching to avoid premature exposure of the antigenic repertoire is unknown. Here we provide evidence for a transcriptional network anchored by a universally conserved gene called var2csa that coordinates the switching process. We describe a structured switching bias that shifts overtime and could shape the pattern of var expression over the course of a lengthy infection. Our results provide an explanation for a previously mysterious aspect of malaria infections and shed light on how parasites possessing a relatively small repertoire of variant antigen encoding genes can coordinate switching events to limit antigen exposure, thereby maintaining chronic infections.

Data availability

Whole genome sequence and transcriptome data are available at the BioProject database of the NCBI. The genome sequencing data can be accessed at this link: http://www.ncbi.nlm.nih.gov/bioproject/515738. The RNAseq data can be accessed at this link: https://www.ncbi.nlm.nih.gov/bioproject/?term=PRJNA802886.

The following data sets were generated
The following previously published data sets were used

Article and author information

Author details

  1. Xu Zhang

    Department of Microbiology and Immunology, Weill Cornell Medicine, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Francesca Florini

    Department of Microbiology and Immunology, Weill Cornell Medicine, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2579-3820
  3. Joseph E Visone

    Department of Microbiology and Immunology, Weill Cornell Medicine, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Irina Lionardi

    Jill Roberts Center for Inflammatory Bowel Disease, Weill Cornell Medicine, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Mackensie R Gross

    Department of Microbiology and Immunology, Weill Cornell Medicine, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Valay Patel

    Department of Microbiology and Immunology, Weill Cornell Medicine, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Kirk W Deitsch

    Jill Roberts Center for Inflammatory Bowel Disease, Weill Cornell Medicine, New York, United States
    For correspondence
    kwd2001@med.cornell.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9183-2480

Funding

National Institute of Allergy and Infectious Diseases (AI 52390)

  • Kirk W Deitsch

National Institute of Allergy and Infectious Diseases (AI99327)

  • Kirk W Deitsch

National Institutes of Health (T32GM008539)

  • Joseph E Visone

Swiss National Science Foundation (P2BEP3_191777)

  • Francesca Florini

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

Reviewing Editor

  1. Olivier Silvie, Sorbonne Université, UPMC Univ Paris 06, INSERM, CNRS, France

Version history

  1. Preprint posted: September 30, 2022 (view preprint)
  2. Received: September 30, 2022
  3. Accepted: December 13, 2022
  4. Accepted Manuscript published: December 14, 2022 (version 1)
  5. Version of Record published: January 11, 2023 (version 2)

Copyright

© 2022, Zhang 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. Xu Zhang
  2. Francesca Florini
  3. Joseph E Visone
  4. Irina Lionardi
  5. Mackensie R Gross
  6. Valay Patel
  7. Kirk W Deitsch
(2022)
A coordinated transcriptional switching network mediates antigenic variation of human malaria parasites
eLife 11:e83840.
https://doi.org/10.7554/eLife.83840

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https://doi.org/10.7554/eLife.83840

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