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Heme-deficient metabolism and impaired cellular differentiation as an evolutionary trade-off for human infectivity in Trypanosoma brucei gambiense

Author

Listed:
  • Eva Horáková

    (Institute of Parasitology, Biology Centre, Czech Academy of Sciences
    University of South Bohemia)

  • Laurence Lecordier

    (Université libre de Bruxelles (ULB))

  • Paula Cunha

    (Université libre de Bruxelles (ULB)
    Universidade Federal de São Paulo)

  • Roman Sobotka

    (University of South Bohemia
    Czech Academy of Sciences)

  • Piya Changmai

    (Institute of Parasitology, Biology Centre, Czech Academy of Sciences
    University of Ostrava)

  • Catharina J. M. Langedijk

    (Institute of Parasitology, Biology Centre, Czech Academy of Sciences
    University Medical Center)

  • Jan Van Den Abbeele

    (Trypanosoma Unit, Institute of Tropical Medicine)

  • Benoit Vanhollebeke

    (Université libre de Bruxelles (ULB)
    Walloon Excellence in Life Sciences and Biotechnology)

  • Julius Lukeš

    (Institute of Parasitology, Biology Centre, Czech Academy of Sciences
    Université libre de Bruxelles (ULB))

Abstract

Resistance to African trypanosomes in humans relies in part on the high affinity targeting of a trypanosome lytic factor 1 (TLF1) to a trypanosome haptoglobin-hemoglobin receptor (HpHbR). While TLF1 avoidance by the inactivation of HpHbR contributes to Trypanosoma brucei gambiense human infectivity, the evolutionary trade-off of this adaptation is unknown, as the physiological function of the receptor remains to be elucidated. Here we show that uptake of hemoglobin via HpHbR constitutes the sole heme import pathway in the trypanosome bloodstream stage. T. b. gambiense strains carrying the inactivating mutation in HpHbR, as well as genetically engineered T. b. brucei HpHbR knock-out lines show only trace levels of intracellular heme and lack hemoprotein-based enzymatic activities, thereby providing an uncommon example of aerobic parasitic proliferation in the absence of heme. We further show that HpHbR facilitates the developmental progression from proliferating long slender forms to cell cycle-arrested stumpy forms in T. b. brucei. Accordingly, T. b. gambiense was found to be poorly competent for slender-to-stumpy differentiation unless a functional HpHbR receptor derived from T. b. brucei was genetically restored. Altogether, we identify heme-deficient metabolism and disrupted cellular differentiation as two distinct HpHbR-dependent evolutionary trade-offs for T. b. gambiense human infectivity.

Suggested Citation

  • Eva Horáková & Laurence Lecordier & Paula Cunha & Roman Sobotka & Piya Changmai & Catharina J. M. Langedijk & Jan Van Den Abbeele & Benoit Vanhollebeke & Julius Lukeš, 2022. "Heme-deficient metabolism and impaired cellular differentiation as an evolutionary trade-off for human infectivity in Trypanosoma brucei gambiense," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-34501-4
    DOI: 10.1038/s41467-022-34501-4
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    References listed on IDEAS

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    1. Pierrick Uzureau & Sophie Uzureau & Laurence Lecordier & Frédéric Fontaine & Patricia Tebabi & Fabrice Homblé & Axelle Grélard & Vanessa Zhendre & Derek P. Nolan & Laurence Lins & Jean-Marc Crowet & A, 2013. "Mechanism of Trypanosoma brucei gambiense resistance to human serum," Nature, Nature, vol. 501(7467), pages 430-434, September.
    2. Binny M. Mony & Paula MacGregor & Alasdair Ivens & Federico Rojas & Andrew Cowton & Julie Young & David Horn & Keith Matthews, 2014. "Genome-wide dissection of the quorum sensing signalling pathway in Trypanosoma brucei," Nature, Nature, vol. 505(7485), pages 681-685, January.
    3. Luc Vanhamme & Françoise Paturiaux-Hanocq & Philippe Poelvoorde & Derek P. Nolan & Laurence Lins & Jan Van Den Abbeele & Annette Pays & Patricia Tebabi & Huang Van Xong & Alain Jacquet & Nicole Moguil, 2003. "Apolipoprotein L-I is the trypanosome lytic factor of human serum," Nature, Nature, vol. 422(6927), pages 83-87, March.
    4. Kristian Stødkilde & Morten Torvund-Jensen & Søren K. Moestrup & Christian B. F. Andersen, 2014. "Structural basis for trypanosomal haem acquisition and susceptibility to the host innate immune system," Nature Communications, Nature, vol. 5(1), pages 1-8, December.
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