Sickle hemoglobin confers tolerance to plasmodium infection

Ana Ferreira, Ivo Marguti, Ingo Bechmann, Viktória Jeney, Ângelo Chora, Nuno R. Palha, Sofia Rebelo, Annie Henri, Yves Beuzard, Miguel P. Soares

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175 Citations (Scopus)

Abstract

Sickle human hemoglobin (Hb) confers a survival advantage to individuals living in endemic areas of malaria, the disease caused by Plasmodium infection. As demonstrated hereby, mice expressing sickle Hb do not succumb to experimental cerebral malaria (ECM). This protective effect is exerted irrespectively of parasite load, revealing that sickle Hb confers host tolerance to Plasmodium infection. Sickle Hb induces the expression of heme oxygenase-1 (HO-1) in hematopoietic cells, via a mechanism involving the transcription factor NF-E2-related factor 2 (Nrf2). Carbon monoxide (CO), a byproduct of heme catabolism by HO-1, prevents further accumulation of circulating free heme after Plasmodium infection, suppressing the pathogenesis of ECM. Moreover, sickle Hb inhibits activation and/or expansion of pathogenic CD8+ T cells recognizing antigens expressed by Plasmodium, an immunoregulatory effect that does not involve Nrf2 and/or HO-1. Our findings provide insight into molecular mechanisms via which sickle Hb confers host tolerance to severe forms of malaria.

Original languageEnglish
Pages (from-to)398-409
Number of pages12
JournalCell
Volume145
Issue number3
DOIs
Publication statusPublished - Apr 29 2011

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Ferreira, A., Marguti, I., Bechmann, I., Jeney, V., Chora, Â., Palha, N. R., Rebelo, S., Henri, A., Beuzard, Y., & Soares, M. P. (2011). Sickle hemoglobin confers tolerance to plasmodium infection. Cell, 145(3), 398-409. https://doi.org/10.1016/j.cell.2011.03.049