RIFINs are adhesins implicated in severe Plasmodium falciparum malaria

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Abstract

Rosetting is a virulent Plasmodium falciparum phenomenon associated with severe malaria. Here we demonstrate that P. falciparum–encoded repetitive interspersed families of polypeptides (RIFINs) are expressed on the surface of infected red blood cells (iRBCs), where they bind to RBCs—preferentially of blood group A—to form large rosettes and mediate microvascular binding of iRBCs. We suggest that RIFINs have a fundamental role in the development of severe malaria and thereby contribute to the varying global distribution of ABO blood groups in the human population.

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Figure 1: A-RIFINs form dimers and preferentially bind blood group A RBCs.
Figure 2: Expression of RIFINs at the iRBC surface and involvement in rosetting.

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Acknowledgements

We thank B. Dobberstein (Ruprecht-Karls-Universität, Heidelberg) for providing dog pancreas microsomes and O. Puijalon (Pasteur Institute, France) for the gift of mAb D15-50. 3-α-N-acetylgalactosaminidase (Azyme) and 3-α-galactosidase (Bzyme) were kindly provided by Henrik Clausen (Copenhagen Center for Glycomics). This study was supported by the Swedish Strategic Foundation to I.M.N. and M.W., the EU Sixth- and Seventh-Framework Programs (MEST-CT-2004-8475 and EviMalar Network of Excellence to I.M.N. and M.W.), the Swedish Research Council (VR/2012-2014/521-2011-3377 to M.W., VR/2011-2018/14251 to M.L.O.), the Söderberg Foundation and Swedish Academy of Sciences, Swedish governmental ALF grants to Lund University Healthcare to J.R.S. and M.L.O., and a Distinguished Professor Award from Karolinska Institutet to M.W. The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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S.G., M.P., K.M., N.J., R.R.A., D.A., M. Westman and H.K. carried out the parasite culturing, protein expression in E. coli and S2-cells, mRNA and nucleic acid preparation, RNA-seq, PCR, plasmid construction, rosette-disruption experiments, FACS experiments, and CHO adhesion experiments, and they participated in the design of the study and writing of the manuscript. L.I. assisted with the sequestration experiments in rats. O.B., C.G.G., J.R.S., A.K.H. provided sialic acid-, Azyme- and Bzyme-treated RBCs and GPA-, GPB- and GPC-RBCs. N.J., P.L., N.M., K.Ö. and I.M.N. carried out transmembrane predictions, in vitro transcription and translation experiments and participated in the design of the study and writing of the manuscript. M. Wahlgren, J.L., G.v.H. and M.L.O. participated in the study design and in the writing of the manuscript.

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Correspondence to Mats Wahlgren.

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Competing interests

M. Wahlgren holds shares in and is a director of the board of Dilaforette AB, a company of the Karolinska Development AB involved in the development of adjunct treatment for severe malaria. The authors declare no other competing financial interests.

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Goel, S., Palmkvist, M., Moll, K. et al. RIFINs are adhesins implicated in severe Plasmodium falciparum malaria. Nat Med 21, 314–317 (2015). https://doi.org/10.1038/nm.3812

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