RIFINs are adhesins implicated in severe Plasmodium falciparum malaria



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.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

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.


  1. 1

    Scherf, A., Lopez-Rubio, J.J. & Riviere, L. Annu. Rev. Microbiol. 62, 445–470 (2008).

    CAS  Article  Google Scholar 

  2. 2

    Miller, L.H., Ackerman, H.C., Su, X. & Wellems, T.E. Nat. Med. 19, 156–167 (2013).

    CAS  Article  Google Scholar 

  3. 3

    Carlson, J. et al. Lancet 336, 1457–1460 (1990).

    CAS  Article  Google Scholar 

  4. 4

    Rowe, A., Obeiro, J., Newbold, C.I. & Marsh, K. Infect. Immun. 63, 2323–2326 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. 5

    Rowe, J.A., Moulds, J.M., Newbold, C.I. & Miller, L.H. Nature 388, 292–295 (1997).

    CAS  Article  Google Scholar 

  6. 6

    Chen, Q. et al. J. Exp. Med. 187, 15–23 (1998).

    CAS  Article  Google Scholar 

  7. 7

    Vigan-Womas, I. et al. PLoS Pathog. 8, e1002781 (2012).

    CAS  Article  Google Scholar 

  8. 8

    Carlson, J., Nash, G.B., Gabutti, V., al-Yaman, F. & Wahlgren, M. Blood 84, 3909–3914 (1994).

    CAS  Article  Google Scholar 

  9. 9

    Carlson, J. & Wahlgren, M. J. Exp. Med. 176, 1311–1317 (1992).

    CAS  Article  Google Scholar 

  10. 10

    Rowe, J.A. et al. Proc. Natl. Acad. Sci. USA 104, 17471–17476 (2007).

    CAS  Article  Google Scholar 

  11. 11

    Cserti, C.M. & Dzik, W.H. Blood 110, 2250–2258 (2007).

    CAS  Article  Google Scholar 

  12. 12

    Fernandez, V. et al. J. Exp. Med. 190, 1393–1404 (1999).

    CAS  Article  Google Scholar 

  13. 13

    Kyes, S.A. et al. Proc. Natl. Acad. Sci. USA 96, 9333–9338 (1999).

    CAS  Article  Google Scholar 

  14. 14

    Petter, M. et al. Mol. Biochem. Parasitol. 156, 51–61 (2007).

    CAS  Article  Google Scholar 

  15. 15

    Joannin, N., Abhiman, S., Sonnhammer, E.L. & Wahlgren, M. BMC Genomics 9, 19 (2008).

    Article  Google Scholar 

  16. 16

    Lavazec, C., Sanyal, S. & Templeton, T.J. Nucleic Acids Res. 34, 6696–6707 (2006).

    CAS  Article  Google Scholar 

  17. 17

    Hessa, T. et al. Nature 433, 377–381 (2005).

    CAS  Article  Google Scholar 

  18. 18

    Liu, Q.P. et al. Nat. Biotechnol. 25, 454–464 (2007).

    CAS  Article  Google Scholar 

  19. 19

    Chen, Q. et al. Nature 394, 392–395 (1998).

    CAS  Article  Google Scholar 

  20. 20

    Gahmberg, C.G., Myllyla, G., Leikola, J. & Pirkola, A. J. Biol. Chem. 251, 6108–6116 (1976).

    CAS  PubMed  Google Scholar 

  21. 21

    Claros, M.G. & von Heijne, G. Comput. Appl. Biosci. 10, 685–686 (1994).

    CAS  PubMed  Google Scholar 

  22. 22

    Tusnády, G.E. & Simon, I. Bioinformatics 17, 849–850 (2001).

    Article  Google Scholar 

  23. 23

    Krogh, A., Larsson, B., von Heijne, G. & Sonnhammer, E.L.J. Mol. Biol. 305, 567–580 (2001).

    CAS  Article  Google Scholar 

  24. 24

    Käll, L. & Sonnhammer, E.L. FEBS Lett. 532, 415–418 (2002).

    Article  Google Scholar 

  25. 25

    Rost, B., Fariselli, P. & Casadio, R. Protein Sci. 5, 1704–1718 (1996).

    CAS  Article  Google Scholar 

  26. 26

    Bernsel, A., Viklund, H., Hennerdal, A. & Elofsson, A. Nucleic Acids Res. 37, W465–W468 (2009).

    CAS  Article  Google Scholar 

  27. 27

    Arai, M. et al. Nucleic Acids Res. 32, W390–W393 (2004).

    CAS  Article  Google Scholar 

  28. 28

    Bendtsen, J.D., Nielsen, H., von Heijne, G. & Brunak, S. J. Mol. Biol. 340, 783–795 (2004).

    Article  Google Scholar 

  29. 29

    Mok, B.W. et al. Mol. Biochem. Parasitol. 151, 184–192 (2007).

    CAS  Article  Google Scholar 

  30. 30

    Moll, K., Kaneko, A., Scherf, A. & Wahlgren, M. Methods in Malaria Research. 6th edn. (EviMalaR, Glasgow, UK & MR4/ATCC, Manassas, VA, USA, 2013).

  31. 31

    Trager, W. & Jensen, J.B. Science 193, 673–675 (1976).

    CAS  Article  Google Scholar 

  32. 32

    Angeletti, D. et al. PLoS ONE 7, e50758 (2012).

    CAS  Article  Google Scholar 

  33. 33

    Kozak, M. Cell 44, 283–292 (1986).

    CAS  Article  Google Scholar 

  34. 34

    Johansson, H.E., Sproat, B.S. & Melefors, Ö. Nucleic Acids Res. 21, 2275–2276 (1993).

    CAS  Article  Google Scholar 

  35. 35

    Lundin, C. et al. FEBS Lett. 580, 2281–2284 (2006).

    CAS  Article  Google Scholar 

  36. 36

    Angeletti, D., Albrecht, L., Wahlgren, M. & Moll, K. Malar. J. 12, 32 (2013).

    CAS  Article  Google Scholar 

  37. 37

    Pettersson, F. et al. Infect. Immun. 73, 7736–7746 (2005).

    CAS  Article  Google Scholar 

Download references


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.

Author information




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.

Corresponding author

Correspondence to Mats Wahlgren.

Ethics declarations

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.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–11 and Supplementary Table 1. (PDF 1387 kb)

Source data

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

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

Download citation

Further reading


Nature Briefing

Sign up for the Nature Briefing newsletter for a daily update on COVID-19 science.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing