In malaria, rosetting is described as a phenomenon where an infected erythrocyte (IRBC) is attached to uninfected erythrocytes (URBC). In some studies, rosetting has been associated with malaria pathogenesis. Here, we have identified a new type of rosetting. Using a step-by-step approach, we identified IGFBP7, a protein secreted by monocytes in response to parasite stimulation, as a rosette-stimulator for Plasmodium falciparum- and P. vivax-IRBC. IGFBP7-mediated rosette-stimulation was rapid yet reversible. Unlike type I rosetting that involves direct interaction of rosetting ligands on IRBC and receptors on URBC, the IGFBP7-mediated, type II rosetting requires two additional serum factors, namely von Willebrand factor and thrombospondin-1. These two factors interact with IGFBP7 to mediate rosette formation by the IRBC. Importantly, the IGFBP7-induced type II rosetting hampers phagocytosis of IRBC by host phagocytes.
This study received financial support from the following funds: WCL, SWH, SKB, BM and
LR were supported by core funding from A*STAR to SIgN. LR was also funded by A*STAR grant
(JCO-DP BMSI/15–800006-SIGN). WCL was also funded by Open Fund- Young Individual Research
Grant (OF-YIRG NMRC/OFYIRG/0070/2018) by the National Medical Research Council, Ministry of
Health, Singapore. RMS was supported by Core funding from IMCB and Young Investigator Grant
YIG 2015 (A*STAR). BR was funded by University of Otago, Dunedin, New Zealand Start-Up Grant.
YL was supported by University of Malaya High Impact Research (HIR) Grant (UM.C/HIR/MOHE/
MED/16) from Ministry of Higher Education, Malaysia. BM is supported by NUHS start-up funding
(NUHSRO/2018/006/SU/01) and NUHS seed fund (NUHRO/2018/094/T1). SMRU is part of the Mahidol-Oxford University Research Unit, supported by the Wellcome Trust of the Great Britain. We thank the HSA Singapore for the supply of healthy uninfected blood. We also thank the flow cytometry team of SIgN for the assistance provided in flow cytometry and cell sorting.