Plasmodium falciparum, the deadliest form of human malaria, remains one of the major threats to human health in endemic regions. Its virulence is attributed to its ability to modify infected red blood cells (iRBC) to adhere to endothelial receptors by placing variable antigens known as PfEMP1 on the iRBC surface. PfEMP1 expression determines the cytoadhesive properties of the iRBCs and is implicated in severe malaria. To evade antibody-mediated responses, the parasite undergoes continuous switches of expression between different PfEMP1 variants. Recently, it became clear that in addition to antibody-mediated responses, PfEMP1 triggers innate immune responses; however, the role of neutrophils, the most abundant white blood cells in the human circulation, in malaria remains elusive. Here, we show that neutrophils recognize and kill blood-stage P. falciparum isolates. We identify neutrophil ICAM-1 and specific PfEMP1 implicated in cerebral malaria as the key molecules involved in this killing. Our data provide mechanistic insight into the interactions between neutrophils and iRBCs and demonstrate the important influence of PfEMP1 on the selective innate response to cerebral malaria.
Bibliographical noteFunding Information:
ZG is supported by Israel Science Foundation (ISF) Grant 405/18, the Israel Cancer Research Fund, the Deutsche Forschungsgemeinschaft (DFG), and the Rosetrees Trust. ZG is also supported by the Samuel and Isabel Friedman Chair in Experimental Medicine. This work was supported partially by the Israeli Academy for Science, Israel Science Foundation (ISF) Grant 1523/18 and in part by European Research Council (erc.europa.eu) Consolidator Grant 615412 (to R.D.). RD is also supported by the Dr. Louis M. Leland and Ruth M. Leland Chair in Infectious Diseases. ARJ is supported by the Lundbeck Foundation (R313‐2019‐322). The Danish Agency for Higher Education and Science International Network Programme supported the collaboration between ARJ and RD (0192‐00058B). We are thankful to Dr. Borko Amulic for kindly providing us with the human myeloid leukemia PLB‐985 cell line.
© 2022 The Authors. Published under the terms of the CC BY NC ND 4.0 license.
- Plasmodium falciparum
- cerebral malaria