CXCR4 regulates Plasmodium development in mouse and human hepatocytes

J Exp Med. 2019 Aug 5;216(8):1733-1748. doi: 10.1084/jem.20182227. Epub 2019 Jun 12.


The liver stage of the etiological agent of malaria, Plasmodium, is obligatory for successful infection of its various mammalian hosts. Differentiation of the rod-shaped sporozoites of Plasmodium into spherical exoerythrocytic forms (EEFs) via bulbous expansion is essential for parasite development in the liver. However, little is known about the host factors regulating the morphological transformation of Plasmodium sporozoites in this organ. Here, we show that sporozoite differentiation into EEFs in the liver involves protein kinase C ζ-mediated NF-κB activation, which robustly induces the expression of C-X-C chemokine receptor type 4 (CXCR4) in hepatocytes and subsequently elevates intracellular Ca2+ levels, thereby triggering sporozoite transformation into EEFs. Blocking CXCR4 expression by genetic or pharmacological intervention profoundly inhibited the liver-stage development of the Plasmodium berghei rodent malaria parasite and the human Plasmodium falciparum parasite. Collectively, our experiments show that CXCR4 is a key host factor for Plasmodium development in the liver, and CXCR4 warrants further investigation for malaria prophylaxis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CRISPR-Cas Systems
  • Calcium / metabolism
  • Cell Line, Tumor
  • Hepatocytes / metabolism*
  • Humans
  • Liver / metabolism
  • Malaria / metabolism*
  • Malaria / parasitology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • NF-kappa B / metabolism
  • Plasmodium berghei / growth & development*
  • Plasmodium falciparum / growth & development*
  • Protein Kinase C / genetics
  • Protein Kinase C / metabolism
  • Proto-Oncogene Proteins c-met / genetics
  • Proto-Oncogene Proteins c-met / metabolism
  • Receptors, CXCR4 / genetics
  • Receptors, CXCR4 / metabolism*
  • Sporozoites / metabolism
  • Transfection


  • CXCR4 protein, human
  • CXCR4 protein, mouse
  • NF-kappa B
  • Receptors, CXCR4
  • HGFR protein, mouse
  • MET protein, human
  • Proto-Oncogene Proteins c-met
  • protein kinase C zeta
  • Protein Kinase C
  • Calcium

Associated data

  • GENBANK/FR180204