CXCR4 regulates development in mouse and human hepatocytes.

The liver stage of the etiological agent of malaria, , is obligatory for successful infection of its various mammalian hosts. Differentiation of the rod-shaped sporozoites of 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 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 Ca levels, thereby triggering sporozoite transformation into EEFs. Blocking CXCR4 expression by genetic or pharmacological intervention profoundly inhibited the liver-stage development of the rodent malaria parasite and the human parasite. Collectively, our experiments show that CXCR4 is a key host factor for development in the liver, and CXCR4 warrants further investigation for malaria prophylaxis.