CXCR4 is a host factor that regulates Plasmodium development in hepatocytes

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?-mediated NF-?B 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 P. berghei rodent malaria parasite and the human P. falciparum parasite also. 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. Overall design: To explore the molecular mechanisms by which the HGF/MET/PKC?/NF-?B pathway regulates P. berghei sporozoite development in hepatocytes, we compared the gene expression patterns in wild-type and PKC?-KO Huh7 cells treated or not treated with HGF. We also analyzed the gene expression profiles in wild type and PKC?-KO Huh7 cells uninfected or infected with P. berghei sporozoites.

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Bando H, Pradipta A, Iwanaga S, Okamoto T, Okuzaki D, Tanaka S, Vega-Rodríguez J, Lee Y, Ma JS, Sakaguchi N, Soga A, Fukumoto S, Sasai M, Matsuura Y, Yuda M, Jacobs-Lorena M, Yamamoto M