TY - JOUR
T1 - CXCR4 regulates Plasmodium development in mouse and human hepatocytes
AU - Bando, Hironori
AU - Pradipta, Ariel
AU - Iwanaga, Shiroh
AU - Okamoto, Toru
AU - Okuzaki, Daisuke
AU - Tanaka, Shun
AU - Vega-Rodríguez, Joel
AU - Lee, Youngae
AU - Ma, Ji Su
AU - Sakaguchi, Naoya
AU - Soga, Akira
AU - Fukumoto, Shinya
AU - Sasai, Miwa
AU - Matsuura, Yoshiharu
AU - Yuda, Masao
AU - Jacobs-Lorena, Marcelo
AU - Yamamoto, Masahiro
N1 - Funding Information:
This work was supported by the Japan Agency for Medical Research and Development Research Program on Emerging and Re-emerging Infectious Diseases (JP18fk0108047), Japanese Initiative for Progress of Research on Infectious Diseases for Global Epidemic (JP18fm0208018), and US–Japan Cooperative Medical Sciences Program Collaborative Awards 2016 (16jk0210010h0001); the Ministry of Education, Culture, Sports, Science and Technology Grant-in-Aid for Scientific Research on Innovative Areas (17K15677 and 19H00970); the Institute for Enzyme Research, Joint Usage/Research Center Cooperative Research Grant; Tokushima University; the Takeda Science Foundation; the Cell Science Research Foundation; the Mochida Memorial Foundation on Medical and Pharmaceutical Research; the Uehara Memorial Foundation; the Naito Foundation; the As-tellas Foundation for Research on Metabolic Disorders; and the Research Foundation for Microbial Diseases of Osaka University. The authors declare no competing financial interests.
Publisher Copyright:
© 2019 Bando et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).
PY - 2019/8/1
Y1 - 2019/8/1
N2 - 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.
AB - 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.
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U2 - 10.1084/jem.20182227
DO - 10.1084/jem.20182227
M3 - Article
C2 - 31189656
AN - SCOPUS:85071068702
VL - 216
SP - 1733
EP - 1748
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
SN - 0022-1007
IS - 8
ER -
