Abstract
Plasmodium, the causative agent of malaria, must first infect hepatocytes to initiate a mammalian infection. Sporozoites migrate through several hepatocytes, by breaching their plasma membranes, before infection is finally established in one of them. Here we show that wounding of hepatocytes by sporozoite migration induces the secretion of hepatocyte growth factor (HGF), which renders hepatocytes susceptible to infection. Infection depends on activation of the HGF receptor, MET, by secreted HGF. The malaria parasite exploits MET not as a primary binding site, but as a mediator of signals that make the host cell susceptible to infection. HGF/MET signaling induces rearrangements of the host-cell actin cytoskeleton that are required for the early development of the parasites within hepatocytes. Our findings identify HGF and MET as potential targets for new approaches to malaria prevention.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Mota, M.M. et al. Migration of Plasmodium sporozoites through cells before infection. Science 291, 141–144 (2001).
McNeil, P.L. et al. Growth factors are released by mechanically wounded endothelial cells. J. Cell Biol. 109, 811–822 (1989).
Muthukrishnan, L. et al. Basic fibroblast growth factor is efficiently released from a cytosolic storage site through plasma membrane disruptions of endothelial cells. J. Cell. Physiol. 148, 1–16 (1991).
McNeil, P.L. & Steinhardt, R.A. Loss, restoration, and maintenance of plasma membrane integrity. J. Cell Biol. 137, 1–4 (1997).
Mota, M.M. & Rodriguez, A. Plasmodium yoelii: efficient in vitro invasion and complete development of sporozoites in mouse hepatic cell lines. Exp. Parasitol. 96, 257–259 (2000).
Kinoshita, T., Hirao, S., Matsumoto, K. & Nakamura, T. Possible endocrine control by hepatocyte growth factor of liver regeneration after partial hepatectomy. Biochem. Biophys. Res. Commun. 177, 330–335 (1991).
Zarnegar, R., DeFrances, M.C., Kost, D.P., Lindroos, P. & Michalopoulos, G.K. Expression of hepatocyte growth factor mRNA in regenerating rat liver after partial hepatectomy. Biochem. Biophys. Res. Commun. 177, 559–565 (1999).
Rong, S. et al. Tumorigenicity of the met proto-oncogene and the gene for hepatocyte growth factor. Mol. Cell. Biol. 12, 5152–5158 (1992).
Bhargava, M. et al. Scatter factor and hepatocyte growth factor: activities, properties, and mechanism. Cell Growth Differ. 3, 11–20 (1992).
Misumi, Y., Miki, K., Takatsuki, A., Tamura, G. & Ikehara, Y. Novel blockade by brefeldin A of intracellular transport of secretory proteins in cultured rat hepatocytes. J. Biol. Chem. 261, 11398–11403 (1986).
McNeil, P.L., Clarke, M.F.S. & Miyake, K. Cell motility, cell wound assays. in Current Protocols in Cell Biology, Supplement 2 (eds. Bonifacino, J.S., Dasso, M., Lippincott-Schwartz, J., Harford, J.B. & Yamada, K.M.) 12.4.1–12.4.15 (John Wiley & Sons, New York, 1999).
Trusolino, L. & Comoglio, P.M. Scatter-factor and semaphorin receptors: cell signaling for invasive growth. Nat. Rev. Cancer 2, 289–300 (2002).
Calvo-Calle, J.M., Moreno, A., Eling, W.M. & Nardin, E.H. In vitro development of infectious liver stages of P. yoelii and P. berghei malaria in human cell lines. Exp. Parasitol. 79, 362–373 (1994).
Naldini, L. et al. Hepatocyte growth factor (HGF) stimulates the tyrosine kinase activity of the receptor encoded by the proto-oncogene c-MET. Oncogene 6, 501–504 (1991).
Park, M. et al. Mechanism of met oncogene activation. Cell 45, 895–904 (1986).
Ponzetto, C. et al. A multifunctional docking site mediates signaling and transformation by the hepatocyte growth factor/scatter factor receptor family. Cell 77, 261–271 (1994).
Prat, M., Crepaldi, T., Pennacchietti, S., Bussolino, F. & Comoglio, P.M. Agonistic monoclonal antibodies against the Met receptor dissect the biological responses to HGF. J. Cell Sci. 111, 237–247 (1998).
Shen, Y., Naujokas, M., Park, M. & Ireton, K. InIB-dependent internalization of Listeria is mediated by the Met receptor tyrosine kinase. Cell 103, 501–510 (2000).
Giordano, S. et al. The semaphorin 4D receptor controls invasive growth by coupling with MET. Nat. Cell Biol. 4, 720–724 (2002).
Royal, I., Lamarche-Vane, N., Lamorte, L., Kaibuchi, K. & Park, M. Activation of cdc42, rac, PAK, and rho-kinase in response to hepatocyte growth factor dofferentially regulates epithelial cell colony spreading and dissociation. Mol. Biol. Cell 11, 1709–1725 (2000).
Morotti, A., Mila, S., Accornero, P., Tagliabue, E. & Ponzetto, C. K252a inhibits the oncogenic properties of Met, the HGF receptor. Oncogene 21, 4885–4893 (2002).
Mota, M.M., Hafalla, J.C.R. & Rodriguez, A. Migration through host cells activates Plasmodium sporozoites for infection. Nat. Med. 8, 1318–1322 (2002).
Jeffers, M., Rong, S., Anver, M. & Vande Woude, G.F. Autocrine hepatocyte growth factor/scatter factor-Met signaling induces transformation and the invasive/metastastic phenotype in C127 cells. Oncogene 13, 853–856 (1996).
Rong, S., Segal, S., Anver, M., Resau, J.H. & Vande Woude, G.F. Invasiveness and metastasis of NIH 3T3 cells induced by Met-hepatocyte growth factor/scatter factor autocrine stimulation. Proc. Natl Acad. Sci. USA 91, 4731–4735 (1994).
Matsumoto, K. & Nakamura, T. Hepatocyte growth factor: molecular structure and implications for a central role in liver regeneration. J. Gastroenterol. Hepatol. 6, 509–519 (1991).
Ljubimova, J.Y., Petrovic, L.M., Wilson, S.E., Geller, S.A. & Demetriou, A.A. Expression of HGF, its receptor c-met, c-myc, and albumin in cirrhotic and neoplastic human liver tissue. J. Histochem. Cytochem. 45, 79–87 (1997).
Pinzon-Ortiz, C., Friedman, J., Esko, J. & Sinnis, P. The binding of the circumsporozoite protein to cell surface heparan sulfate proteoglycans is required for Plasmodium sporozoite attachment to target cells. J. Biol. Chem. 276, 26784–26791 (2001).
Pradel, G., Garapaty, S. & Frevert, U. Proteoglycans mediate malaria sporozoite targeting to the liver. Mol. Microbiol. 45, 637–651 (2002).
Silvie, O. et al. Hepatocyte CD81 is required for Plasmodium falciparum and Plasmodium yoelii sporozoite infectivity. Nat. Med. 9, 93–96 (2003).
Naoumov, N.V. & Eddleston, A.L. Host immune response and variations in the virus genome: pathogenesis of liver damage caused by hepatitis B virus. Gut 35, 1013–1017 (1994).
Thursz, M.R. et al. Association of hepatitis B surface antigen carriage with severe malaria in Gambian children. Nat. Med. 1, 374–375 (1995).
Serghides, L. & Kain, K.C. Mechanism of protection induced by vitamin A in falciparum malaria. Lancet 359, 1404–1406 (2002).
Gohda, E. Function and regulation of production of hepatocyte growth factor (HGF). Nippon Yakurigaku Zasshi 119, 287–294 (2002).
Mazier, D. et al. Complete development of hepatic stages of Plasmodium falciparum in vitro. Science 227, 440–442 (1985).
Tsuji, M., Mattei, D., Nussenzweig, R.S., Eichinger, D. & Zavala, F. Demonstration of heat-shock protein 70 in the sporozoite stage of malaria parasites. Parasitol. Res. 80, 16–21 (1994).
Acknowledgements
We thank W. Haas, A. Jacinto, L. Parreira and M.C. Soares for critically reviewing the manuscript; T. Maciag for the FGF dominant negative construct; V.E. do Rosário, C. Casimiro and C. Alves for providing P. berghei-infected mosquitoes; and L. Naldini, A. Follenzi and M. Mazzone for kindly providing lentiviral vectors and experimental support. Funding was provided by Fundação para a Ciência e Tecnologia (Projects POCTI/38563/MGI/2001 and POCTI/MGI/44517/2002) and the National Institutes of Health (grants AI 49432 and AI 53698). M.C., L.C.-S., A.M.V., S.S., P.L., D.C. and M.M.M. are supported by Fundação para a Ciência e Tecnologia.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing financial interests.
Rights and permissions
About this article
Cite this article
Carrolo, M., Giordano, S., Cabrita-Santos, L. et al. Hepatocyte growth factor and its receptor are required for malaria infection. Nat Med 9, 1363–1369 (2003). https://doi.org/10.1038/nm947
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/nm947
This article is cited by
-
Management of cell death in parasitic infections
Seminars in Immunopathology (2021)
-
Analysis of erythrocyte signalling pathways during Plasmodium falciparum infection identifies targets for host-directed antimalarial intervention
Nature Communications (2020)
-
Multiplexed quantitative proteomics provides mechanistic cues for malaria severity and complexity
Communications Biology (2020)
-
The role of the liver in the migration of parasites of global significance
Parasites & Vectors (2019)
-
Towards a Humanized Mouse Model of Liver Stage Malaria Using Ectopic Artificial Livers
Scientific Reports (2017)