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Hepatocyte growth factor and its receptor are required for malaria infection

Nature Medicine volume 9, pages 1363–1369 (2003)Cite this article

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.

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Figure 1: Sporozoite migration through cells and mechanical cell wounding induce the release of ISIF.
Figure 2: HGF secreted by sporozoite-traversed host cells is required for infection.
Figure 3: HGF activity correlates with infection level.
Figure 4: Effect of HGF on Plasmodium infection is mediated through its receptor, MET.
Figure 5: HGF/MET signaling is required for early development of parasites inside host cells, and involves host-cell actin cytoskeleton reorganization.
Figure 6: MET activation is required during natural in vivo malarial infection.

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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.

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Authors and Affiliations

  1. Instituto Gulbenkian de Ciência, Rua da Quinta Grande 6, Oeiras, 2780-156, Portugal

    Margarida Carrolo, Laura Cabrita-Santos, Ana M Vigário, Susana Silva, Patricia Leirião, Daniel Carapau & Maria M Mota

  2. Department of Medical and Molecular Parasitology, New York University School of Medicine, 341 E 25th Street, New York, 10010, New York, USA

    Laura Cabrita-Santos & Ana Rodriguez

  3. Institute for Cancer Research and Treatment, University of Torino School of Medicine, Strada Provinciale 142, Candiolo, 10060, Torino, Italy

    Silvia Giordano, Simona Corso & Paolo M Comoglio

  4. Departamento de Biología, Facultad de Ciencias, Universidad Autónoma de Madrid, Madrid, 28049, Spain

    Rosario Armas-Portela

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  1. Margarida Carrolo
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Correspondence to Maria M Mota.

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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

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