Abstract
Plasmodium sporozoites, the infective stage of the malaria parasite transmitted by mosquitoes, migrate through several hepatocytes before infecting a final one. Migration through hepatocytes occurs by breaching their plasma membranes, and final infection takes place with the formation of a vacuole around the sporozoite1. Once in the liver, sporozoites have already reached their target cells, making migration through hepatocytes prior to infection seem unnecessary. Here we show that this migration is required for infection of hepatocytes. Migration through host cells, but not passive contact with hepatocytes, induces the exocytosis of sporozoite apical organelles, a prerequisite for infection with formation of a vacuole. Sporozoite activation induced by migration through host cells is an essential step of Plasmodium life cycle.
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References
Mota, M.M. et al. Migration of plasmodium sporozoites through cells before infection. Science 291, 141–144 (2001).
Bannister, L.H. & Mitchell, G.H. The fine structure of secretion by Plasmodium knowlesi merozoites during red cell invasion. J. Protozool. 36, 362–367 (1989).
Carruthers, V.B., Giddings, O.K. & Sibley, L.D. Secretion of micronemal proteins is associated with toxoplasma invasion of host cells. Cell Microbiol. 1, 225–235 (1999).
Bumstead, J. & Tomley, F. Induction of secretion and surface capping of microneme proteins in Eimeria tenella. Mol. Biochem. Parasitol. 110, 311–321 (2000).
Stewart, M.J. & Vanderberg, J.P. Malaria sporozoites leave behind trails of circumsporozoite protein during gliding motility. J. Protozool. 35, 389–393 (1988).
Stewart, M.J., Nawrot, R.J., Schulman, S. & Vanderberg, J.P. Plasmodium berghei sporozoite invasion is blocked in vitro by sporozoite-immobilizing antibodies. Infect. Immun. 51, 859–864 (1986).
Gantt, S. et al. Antibodies against thrombospondin-related anonymous protein do not inhibit Plasmodium sporozoite infectivity in vivo. Infect. Immun. 68, 3667–3673 (2000).
Coppens, I., Andries, M., Liu, J.L. & Cesbron-Delauw, M.F. Intracellular trafficking of dense granule proteins in Toxoplasma gondii and experimental evidences for a regulated exocytosis. Eur. J. Cell. Biol. 78, 463–472 (1999).
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).
Karsten, V. et al. The protozoan parasite Toxoplasma gondii targets proteins to dense granules and the vacuolar space using both conserved and unusual mechanisms. J. Cell. Biol. 141, 1323–1333 (1998).
Blanco, A.R. et al. The biosynthesis and post-translational modification of Pbs21 an ookinete-surface protein of Plasmodium berghei. Mol. Biochem. Parasitol. 98, 163–173 (1999).
Howard, R.F., Narum, D.L., Blackman, M. & Thurman, J. Analysis of the processing of Plasmodium falciparum rhoptry-associated protein 1 and localization of Pr86 to schizont rhoptries and p67 to free merozoites. Mol. Biochem. Parasitol. 92, 111–122 (1998).
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).
Matuschewski, K., Mota, M.M., Pinder, J.C., Nussenzweig, V. & Kappe, S.H. Identification of the class XIV myosins Pb-MyoA and Py-MyoA and expression in Plasmodium sporozoites. Mol. Biochem. Parasitol. 112, 157–161 (2001).
Dobrowolski, J.M., Carruthers, V.B. & Sibley, L.D. Participation of myosin in gliding motility and host cell invasion by Toxoplasma gondii. Mol. Microbiol. 26, 163–173 (1997).
Briones, M.R., Tsuji, M. & Nussenzweig, V. The large difference in infectivity for mice of Plasmodium berghei and Plasmodium yoelii sporozoites cannot be correlated with their ability to enter into hepatocytes. Mol. Biochem. Parasitol. 77, 7–17 (1996).
Mota, M.M. & Rodriguez, A. Migration through host cells by apicomplexan parasites. Microbes Infect. 3, 1123–1128 (2001).
Chobotar, B., Danforth, H.D. & Entzeroth, R. Ultrastructural observations of host-cell invasion by sporozoites of Eimeria papillata in vivo. Parasitol. Res. 79, 15–23 (1993).
Danforth, H.D., Entzeroth, R. & Chobotar, B. Scanning and transmission electron microscopy of host cell pathology associated with penetration by Eimeria papillata sporozoites. Parasitol. Res. 78, 570–573 (1992).
Speer, C.A., Dubey, J.P., Blixt, J.A. & Prokop, K. Time lapse video microscopy and ultrastructure of penetrating sporozoites, types 1 and 2 parasitophorous vacuoles, and the transformation of sporozoites to tachyzoites of the VEG strain of Toxoplasma gondii. J. Parasitol. 83, 565–574 (1997).
Yoshida, N., Nussenzweig, R.S., Potocnjak, P., Nussenzweig, V. & Aikawa, M. Hybridoma produces protective antibodies directed against the sporozoite stage of malaria parasite. Science 207, 71–73 (1980).
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).
McNeil, P.L., Clarke, M.F.S. & Miyake, K. Cell motility, cell wound assays. in Current Protocols in Cell Biology, Vol. 2 Supplement 2 (John Wiley & Sons Publisher) 12.4.1–12.4.15 (1999).
Bruna-Romero, O. et al. Detection of malaria liver-stages in mice infected through the bite of a single Anopheles mosquito using a highly sensitive real-time PCR. Int. J. Parasitol. 31, 1499–1502 (2001).
Acknowledgements
We thank P. Bhanot, S. Dias and M. Ronemus for critically reviewing the manuscript; C. Figueiredo for help with real-time PCR assay; P. Sinnis for help with the gliding motility assay; S. Lu and J. Ross for help with the western blots; and E. Nardin for the anti-TRAP mAb (F3B5). The anti-EBA175 rabbit antiserum was provided by the Malaria Research and Reference Reagent Resource Center (MR4). Support was provided by the Fundação para a Ciência e Tecnologia (to M.M.M.) and American Liver Foundation (to A.R.).
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Mota, M., Hafalla, J. & Rodriguez, A. Migration through host cells activates Plasmodium sporozoites for infection. Nat Med 8, 1318–1322 (2002). https://doi.org/10.1038/nm785
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DOI: https://doi.org/10.1038/nm785
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