Photini Sinnis, MD, Assistant Professor

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Plasmodium sporozoites initiate malaria infection in the human host. Their journey, from the midgut wall of the mosquito to the human liver is the focus of our research. Sporozoites develop in oocysts on the midgut wall of infected mosquitoes, are released into the hemocoel and invade salivary glands where they wait to be injected into a vertebrate host during the mosquito’s bloodmeal.

We have shown that the major surface protein of sporozoites binds preferentially to mosquito salivary glands compared to other organs in the hemocoel. We are currently characterizing the salivary gland molecule(s) which are responsible for this recognition.

Fig. 1: Shown is a pair of mosquito salivary glands after incubation with the circumsporozoite protein, the major surface protein of the sporozoite. Protein binding is indicated by a blue color. Other mosquito organs do not stain blue in this assay.

During bloodfeeding, mosquitoes inject sporozoites into the skin of the vertebrate host. To date, little is known about the biology of sporozoites at the injection site. Using real time PCR and confocal microscopy, we are beginning to investigate what happens to sporozoites before they enter the bloodstream, how long they remain in the skin, what percentage of sporozoites leave the injection site and whether there is an immune response to the parasites that remain in the skin.

Fig. 2 (A) mosquito probing for blood . (B). Mosquitoes infected with sporozoites transgenic for β-galactosidase were allowed to probe on a mouse’s ear which was then removed and incubated with X-gal to reveal the injected sporozoites which stain blue.

After their entry into the bloodstream, sporozoites rapidly go the liver and invade hepatocytes. The basis of sporozoite arrest in the liver is likely the binding between its major surface protein, the circumsporozoite protein (CSP) and heparan sulfate proteoglycans (HSPGs) on the hepatocyte surface. Previous work in our laboratory has characterized both the sporozoite ligand and the hepatic binding sites. Recently, we have found that CSP is proteolytically processed and that this processing is required for hepatocyte invasion. We are now investigating the role of HSPGs in inducing proteolytic cleavage of CSP, the identity of the protease that cleaves CSP, and the effect of protease inhibition in prevention of malaria infection.

	Fig. 3 Immunofluorescence of sporozoites staining with antiserum that only recognizes full-length CSP. When these sporozoites contact cells they no longer stain with this antiserum indicating that cell contact is the signal for CSP cleavage.

Selected Publications

1. Sinnis P. and Coppi A. A Long and Winding Road: The Plasmodium Sporozoite's Journey in the Mammalian Host. Parasitology International. 2007 Sep;56(3):171-8. Epub 2007 Apr 24.
2. Bhandari R, Janos DP, Sinnis P. Furuncular myiasis caused by dermatobia hominis in a returning traveler. Am J Trop Med Hyg. 2007 Mar:76(3);598-9.
3. Yamauchi LM, Coppi A, Snounou G, Sinnis P. Plasmodium sporozoites trickle out of the injection site. Cell. Micobiol. 2007 9(5);1215-1222.
4. Coppi, A., Cabinian, M., Mirelman, D. and Sinnis, P. Antimalarial Activity of Allicin, a Biologically Active Compound From Garlic Cloves. Antimicrobial Agents and Chemotherapy. 2006 May;50(5):1731-1737.
5. Engelmann S, Sinnis P, Matuschewski K. Transgenic Plasmodium berghei sporozoites expressing beta-galactosidase for quantification of sporozoite transmission. Mol Biochem Parasitol. 2006 Mar;146(1):30-7.
6. Medica DL, Sinnis P. Quantitative dynamics of Plasmodium yoelii sporozoite transmission by infected anopheline mosquitoes. Infect Immun. 2005 Jul;73(7):4363-9.
7. Coppi, A., Pinzon-Ortiz, C., Hutter, C. and Sinnis, P. The Plasmodium circumsporozoite protein is proteolytically processed during cell invasion. J. Exp. Med. 2005;201:27-33.
8. Mo Myung J., Marshall P. and Sinnis, P. The Plasmodium circumsporozoite protein is involved in mosquito salivary gland invasion by sporozoites, Mol. Biochem. Parasitol. 2004;133:53-59. (#J67207)
9. Pinzon-Ortiz, C., Friedman, J., Esko, J., and 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. 2001;276:26784-26791. (#J22582)
10. Sidjanski, S.P., Vanderberg, J.P. and Sinnis, P. Anopheles stephensi salivary glands bear receptors for region I of the circumsporozoite protein of Plasmodium falciparum. Mol. Biochem. Parasitol. 1997;90:33-41. (#J03169)
11. Sinnis, P. and Sim, B.K.L. Cell invasion by the vertebrate stages of Plasmodium. Trends in Microbiology. 1997;5: 52-58. (#J04356)
12. Sinnis, P., Willnow, T.E., Briones, M.R.S., Herz, J. and Nussenzweig, V. Remnant lipoproteins inhibit malaria sporozoite invasion of hepatocytes. J. Exp. Med. 1996;184: 945-954. (#J04527)
13. Sinnis P.  Giardia. In: Parasitology. Edited by A. Satoskar, G. Simon, P. Hotez and M. Tsuji, Landes Bioscience, Austin Texas. 2007 In Press