|Department Affiliations||Molecular Microbiology & Immunology, Department of Medicine|
|SOM Address||E4626 Bloomberg School of Public Health Building|
Malaria remains one of the most important infectious diseases in the world. Our group is focused on understanding the fundamental biology of the pre-erythrocytic stages of malaria. This includes sporozoites and the liver stages into which they develop. Sporozoites are the infective form of the parasite and are injected into the skin of the mammalian host as infected mosquitoes probe for blood. Sporozoites make an impressive journey that begins in the midgut wall of the mosquito, passes through mosquito salivary glands and mammalian dermis and ends in the mammalian liver. We have found that the conformation of the sporozoite’s major surface protein is critical for the completion of this journey. As sporozoites migrate this protein is in a non-adhesive state; however upon reaching the liver, a regulated proteolytic cleavage event occurs that leads to the exposure of a cell-adhesion domain and the switch to an invasive state. We are now working to identify the protease and the signaling events responsible for this cleavage. In addition, we are using a variety of techniques including intravital imaging to better understand how sporozoites exit the skin to enter the blood circulation. The overall goals of our research are to: 1) elucidate the molecular interactions between the parasite and its mosquito and mammalian hosts that make infection possible; 2) understand the molecular events involved in hepatocyte invasion; 3) translate our findings to develop drugs and a vaccine that target this stage of the malaria parasite.
- Coppi A., Tewari R., Bishop J.R., Bennett B.L., Lawrence R., Esko J., Billker O. and Sinnis P. Heparan sulfate proteoglycans provide a signal to Plasmodium sporozoites to stop migrating and productively invade cells. Cell Host Microbe 2:316-327, 2007 PMID 18005753
- Coppi A., Natarajan R., Pradel G., Bennett B.L., James E.R., Roggero M.A., Corradin G., Persson C., Tewari R. and Sinnis P. The malaria circumsporozoite protein has two functional domains each with distinct roles as sporozoites journey from mosquito to mammalian host. J Exp Med 208:341-36, 2011.PMID 21262960
- Ejigiri I., Ragheb D.R.T., Pino P., Coppi A., Bennett B.L., Soldati-Favre D. and Sinnis P. Shedding of TRAP by a rhomboid protease from the malaria sporozoite surface is essential for gliding motility and sporozoite infectivity. PLoS Pathogens 8:e1002725, 2012. PMID 22911675
- Espinosa D.A., Gutierrez G.M., Rojas-López M., Noe A.R., Shi L., Tse S.W., Sinnis P., Zavala F. Proteolytic Cleavage of the Plasmodium falciparum Circumsporozoite Protein Is a Target of Protective Antibodies. J Infect Dis, In Press. PMID 25762791
- Hopp C.S., Chiou K., Ragheb D.R.T., Salman A., Khan S.M., Liu A.J., Sinnis P Longitudinal analysis of Plasmodium sporozoite motility in the dermis reveals component of blood vessel recognition. eLife, In Press. PMID 26271010