The Sinnis Laboratory is part of the Johns Hopkins Malaria Research Institute, committed to the pursuit of basic science research that translates into solutions targeting one of the most important infectious diseases in the world. Malaria, caused by protozoan parasites of the genus Plasmodium, is transmitted to humans by infected Anopheles mosquitoes. The evolution of drug resistance by the parasite, and insecticide resistance by the mosquito, have created an urgent need for new strategies to control and ultimately eradicate this scourge.
We focus on the transmission of sporozoites from mosquito to mammalian host and how these parasites overcome physical and immunological obstacles to establishing infection. Sporozoites, the infective stage of the malaria parasite, make an impressive journey from the midgut wall of the mosquito where they emerge from oocysts, to their final destination in the mammalian liver (see picture below). Using biochemical, cell biological and genetic approaches, as well as intravital imaging, we aim to understand the molecular interactions between sporozoites and their mosquito and mammalian hosts that enable the parasite to initiate infection.
Mosquitoes inoculate sporozoites into the dermis of the mammalian host as they probe for blood. Once inoculated, sporozoites actively move through the dermis to fine a blood vessel, which they penetrate to enter the circulation and go to the liver. Using a rodent malaria model we have determined the sporozoite inoculum (Medica & Sinnis 2005), the kinetics with which sporozoites exit the dermis (Yamauchi et al. 2007), and the probability of infection after a single infectious bite (Aleshnick et al., unpublished data). Our work suggests that this is a significant bottleneck for the parasite. Recently we have been imaging sporozoites in the skin, observing their movement and interactions with blood vessels (Hopp et al. 2015). Current work focuses on the host innate and adaptive immune response to sporozoites at the inoculation site and understanding the mechanism(s) by which sporozoites recognize and penetrate blood vessels.
CSP, is the major surface protein of the sporozoite, forming a dense coat on the surface of the parasite. CSP is also the basis of RTS,S, the only malaria vaccine candidate to show efficacy in Phase III clinical trials. Despite its importance, our understanding of CSP structure and function is limited and we believe that elucidating how this protein functions will inform future malaria vaccine design.
Our previous studies demonstrate that CSP has two conformational states, an adhesive conformation in which the TSR domain is exposed and a nonadhesive conformation in which the N-terminus masks this domain. As sporozoites travel from mosquito midgut to mammalian liver, the cell-adhesion domain is masked, maintaining sporozoites in a migratory state (Coppi et al., 2011). Upon arrival in the liver, the N-terminal domain is proteolytically cleaved and the cell-adhesion domain is exposed (Coppi et al., 2005; Coppi et al., 2011). Processing is triggered by the highly sulfated heparan sulfate proteoglycans of the liver, which serves as a signal for the sporozoite to switch from a migratory to an invasive state (Coppi et al 2007). We are currently focused on determining the structure of the N-terminus of CSP, the function of the central repeat region and the identity of the parasite protease that cleaves CSP.
Our work on CSP and another sporozoite adhesin, TRAP (Ejigiri et al 2012), demonstrates the vital role that parasite proteases play in sporozoite motility and infectivity. We are actively working to identify the CSP protease and have expanded our work to dissect the function of other Plasmodium serine and cysteine proteases expressed by pre-erythrocytic stages. Ultimately the goal of this work is to screen inhibitors of critical proteases and validate them as drug targets.
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Graduate Student (PhD),
Research Tech (ScM Graduate),
Graduate Student (ScM),
New York City, NY
National Institutes of Health
Staff Scientist, Naval Medical Research Center
Retired; Relaxing & spending time with family in China
Visiting Fellow, National Institutes of Health
Senior Scientist, CSIR-Central Drug Research Institute, Lucknow, India
Director of Program Management, Regeneron Pharmaceuticals
Graduate student, Columbia University
Senior Staff Scientist, Regeneron Pharmaceuticals
Resident in Internal Medicine, Emory University School of Medicine
Assistant Professor, Pediatric Infectious Diseases, University of Mississippi Medical Center
Penn State University
Associate Professor, Biological Sciences Department, City University of New York
Professor, Universidade Estadual de Londrina, Parana, Brasil
Professor, Department of Biology, Pennsylvania State University
Program Officer, National Institutes of Health
Scientist, AstraZenica Pharmaceuticals
June 2017: Photini was elected as a Fellow of the American Society of Microbiology
Summer 2017: Photini is co-directing the Biology of Parasitism Course at the Marine Biological Laboratory in Woods Hole, Massachusetts
May 2017: Congratulations to our Graduates! Gibbs Nasir, Natasha Vartak, and Enoch Chan received their Master of Science degrees
April 2017: Sinnis lab research featured in a video about the Johns Hopkins Malaria Research Institute Click Here to Watch!
January 2017: Melanie Shears received a Johns Hopkins University Provost's Postdoctoral Fellowship and was recognized at the Annual Honors and Awards Ceremony. Congratulations Melanie!
October 2016: Gibbs Nasir and Melanie Shears both received Best Poster Awards at the 2016 Molecular Parasitology Meeting in Woods Hole
Good times from years past...
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Johns Hopkins Malaria Research Institute
Dept. Molecular Microbiology & Immunology PhD Program
Dept. Biochemistry & Molecular Biology PhD Program
Cellular & Molecular Medicine PhD Program
Malaria Institute Insectary Core Facility
Malaria Institute Parasite Core Facility
PlasmoDB: The Plasmodium Genome Resource
MVI PATH Malaria Vaccine Initiative
Internal MMI Portal
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