Sinnis Laboratory

Structure-function studies of the circumsporozoite protein (CSP)

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.

The role of parasite proteases in the establishment of malaria infection.

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.