[Show abstract][Hide abstract] ABSTRACT:
Malaria is transmitted through the bite of an infected mosquito that deposits Plasmodium sporozoites under the skin. These sporozoites migrate from the skin into the circulation and then enter the liver to start a new infection inside hepatocytes. Sporozoites have the capacity to traverse mammalian cells. They breach their membranes and migrate through their cytosol. This process is required for infection of the liver and triggers the exposure of adhesive proteins in the apical end of sporozoites, a process that facilitates invasion of hepatocytes. We found that elevations of cAMP inside sporozoites mediate the exposure of adhesive proteins and therefore the infection process. Mutant sporozoites that do not express adenylyl cyclase, the enzyme that synthesizes cAMP, are not able to expose the adhesive proteins and their infectivity is reduced by half. Reinsertion of adenylyl cyclase gene in the mutant sporozoites recovers their capacity to expose adhesive proteins and to infect hepatocytes, confirming the specific role of this protein in infection. These results demonstrate the importance of cAMP and the exposure of adhesive proteins in sporozoites, but also show that Plasmodium sporozoites have other mechanisms to invade host hepatocytes that are not inhibited in the mutant parasites.