Investigation of liver infection mechanisms of malaria parasites

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Malarial sporozoites, the liver-invasive forms, are injected into the skin by a mosquito bite. We found that cell traversal is important for sporozoites migrate to the circulation through the host dermis. This ability prevents sporozoite destruction by phagocytes and arrest by nonphagocytic cells in the host dermis. Then they are effectively targeted to hepatocytes and proliferate in them. So far, however, sporozoite molecules that mediate the specific infection of the liver remain unknown. We found that two proteins, Pbs36p and Pbs36, belonging to the plasmodium 6-cys domain protein family, and another novel protein, designated Pbs41, carry out this function. These molecules are specifically produced in liver-infective sporozoites. Target disruption of the respective genes nearly abolished sporozoite infectivity in the mammalian host. Invasion assays revealed that the mutant parasites could not commit to infection, even when they encounter with hepatocytes, resulting in continuous traversal of hepatocytes. These results suggest that these proteins are necessary for sporozoites to recognize hepatocytes and commit to infection. This finding might lead to novel anti-malarial strategies that prevent sporozoite infection of the hepatocyte.