Hepatic Kupffer cells: The portal that permits infection of hepatocytes bymalarial sporozoites?

Malaria sporozoites ha ve to cross the layer of sinusoidal liver cells to r each their initial site of multiplication in the mammalian host, the hepato cytes. To determine the sinusoidal cell type sporozoites use for extravasat ion, endothelia or Kupffer cells, we quantified sporozoite adhesion to and invasion of sinusoidal cells isolated from rat liver. In vitro invasion ass ays reveal that Plasmodium berghei and P. yoelii sporozoites attach to and enter Kupffer cells, but not sinusoidal endothelia. Unlike hepatocytes and other nonphagocytic cells, which are invaded in vitro only within the first hour of parasite exposure, the number of intracellular sporozoites in Kupf fer cells increases for up to 12 hours. By confocal and electron microscopy , sporozoites are enclosed in a vacuole that does not colocalize with lysos omal markers. Inhibition of phagocytosis with gadolinium chloride has no ef fect on Kupffer cell invasion, but abolishes phagocytosis of inactivated sp orozoites. Furthermore, sporozoites traverse in vitro from Kupffer cells to hepatocytes where they eventually develop into exoerythrocytic schizonts. Thus, malaria sporozoites selectively recognize and actively invade Kupffer cells, avoid phagosomal acidification, and safely passage through these ph agocytes.