Figure 4. How does the Plasmodium sporozoite leave the lumen of the liver sinusoid and invade a hepatocyte inside a PV?

It is still unclear whether Kupffer cells are embedded in the sinusoidal barrier (A) or sit on the top of endothelial cells (B). If (A) occurs, then traversal of Kupffer cells (either by transcytosis, i.e., involving sporozoite entry inside a PV followed by escape from the cell, or by disrupting the Kupffer cell membranes and migrating through the cell) would be sufficient for crossing the sinusoidal barrier. If (B) occurs, then the sporozoite may, after traversing Kupffer cells, cross the endothelial barrier either by a paracellular route (2) or by traversing endothelial cells (3). Once in the parenchyma, the sporozoite traverses several hepatocytes (4) before invading a final one inside a PV (5), the only niche where a sporozoite can fully develop (6). In two opposing views, the final invasion step is either activated by prior hepatocyte traversal or instead constitutively available and requires inhibition of cell traversal.