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Which method of transmigration sporozoites use in vivo to reach hepatocytes remains to be shown, but the less‐aggressive method of membrane invagination and fusion could be advantageous to the parasite because it is immunologically silent. The observation that sporozoites squeeze through a single constriction in the membrane of the transmigrated cell (Amino 2008) fits better with the membrane‐invagination and membrane‐fusion model than with the wounding model, considering that for the latter, one would predict two parasite‐constriction events, one upon entry and one upon exit.
Importantly, both proteases, DPAP3 and subtilisin, are expressed by late liver stage parasites, further supporting the idea of a functional proteolytic cascade that induces PVM rupture. Even more interesting is whether one of the proteases in this cascade is responsible for triggering host cell death that is induced upon PVM breakdown (Heussler 2010; Sturm 2006). This parasite‐ dependent host cell death is characterized by cytochrome c release from mitochondria and nuclear condensation but with retention of an intact cell membrane (Graewe 2011; Heussler 2010; Sturm 2006).
From there they have to find their way to the blood vessel (Frischknecht 2004). 1). The connection to the surface on which the sporozoites glide is made by secreted adhesion molecules like CSP (circumsporozoite protein) and TRAP (thrombospondin‐related anonymous protein). Because reaching a blood vessel occurs by chance rather than by chemotaxis, only a fraction of sporozoites finally arrive at their destination, whereas the majority do not leave the skin, or they enter lymph vessels and reach the draining lymph node, from where they are eventually removed (Amino 2006).