Hepatocyte growth factor and its receptor are required for malaria infection

Abstract

Plasmodium, the causative agent of malaria, must first infect hepatocytes to initiate a mammalian infection. Sporozoites migrate through several hepatocytes, by breaching their plasma membranes, before infection is finally established in one of them. Here we show that wounding of hepatocytes by sporozoite migration induces the secretion of hepatocyte growth factor (HGF), which renders hepatocytes susceptible to infection. Infection depends on activation of the HGF receptor, MET, by secreted HGF. The malaria parasite exploits MET not as a primary binding site, but as a mediator of signals that make the host cell susceptible to infection. HGF/MET signaling induces rearrangements of the host-cell actin cytoskeleton that are required for the early development of the parasites within hepatocytes. Our findings identify HGF and MET as potential targets for new approaches to malaria prevention.

Illuminating the host – How RNAi screens shed light on host‐pathogen interactions

“…This three-step screen employed increasingly stringent selection criteria, and resulted in a list of five "hits" whose influence on infection was consistently observed. One of the genes identified, MET, is, in fact, the first host signaling molecule to have previously been implicated in Plasmodium liver infection [24,25]. One other protein identified in this screen, the atypical PKCζ, was shown by the authors to influence the early stages of Plasmodium infection of hepatocytes, once again lending support to the RNAi-based strategy employed to assess the role of an informed selection of genes on malaria liver infection [20].…”

A long and winding road: The Plasmodium sporozoite's journey in the mammalian host

“…Another possibility is that continued cell traversal activity further activates the sporozoite for invasion [32]. This continued migration in the liver also leads to the release of hepatocyte growth factor from wounded hepatocytes, making the surrounding hepatocytes more resistant to apoptosis and therefore better host cells for sporozoite development [34].…”

Molecular and functional aspects of parasite invasion

“…Entry into hepatocytes might occur either by disruption of the plasma membrane and parasite migration through cells, or by vacuole formation followed by parasite division [18]. Recent data suggest that migration through cells has an effect on both sporozoite infectivity (by inducing the exocytosis of sporozoite apical organelles) [19], and on the permissiveness of the surrounding hepatocytes through the secretion of hepatocyte growth factor (HGF), which increases their susceptibility to infection [20]. The recent discovery of a sporozoite microneme protein essential for cell traversal (SPECT) sheds new light on migration into the liver.…”