Malaria infection starts when the sporozoite stage of the Plasmodium parasite is injected into the skin by a mosquito. Sporozoites are known to traverse host cells before finally invading a hepatocyte and multiplying into erythrocyte-infecting forms. Without infection of the liver, the parasites cannot multiply or spread to the blood. Infection of the blood causes illness, spread of the disease, and, ultimately, death. However, it remains unclear just how sporozoites reach hepatocytes in the liver and facilitates productive infection. Now, a study from researchers at the Center for Infectious Disease Research has identified the cellular mechanisms involved in the malaria parasite invading its initial target organ, the liver. The team state that their findings will facilitate the design of new drugs and new vaccines. The study is published in the journal Science.
Previous studies show that the malaria-causing Plasmodium parasite is transmitted during the bite of an infected mosquito. The parasite, a highly motile cell called sporozoite at this stage, is inoculated into the skin of the host, invades dermal blood vessels to reach the bloodstream, and arrests in the liver. The sporozoite then invades a hepatocyte inside a vacuole, where a single sporozoite transforms into thousands of the erythrocyte-infecting merozoite forms of the parasite. Merozoites released into the blood then invade erythrocytes, initiating the symptomatic phase of the disease of iterative parasite multiplication cycles in erythrocytes. It is known that Plasmodium sporozoites can traverse host cells, i.e., breach the cell plasma membrane, glide through the cytosol, and exit the host cell. This cell traversal (CT) behaviour was first observed with peritoneal macrophages and later with various other cell types, including hepatocytes, with several mechanisms of hepatocyte traversal being reported. Recent studies show that sporozoites can cross the liver sinusoidal barrier targeting Kupffer cells (KC) or endothelial cells and associated or not with the parasite CT activity. It has been shown that the primary role of CT is to inhibit sporozoite clearance by KC during locomotion inside the sinusoid lumen, before crossing the barrier. By being involved in multiple steps of the sporozoite journey from the skin to the final hepatocyte, the parasite proteins mediating host CT have emerged as ideal antibody targets for vaccination against the parasite.
The current study shows that the hepatocyte EphA2 receptor is critical for establishing a permissive intracellular replication compartment, the parasitophorous vacuole. Results show that sporozoites productively infected hepatocytes with high EphA2 expression, and the deletion of EphA2 protected mice from liver infection. Data findings show that lack of host EphA2 phenocopied the lack of the sporozoite proteins P52 and P36. The lab state that this suggests that P36 engages EphA2, which is likely to be a key step in establishing the permissive replication compartment.
The team team surmise that this discovery is significant because it reveals a vital interaction between the malaria parasite and the person it infects. For the future, the researchers state that the findings on the liver receptor EphA2 for malaria parasite sporozoite invasion of liver cells is a critically important advance and allows the global research community to devise new strategies to block parasite infection.
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