Plasmodium falciparum's Liver Stage Proteins: A Key to Malaria Control?

Shining a Spotlight on the Plasmodium falciparum Parasite

The parasite is grouped as an eukaryote - which is to say that it has a nucleus. It's in the Phylum Apicomplexa which includes parasites such as Toxoplasma and Theileria. Three organelles on the invasive (apical) end of these parasites (rhoptries, micronemes, and dense granules) define the phylum Apicomplexa. These apicomplexan parasites are obligate intracellular parasites. This means that throughout their life cycle, they must invade host cells in order to complete development. They cause diseases such as malaria (genus Plasmodium), toxoplasmosis (Toxoplasma gondii) and cryptosporidiosis (Cryptosporidium spp). While there are hundreds of plasmodium species, only five are known to cause malaria. Of these five, Plasmodium falciparum causes the deadliest form of malaria. 

P. falciparum has two hosts: humans and mosquitoes. The mosquito is considered the definitive host, because that's where sexual reproduction happens.

Proteins Involved in Plasmodium falciparum Infection and Development

Plasmodium falciparum has stage-specific proteins that facilitate its infection, survival, and transmission across different host environments. Below is a walkthrough of key proteins used by the parasite in the asymptomatic liver stage infection.

Liver Stage (Hepatic Stage) – Infection of Human Hepatocytes

If a mosquito is infected with a malaria-causing parasite such as Plasmodium falciparum, the infectious form of the parasite is in the mosquito’s salivary gland. If such a mosquito bites a human, a sporozoite is injected into the skin of the human. 

The mosquito bites the human because it's looking for a blood meal. So, in order to stop the blood from clotting as it sucks the blood, it injects its saliva. The saliva of the mosquito (if infected) is teeming with sporozoites and these sporozoites find their way from the skin, into the bloodstream. 

Within a few minutes of entering the bloodstream, the sporozoite  quickly makes its way to the liver. Once in the liver, they traverse multiple cell types such as Kupffer Cells and Hepatic Stellate Cells, to invade hepatocytes and form liver-stage schizonts. Schizonts subsequently rupture, releasing thousands of merozoites into the bloodstream.

Here’re the key proteins that facilitate the migration of the sporozoite form from mosquito salivary glands, into human liver cells (hepatocytes).

Protein	Function
CSP (Circumsporozoite Protein)	Major surface protein of P. falciparum sporozoites. Helps sporozoites migrate (motility) from mosquito saliva to liver hepatocytes.  Essential for binding to hepatocytes via interactions with heparan sulfate proteoglycans.  A target for malaria vaccines such as RTS,S. Forms a protective coat.
TRAP (Thrombospondin-Related Anonymous Protein)	A micronemal protein crucial for sporozoite gliding motility and host cell (hepatocyte) invasion.  Contains adhesive domains that mediate interactions with host cell receptors.  Required for sporozoite migration through tissues and hepatocyte invasion.
MAEBL (Merozoite Adhesive Erythrocytic Binding-Like Protein)	Expressed in both sporozoites and merozoites. Plays a role in sporozoite invasion of mosquito salivary glands. Assists sporozoite adhesion to hepatocytes. Essential for erythrocyte invasion during the blood stage.
Micronemal P52/P36 Complex	Essential for ookinete-to-oocyst transition in the mosquito midgut. Required for successful sporozoite development within oocysts. Plays a role in gametocyte development and transmission.
EXP1 (Exported Protein 1)	A parasitophorous vacuole membrane (PVM) protein. Involved in protecting developing parasites inside hepatocytes. Functions as a glutathione-S-transferase, protecting the parasite from oxidative stress. Involved in nutrient transport between the parasite and host cell.
UIS3 (Upregulated in Infectious Sporozoites 3)	Interacts with host liver cell lipid droplets to facilitate parasite survival. Critical for survival inside hepatocytes by modifying host cell membranes. Modulates host immune responses to evade detection.
UIS4 (Upregulated in Infectious Sporozoites 4	Localizes to the PVM in liver-stage parasites. Helps remodel the PVM to protect the developing parasite. Facilitates nutrient uptake and communication between the parasite and host cell.
LISP1 (Liver-Specific Protein 1)	Critical for the transition from liver-stage schizonts to merozoites. Important for parasite exit from the hepatocyte (merozoite egress). Plays a role in host cell rupture and merozoite release into the bloodstream. Essential for successful blood-stage infection.
LSA-1 (Liver-stage specific antigen 1)	Highly expressed in liver-stage parasites. Likely involved in host immune evasion and intracellular survival. A potential target for pre-erythrocytic stage malaria vaccines.

When merozoites are released into the bloodstream they have approximately thirty seconds to find their way into red blood cells (erythrocytes) and invade. Failure to do so would result in the host's immune system recognising merozoites as foreign invaders. Antibodies and other immune cells would target and attempt to eliminate them rapidly.

Hence, merozoites, like sporozoites, utilise various proteins to mediate invasion of host erythrocytes via specific receptor/ligand interactions. We will look at the specific proteins in the next blog post.

Bibliography

1. Sanchez, G. I., Rogers, W., Mellouk, S., & Hoffman, S. (1994). Plasmodium falciparum: exported protein-1, a blood stage antigen, is expressed in liver stage parasites. Experimental Parasitology, 79(1), 59-62.
   
   

2. Vaughan, A., Mikolajczak, S., Wilson, E. M., Grompe, M., Kaushansky, A., Camargo, N. M., Bial, J., Ploss, A., & Kappe, S. (2012). Complete Plasmodium falciparum liver-stage development in liver-chimeric mice. The Journal of Clinical Investigation, 122(10), 3618-3628.
   
   

3. March, S., Ng, S., Velmurugan, S., Galstian, A., Shan, J., Logan, D. J., Carpenter, A. E., Thomas, D., Sim, B., Mota, M., Hoffman, S., & Bhatia, S. (2013). A microscale human liver platform that supports the hepatic stages of Plasmodium falciparum and vivax. Cell Host & Microbe, 14(1), 104-115. 

4. Mikolajczak, S., Sacci, J. B. Jr., de la Vega, P., Camargo, N. M., Vanbuskirk, K., Krzych, U., Cao, J., Jacobs-Lorena, M., Cowman, A., & Kappe, S. (2011). Disruption of the Plasmodium falciparum liver‐stage antigen‐1 locus causes a differentiation defect in late liver‐stage parasites. Cellular Microbiology, 13. 

 

February 20, 2025 Tags : globalhealth , health , infection , liverstage , malaria , parasite , plasmodiumfalciparum , proteins , research , science

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