Mechanisms of Plasmodium Sporozoite Host Cell Invasion

Plasmodium sporozoites, the motile forms injected into the skin by infected Anopheles mosquitoes, undertake a complex journey to hepatocytes in the liver. Initial dermal migration relies on gliding motility powered by an actomyosin motor complex known as the glideosome. Secretion of adhesive proteins from apical organelles—micronemes and rhoptries—mediates substrate attachment and host cell engagement. Key adhesins such as TRAP and AMA-1 are translocated rearwards through the parasite membrane, generating traction for forward movement. Proteolytic cleavage of these adhesins by rhomboid and other serine proteases is essential to disengage attachments and sustain continuous motility. In the dermis, sporozoites adopt alternating modes of migration: rapid, superdiffusive exploration to locate blood vessels, followed by slower, confined probing near pericyte-associated intravasation hotspots. Entry into the bloodstream (intravasation) is facilitated by transient wounding of endothelial barriers and exploitation of Kupffer cells in the liver sinusoid. Upon arrival in the hepatic sinusoid, sporozoites traverse several hepatocytes through sequential cell traversal activities before establishing a productive parasitophorous vacuole in a final host cell. Intricate control of gene expression, including temporally regulated translational repression during sporozoite maturation, ensures stage-specific deployment of invasion factors. Together, these coordinated events underlie the efficiency of host cell invasion and represent potential targets for transmission-blocking interventions.

Research from Nature Portfolio

Recent studies have elucidated how sporozoites optimise their search for blood vessels in the dermis by alternating between high-velocity, superdiffusive Lévy-like migration and low-motility probing near pericytes. This dynamic switching enhances the likelihood of encountering permissive entry sites without excessive energy expenditure. Concurrently, investigations into Plasmodium falciparum formin proteins have revealed distinct roles for FRM1 and FRM2 in host cell invasion and cytoskeletal regulation. FRM1 is indispensable for effective invasion of hepatocytes, while FRM2 orchestrates actin and microtubule dynamics during sporozoite development. Chemical inhibition of formin homology domains disrupts sporozoite motility and invasion, highlighting actin nucleation as a viable antimalarial strategy.

Mechanisms of Plasmodium Sporozoite Host Cell Invasion publication trend

The graph below shows the total number of articles in mechanisms of plasmodium sporozoite host cell invasion across all publications each year (not limited to Nature Index journals).

Technical terms

Sporozoite: The motile, infective stage of Plasmodium transmitted by mosquitoes and responsible for initiating liver infection.

Microneme: Apical secretory organelle containing proteins required for adhesion and host cell engagement.

Glideosome: Actomyosin motor complex that powers substrate-dependent gliding motility in apicomplexan parasites.

Rhomboid protease: Intramembrane serine protease that cleaves transmembrane adhesins to enable parasite movement.

Cell traversal: Process by which sporozoites wound through host cells to reach permissive hepatocytes.

Intravasation: Entry of sporozoites into blood vessels, often facilitated by interactions with pericytes and endothelial cells.

References

1. Plasmodium sporozoite search strategy to locate hotspots of blood vessel invasion. Nature Communications (2023).
2. Plasmodium falciparum formins are essential for invasion and sexual stage development. Communications Biology (2023).
3. The claudin-like apicomplexan microneme protein is required for gliding motility and infectivity of Plasmodium sporozoites. PLOS Pathogens (2023).
4. Transcriptomics and proteomics reveal two waves of translational repression during the maturation of malaria parasite sporozoites. Nature Communications (2019).
5. Shedding of TRAP by a Rhomboid Protease from the Malaria Sporozoite Surface Is Essential for Gliding Motility and Sporozoite Infectivity. PLOS Pathogens (2012).
6. Cell-Passage Activity Is Required for the Malarial Parasite to Cross the Liver Sinusoidal Cell Layer. PLOS Biology (2004).