**23. Host cell invasion**

Malaria parasites are members of the Apicomplexa. Apicomplexa are characterized by a set of organelles found in some stage of the parasite's life cycle. These organelles, collectively known as apical organelles because of their localization at one end of the parasite, are involved in interactions between the parasite and host. In particular, the apical organelles have been implicated in the process of host celll invasion. In the case of *Plasmodium,* three distinct invasive forms have been identified: sporozoite, merozoite, and ookinete (see *Plasmodium* Life Cycle). The following discussion focuses on the cellular biology of merozoites and erythrocyte invasion. Reference to other Apicomplexa and *Plasmodium* sporozoites will be made to illustrate common features.

Merozoites rapidly (approximately 20sec.) and specifically enter erythrocytes. This specificity is manifested both for erythrocytes as the preferred host cell type and for a particular host species, thus implying receptor – ligand interactions. Erythrocyte invasion is a complicated process which is only partially understood at the molecular and cellular levels.[53] Four distinct steps in the invasion process can be recognized:


Biology of Malaria Parasites 25

The contents of the apical organelles are expelled as the parasite invades, thus suggesting that these organelles play some role in invasion. Experiments in *Toxoplasma gondii* indicate that the micronemes are expelled first and occur with initial contact between the parasite and host.[59] An increase in the cytoplasmic concentration of calcium is associated with

Dense granule contents are released after the parasite has completed its entry, and therefore, are usually implicated in the modification of the host cell. For RESA is localized to dense granules in merozoites and is transported to the host erythrocyte membrane shortly after merozoite invasion.[61] However, subtilisin-like proteases, which are implicated in the secondary proteolytic processing of MSP-I (discussed above), have also been localized to *Plasmodium* dense granules.[62,63] If MSP-I processing is catalyzed by these proteases, then at

Following merozoite reorientation and microneme discharge a junction forms between the parasite and host cell. Presumably, microneme proteins are important for junction

• SSP2, *Plasmodium* sporozoite surface protein-2. Also known as TRAP (thrombospondin-

• Proteins with homology to SSP2/TRAP from *Toxoplasma* (MIC2), *Eimeria* (Etp100), and

• CTRP, circumsporozoite- and TRAP- related protein of *Plasmodium* found in the

Of particular note are EBA-175 and DBP which recognize sialic acid residues of the glycohorins and the Duffy antigen, respectively. In other words, these parasite protein are probably involved in receptor-ligand interaction with proteins exposed on the erythrocyte surface. Disruption of the EBA-175 gene results in the parasite switchingfrom a sialic aciddependentpathway to a sialic acid-independent pathway [64], indicating that there is some

Comparison of sequences of EBA-175 and DBP reveal conserved structural features. These include trans-membrane domains and receptor-binding domains.[65] The receptor-binding activity has been mapped to a domain in which the cysteine and aromatic amino acid residues are conserved between species. This putative binding domain is duplicated in EBA-175. The topography of the trans-membrane domain is consistent with the parasite ligands being integral membrane proteins with the receptor-binding domain exposed on the

The other microneme protein in the 'TRAP' family have also been implicated in locomotion and / or cell invasion.[66] All of these proteins have domains that are presumably involved in cell-cell adhesion, as N-terminal single sequences and trans-membrane domains at their

microneme discharge.[60] as is typical of regulated secretion in other eukaryotes.

least some dense granules must be discharged at the time of invasion.

**26. Specific interactions and junction formation** 

formation. Proteins localized to the micromenes include:

related adhesive protein).

*Cryptosporidium*

ookinete stage.

C- terminal.

• EBA-175, a 175 kDa 'erythrocyte binding antigen *P. falciparum* • DBP, Duffy-binding protein from *P. vivax* and *P. knowlesi*

redundancy with regards to the receptor – ligand interactions.

merozoite surface following microneme discharge.
