Invasion of red blood cells (RBCs) by malaria parasites

We now know that once small malarial parasite cells, or merozoites, enter the bloodstream of a patient, they are able to enter red blood cells (RBCs). But how does RBC invasion take place?

First, we need to identify which RBCs will be targeted. In the eyes of some malaria parasites, not all red blood cells are created equal. As it turns out, different species of Plasmodium are able to invade red cells at different stages of development.

Let’s take a minute to look at the various types of RBCs found in a blood smear:

1. Large, young red blood cells, or reticulocytes, which comprise 1–2% of cells in a blood smear.
2. Regular-sized, mature red blood cells, comprising 96–98% of cells in a blood smear.
3. Smaller, osmotically unstable, senescent red blood cells, comprising 1–2% of cells in a blood smear.

P. vivax, P. ovale, and P. knowlesi have receptors only for reticulocytes. Given what we know about the proportion of reticulocytes in the blood stream, only a small percentage of cells will be infected by these strains, and the patient will not have high levels of parasites in their blood. This is called low-grade parasitemia.

In contrast, P. malariae only invades senescent RBCs. But, these small cells are again less abundant, so the patient will still have low-grade parasitemia.

Now, P. falciparum just doesn't care. It will infect any red blood cell it encounters, regardless of age. You can expect high-grade parasitemia with falciparum malaria, which is why it is so deadly.

Regulation of parasite orientation using the apical complex

Regardless of cell type, merozoites use the same mechanism to invade red blood cells. The malaria parasite has a unique shape—an apical complex at one end of the cell. Once a merozoite bumps into an age-appropriate RBC, it uses this apical complex to reorient itself to enable binding to and entry into the cell.

Binding of malaria merozoite and entry into RBCs

Now that it’s pointed in the right direction, the parasite creates a protein complex on its surface that attaches to specialized receptors on the RBC membrane. Specifically, this complex is made of a protein, P113, on the surface of the merozoite, and a protein, RH5, that is created by the merozoite which binds to basigin, a receptor on the RBC membrane. Together, they allow the organism to stick to the red blood cell and the invasion begins. The junction between the RBC and the parasitic cell moves upward, allowing the parasite to move further through the membrane until it enters the red cell.

Stages of Plasmodium development inside RBCs

In the first five minutes of invasion, we see a tiny bit of cytoplasm and a dot of nucleus entering the cell. This will be difficult for anyone but a malariologist to recognize.

What we can begin to recognize are ring forms—known as ring trophozoites—which are a further development of the malarial parasite into the activated, feeding stage. Ring trophozoites look like a tiny signet ring. They continue to grow and at 24 to 36 hours after invasion, they take on more of an amorphous shape with a pigmented center. This pigmentation is hemozoin. It is formed when the parasite breaks down hemoglobin into heme and then hematin. Both heme and hematin are lethal to the parasite, so they are quickly converted by heme polymerase into a non-toxic form—hemozoin.

By 36 to 48 hours after invasion, more hemozoin will appear, which is used by the parasite to build essential amino acids for replication. Now, active schizogony will begin to take place. At this point, the cell is called a schizont. And remember, as the schizont matures, the RBC will eventually burst, which coincides with the fever and chills seen clinically in malaria cases.

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