Invasion of red blood cells (RBCs) by malaria parasites

In this short Medmastery article, learn the mechanisms behind how malaria invades red blood cells.
Last update29th Apr 2021

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?

Selective targeting of RBC subtypes by malaria species

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.
Figure 1. The three types of red blood cells (RBCs) and the relative proportions of each type 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.

Figure 2. P. vivax, P. ovale, and P. knowlesi only invade young red blood cells called reticulocytes.

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.

Figure 3. P. malariae only invades old, or senescent, red blood cells.

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.

Figure 4. P. falciparum invades all red blood cells, regardless of their age.

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The mechanics and stages of RBC invasion by Plasmodium

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.

Figure 5. A merozoite can reorient itself via its apical complex to attach to a red blood cell membrane.

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.

Figure 6. Parasitic surface proteins P113 and RH5 attach to basigin receptors on red blood cell membranes to invade the red blood 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.

Figure 7. a) After a malaria parasite enters a red blood cell (RBC), b) it enters the activated feeding stage and forms a ring trophozoite, c–d) this trophozoite becomes more pigmented and changes shape until schizogony begins to occur, e) the parasite bursts out of the mature schizont at least 48 hours after it enters the RBC.

That’s it for now. If you want to improve your understanding of key concepts in medicine, and improve your clinical skills, make sure to register for a free trial account, which will give you access to free videos and downloads. We’ll help you make the right decisions for yourself and your patients.

Recommended reading

  • Ashley, EA, Phyo, AP, and Woodrow, CJ. 2018. Malaria. Lancet391:1608­–1621. PMID: 29631781
  • Fairhurst, RM and Wellems, TE. 2014. “Malaria (Plasmodium Species)”. In: Mandell, Douglas, and Bennett’s Principles and Practice of Infectious Diseases, edited by Bennett, JE, Dolin, R, Blaser, MJ. 8th edition. Philadelphia: Elsevier Saunders. (Fairhurst and Wellems 2014, 3070-3090)
  • Phillips, MA, Burrows, JN, Manyando, C, et al. 2017. Malaria. Nat Rev Dis Primers. 3: 17050. PMID: 28770814
  • World Health Organization. 2019. World malaria report 2019. World Health Organization

About the author

John F. Fisher, MD MACP FIDSA
John is a Professor of Medicine (Infectious Diseases) at the Medical College of Georgia, Augusta University, USA.
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