Understanding the mechanism of Toxoplasma gondii infection

Aqsa, Jamia Millia Islamia

Toxoplasma gondii is an obligate intracellular parasite that is responsible for causing toxoplasmosis. This protozoan infects humans and other animals as well. Data shows that up to 30% of the world’s population remains chronically infected with this protozoan, but a large number of them do not show any symptoms. Most of the infected people have no symptoms because their immune systems are strong and prevent the parasite from causing much harm. Toxoplasmosis infection can occur by eating uncooked or contaminated food, drinking water contaminated by Toxoplasma gondii, congenital transfusion, or by transfusion of infected blood.

Mechanism of invasion:

Toxoplasma gondii invades the host cells by invasion machinery into the host cell’s plasma membrane. It does not require a specific host receptor or protein to invade and enters the host cell while dragging the host membrane with it. As a result, the parasite becomes surrounded by the host membranes and produces a parasitophorous vacuole. Inside this vacuole, the parasite replicates asexually. It contains two secretory organelles, micronemes, and rhoptries.

The micronemes contain proteins required for invasion and extracellular motility, and the rhoptries contain proteins for invasion. The rhoptry proteins get released into the host cell at the time of the invasion. There is a third type of secretory organelle in Toxoplasma gondii, known as dense granules. These contain different proteins that get released into the host cell at the time of the invasion. The proteins secreted by the rhoptries and dense granules remain within the vacuole for establishing a tubular network that allows the parasite to access the host cell cytoplasm. After successful invasion into the host cell, it now uses the host’s machinery to its advantage by multiplying massively.

Recent insights into the mechanism of invasion:

Recent research has revealed that an essential protein, RON13 plays a crucial role in the process of invasion. It is the main protein that helps the parasite to invade the host cell.

RON13 is a 153 kDa (kilo-Dalton), transmembrane kinase protein with serine/threonine kinase domain and a large luminal carboxy-terminal extension (CTE). RON13 remains located in a compartment of the parasite, containing proteins that are injected into the host.

An experiment was carried out to prove the findings. A strain of the parasite that does not express the RON13 protein was made to infect mice. As a result, the parasite did not affect the mice, and no immune response was observed in the mice.

Another crucial thing about this protein is the presence of a large luminal carboxyl-terminal extension (CTE). CTE is composed of 550 amino acids that share no sequence homology with any other proteins. This sequence makes the RON13 protein insensitive to an inhibitor that is effective on the majority of kinases.

We can use it to our advantage by generating treatments that target only this specific protein kinase. As a result, human kinases are not affected, and the risk of side effects of the treatment can be eliminated. It also helps in generating treatments for the pathogens that use the same invasion pathway.

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Reference:

1. Lentini, G., Ben Chaabene, R., Vadas, O., Ramakrishnan, C., Mukherjee, B., Mehta, V., Lunghi, M., Grossmann, J., Maco, B., Visentin, R., Hehl, A. B., Korkhov, V. M., & Soldati-Favre, D. (2021). Structural insights into an atypical secretory pathway kinase crucial for Toxoplasma gondii invasion. Nature Communications, 12(1), 3788. https://doi.org/10.1038/s41467-021-24083-y

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