Studies by researchers at Stockholm University have shown how a microscopic parasite that is carried by a large portion of the global human population, can successfully spread in the body, and even reach the brain, potentially causing life-threatening encephalitis. The team’s research demonstrated how Toxoplasma gondii can infect macrophage immune cells and effectively hijack their identity, making them behave like dendritic cells (DCs). The scientists suggested that their findings could point to new strategies for the development of cell therapies.
Arne ten Hoeve, PhD, a researcher at Stockholm University’s Wenner-Gren Institute Department of Molecular Biosciences, said, “We have now discovered a protein that the parasite uses to reprogram the immune system.” The team reported the findings in Cell Host & Microbe, in a paper titled, “The Toxoplasma effector GRA28 promotes parasite dissemination by inducing dendritic-cell-like migratory properties in infected macrophages,” in which they noted, “The data demonstrate that infection with T. gondii allows normally sessile macrophages to acquire migratory features typically attributed to DCs.”
T. gondii is possibly the most common parasitic infection in humans globally, the authors suggested, citing an estimate indicating that “one-third of the global human population encounters T. gondii during a lifetime.” The majority of healthy infected people wouldn’t know they are carriers. In fact, the parasite also infects many animal species, including our pets. All felines, and not just domestic cats, play a central role in the life cycle of Toxoplasma, as the parasite can only sexually reproduce in the cat’s intestines. In other hosts, for example, humans, dogs, or birds, reproduction takes place by the parasite dividing.
Toxoplasma is spread through food and contact with cats. In nature, it spreads preferentially between cats and rodents. The parasites can remain dormant in the rodent’s brain, then when the cat eats the rodent, the parasite multiplies in the cat’s intestine and enters the environment via cat feces. Rodents eating vegetation or other matter on which there may be cat feces can then become infected. Humans become infected through meat consumption, or through contact with cat feces.
The Toxoplasma parasite can cause the disease toxoplasmosis. When a person is infected for the first time, mild symptoms occur that can resemble a cold or the flu. The parasite spreads widely throughout the body. “Following oral infection, T. gondii disseminates widely from the intestine to reach peripheral organs, such as the central nervous system,” the investigators wrote.
And after the first infection phase, the parasite transitions to a dormant, or sleeping stage in the brain and begins a chronic silent infection that can last for decades or for life. While this chronic infection usually causes no symptoms in healthy individuals, it can cause life-threatening brain infections in people with a weakened immune system—such as those with HIV, organ transplant recipients, or patients undergoing chemotherapy—and can be dangerous to the fetus during pregnancy. Eye infections can occur in otherwise healthy individuals.
In order to fight infections, the various roles of immune cells in the body are very strictly regulated. Scientists have long wondered how Toxoplasma manages to infect so many people and animal species and spread so efficiently. The authors noted that studies in mice have shown that dendritic cells can act as “Trojan horses” for T. gondii dissemination. “DCs can act as ‘Trojan horses’ for T. gondii dissemination in mice in a parasite genotype-related fashion.” So when DCs are invaded by the parasite, they are induced to migrate.
The newly reported study demonstrated that the parasite can make macrophages act like migratory dendritic cells. The results showed that T. gondii effectively injects an effector protein, GRA28, into the nucleus of parasitized macrophage immune cells, which impacts on the host cell gene transcription, effectively tricking it into acting as if it is a dendritic cell, and promoting migratory behavior, enabling the parasite to spread in the body. “Following oral infection, T. gondii encounters sessile macrophages in the intestine and other peripheral tissues,” they wrote. “ … upon T. gondii infection, macrophages initiate the expression of transcription factors normally attributed to DCs … infection led to transcriptional signatures consistent with the acquisition of DC-like migratory properties … Dissemination of T. gondii from the intestine is rapid, asymptomatic, and without generalized inflammation ….”
The study provides a molecular explanation for the phenomenon, and showed that the parasite is much more targeted in its spread than previously thought. “… we identified the parasite effector GRA28 as the mediator of upregulated CCR7 expression and chemotaxis in parasitized macrophages … the migratory responses of macrophages impacted parasite dissemination in mice.”
The work was led by Antonio Barragan, PhD, in collaboration with researchers from France and the United States. Barragan added, “It is astonishing that the parasite succeeds in hijacking the identity of the immune cells in such a clever way. We believe that the findings can explain why Toxoplasma spreads so efficiently in the body when it infects humans and animals.”
The authors concluded, “Our data highlight a mechanism by which T. gondii exploits the migratory plasticity of parasitized macrophages to potentiate its dissemination… The findings unveil putative alternative pathways by which mononuclear phagocytes can be made migratory or activated, which could—by extension—be exploited, for example, in cell therapies.”