How Immune Cells Use Caspase-8 to Fight a Brain Parasite

A parasite that may already live in your brain can infect the same immune cells meant to destroy it, but new research published in Science Advances has uncovered how the body defends itself. The parasite, Toxoplasma gondii, infects warm-blooded animals and is usually transmitted to humans through cats, contaminated produce, or undercooked meat. Once inside, the parasite spreads throughout the body and establishes a lasting presence in the brain. It is estimated that about one-third of the world’s population carries it, yet most people experience no symptoms. The illness it can cause, toxoplasmosis, primarily affects those with weakened immune systems.

A team led by Tajie Harris at the University of Virginia School of Medicine, examined how CD8+ T cells—the immune system’s key defenders—respond to T. gondii when the parasite invades them. “We know that T cells are really important for combatting Toxoplasma gondii, and we thought we knew all the reasons why,” said Harris. “T cells can destroy infected cells or cue other cells to destroy the parasite. We found that these very T cells can get infected, and, if they do, they can opt to die. Toxoplasma parasites need to live inside cells, so the host cell dying is game over for the parasite.”

Harris and her collaborators found that this defense depends on an enzyme called caspase-8, which regulates immune activity and controls when cells self-destruct. In experiments using mice, animals lacking caspase-8 in their T cells developed far higher levels of T. gondii in their brains compared with those that retained the enzyme, even though both groups mounted immune responses. Mice with caspase-8 stayed healthy, while those without it became ill and died. Examination of their brain tissue revealed that the CD8+ T cells of the sick mice were more heavily infected.

These findings show that caspase-8 is critical for controlling T. gondii inside T cells and may be central to how the body prevents the parasite from overwhelming the brain. “We scoured the scientific literature to find examples of pathogens infecting T cells. We found very few examples,” Harris said. “Now, we think we know why. Caspase-8 leads to T cell death. The only pathogens that can live in CD8+ T cells have developed ways to mess with Caspase-8 function. Prior to our study, we had no idea that Caspase-8 was so important for protecting the brain from Toxoplasma.”