A common parasite, often residing undetected in the brains of roughly one in three people worldwide, can infect the very immune cells tasked with eliminating it. However, new research from the University of Virginia (UVA) Health reveals a crucial defense mechanism the body employs to keep this infection in check.
Toxoplasma gondii, an opportunistic parasite, infects warm-blooded animals and is typically transmitted to humans through contact with cats – often via litter boxes – consumption of contaminated fruits or vegetables, or eating undercooked meat. Once inside the body, the parasite can travel to various organs, ultimately establishing a long-term presence within the brain. Remarkably, most infected individuals experience no noticeable symptoms, highlighting the body’s inherent ability to manage this persistent infection. However, toxoplasmosis can pose a serious health risk to those with weakened immune systems.
Researchers, led by Tajie Harris, PhD, director of the Center for Brain Immunology and Glia (BIG Center) at UVA, investigated how the immune system responds when Toxoplasma gondii infiltrates CD8+ T cells – specialized immune cells critical for eliminating infected cells. Their findings, published in the journal Science Advances, reveal a surprising self-destruct mechanism within these very immune cells that ultimately limits the parasite’s spread.
“We know that T cells are really important for combatting Toxoplasma gondii, and we thought we knew all the reasons why. T cells can destroy infected cells or cue other cells to destroy the parasite,” explained Harris. “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.”
Caspase-8: The Immune System’s “Kill Switch”
The research team discovered that CD8+ T cells rely on an enzyme called caspase-8 to control T. Gondii. Caspase-8 plays a central role in regulating immune responses and can trigger programmed cell death, also known as apoptosis.
In laboratory experiments involving mice, those lacking caspase-8 in their T cells developed significantly higher levels of T. Gondii in their brains compared to mice with functional caspase-8. This occurred despite both groups mounting comparable immune responses against the infection. The difference in outcomes was stark: mice with caspase-8 remained healthy, while those without it became severely ill and ultimately succumbed to the infection. Examination of brain tissue revealed that the CD8+ T cells of mice lacking caspase-8 were much more susceptible to infection by the parasite.
These findings indicate that caspase-8 plays a crucial role in limiting T. Gondii infection within T cells. The results also contribute to growing evidence suggesting that this enzyme is broadly important in helping the body control various infectious threats.
“We scoured the scientific literature to find examples of pathogens infecting T cells. We found very few examples,” said Harris, who is also part of UVA’s Department of Neuroscience. “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 interfere with Caspase-8 function. Prior to our study, we had no idea that Caspase-8 was so important for protecting the brain from Toxoplasma.”
Implications for Immunocompromised Individuals
Understanding how the immune system fights Toxoplasma is particularly important for individuals with compromised immune systems, who are more vulnerable to severe illness from toxoplasmosis. The research provides a better understanding of why these individuals are at risk and how potential therapies might be developed to help them fight the infection.
While the vast majority of people infected with Toxoplasma gondii remain asymptomatic, the parasite can cause serious complications in those with weakened immunity. This research offers a new avenue for exploring strategies to bolster the immune response and protect vulnerable populations.
The study, published on , was conducted by a team including Lydia A. Sibley, Maureen N. Cowan, Abigail G. Kelly, NaaDedee A. Amadi, Isaac W. Babcock, Sydney A. Labuzan, Michael A. Kovacs, Samantha J. Batista, John R. Lukens and Harris. The scientists reported no financial conflicts of interest.
Funding for the research came from the National Institutes of Health (grants R01NS112516, R01NS134747, R21NS12855, T32GM008715, T32AI007496, T32AI007046, T32NS115657, F30AI154740, T32AI007496 and T32GM007267), a University of Virginia Pinn Scholars Award, a UVA Shannon Fellowship, and UVA’s Strategic Investment Fund.
