A brain parasite infects millions of people. A new study reveals why most don't get sick.

Across the globe, many cat owners pick up a pet-linked parasite without ever knowing. In the United States alone, more than 40 million Americans are infected with Toxoplasma gondii — a brain parasite that's spread by eating undercooked, contaminated meat, drinking contaminated water, and yes, accidentally swallowing a bit of cat poop.

The parasite is one of the most common parasites on Earth, infecting up to a third of the world population. As of now, there's no way to tell exactly which route of transmission is how one individual becomes infected.

But we are getting closer to understanding why most infections don't result in symptoms (in rare cases, it can cause lasting damage). In a recent study, scientists discovered the immune cells that run crucial interference between Toxoplasma gondii and the brain.

These immune cells are called microglia and they help take down the parasite before it can wage war on the brain.

When fighting the parasite, microglia burst, releasing a unique immune molecule called IL-1α that recruits immune cells from the blood to control the parasite in the brain. This keeps people from ever developing symptomatic toxoplasmosis, the disease the parasite causes, the study suggests.

These findings go far beyond cat lovers. Researchers say understanding microglia's defense capabilities could lead to better ways of treating other brain infections, including neurodegenerative diseases like Alzheimer's, and autoimmune disorders, like multiple sclerosis and strokes.

“The immune system must enter the brain to fight dangerous infections,” co-author and neuroscientist Tajie Harris, interim director of the Center for Brain Immunology and Glia (BIG) at the University of Virginia, explains. The findings were published on July 23 in the journal Nature Communications.

“We now understand how microglia sound the alarm to protect the brain," Harris says. "We suspect that similar signals are missed or misinterpreted in Alzheimer’s disease, opening up an exciting new research avenue in the lab.”

Brain burst — To unravel microglia's role in defending the brain, researchers infected mice with Toxoplasma gondii. Then the team mapped the mice's brain responses and immune signaling, honing in on microglia.

After detailed analysis, the team discovered that the parasite infection caused microglia to die in an inflammatory fashion. The microglia burst and release IL-1α, sending out an SOS flare and spurring other immune cells into action. IL-1α then recruits immune cells called macrophages to control the Toxoplasma gondii infection.

“Microglia must die to save the brain from this infection,” Harris said. “Otherwise the IL-1α remains stuck inside the microglia and wouldn’t alert the immune system that something is wrong.”

Living with parasites — For most people, this process means they have no trouble controlling the parasite. However, when people's immune systems are compromised, through conditions like HIV, they may have trouble triggering this immune defense, and in turn, become very sick.

These findings offer clues for how this system might be manipulated to handle other brain conditions, especially those with an immunological component.

“Understanding pathways like this could be beneficial for other diseases involving neuroinflammation,” Samantha Batista, a study co-author and researcher at the University of Virginia, said.

“We can ask whether promoting this pathway is helpful in situations where you need more of an immune presence in the brain such as infections or cancers, and also whether inhibiting this molecule could be helpful in diseases driven by too much neuroinflammation, like multiple sclerosis."

Researchers still don't fully understand the downstream effects of Toxoplasma gondii.

For years, people linked this crazy cat parasite to "crazy cat people's" seemingly odd behavior. Others associated the brain parasite with mental health disorders like schizophrenia. Long-term research debunks these strange claims, showing the parasite does not cause population-wide mental health effects. But, in rare cases, the infection can cause acute, and sometimes devastating health consequences, especially if someone is immunocompromised.

To reduce exposure, cook food well, change the litter box often, and if pregnant, avoid contact with cat poo.

Abstract: Microglia, resident immune cells of the CNS, are thought to defend against infections. Toxoplasma gondii is an opportunistic infection that can cause severe neurological disease. Here we report that during T. gondii infection a strong NF- B and inflammatory cytokine transcriptional signature is overrepresented in blood-derived macrophages versus microglia. Interestingly, IL-1α is enriched in microglia and IL-1β in macrophages. We find that mice lacking IL-1R1 or IL-1α, but not IL-1β, have impaired parasite control and immune cell infiltration within the brain. Further, we show that microglia, not peripheral myeloid cells, release IL-1α ex vivo. Finally, we show that ex vivo IL-1α release is gasdermin-D dependent, and that gasdermin-D and caspase-1/11 deficient mice show deficits in brain inflammation and para- site control. These results demonstrate that microglia and macrophages are differently equipped to propagate in!ammation, and that in chronic T. gondii infection, microglia can release the alarmin IL-1α, promoting neuroinflammation and parasite control.