Common “cat poop” parasite hijacks brain chemistry through infected neuron vesicles

A new study published in PLOS Pathogens has uncovered how a common brain parasite, Toxoplasma gondii, can disrupt communication between brain cells by altering the content of extracellular vesicles released by neurons. The research shows that neurons infected with Toxoplasma cysts produce fewer extracellular vesicles—small packages used to send signals to other cells. These altered signals can trigger inflammation and disrupt how nearby support cells, called astrocytes, manage brain chemicals. The findings suggest that even a few infected neurons could throw off the brain’s balance in subtle but lasting ways.

Toxoplasma gondii is a widespread single-celled parasite estimated to infect about one-third of the global population. In the United States, approximately 10 to 30 percent of people are believed to carry the parasite, typically without symptoms.

Toxoplasma infection is usually contracted through undercooked meat or exposure to cat feces. Once inside the body, the parasite can travel to the brain and form dormant cysts inside neurons, where it can persist for the lifetime of the host. While the infection is usually silent in healthy individuals, it can cause serious illness in people with weakened immune systems. There is growing scientific interest in understanding how even dormant infections might influence brain function over time.

The research team, led by Emma H. Wilson at the UC Riverside School of Medicine, aimed to explore how Toxoplasma infection alters neural signaling at the molecular level. Previous work by the same lab had shown that infection leads to a decrease in the expression of GLT-1, a glutamate transporter found in astrocytes, which are support cells that regulate the brain’s chemical environment.

GLT-1 is responsible for clearing excess glutamate from synapses—a process critical to preventing overstimulation and excitotoxicity. Because neurons can influence astrocytes via small membrane-bound particles called extracellular vesicles, the researchers wanted to know whether infected neurons were releasing different vesicles, and if so, how these might affect astrocyte function.

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“I have been researching Toxoplasma infection in the brain for over 20 years. It is a chronic infection that stimulates an immune response in the brain that is protective and rarely pathological,” explained Wilson, a professor of biomedical sciences. “In fact, the only time that people really get very sick from chronic toxoplasmosis is when they are severely immunocompromised.”

“I am very interested in understanding the mechanisms of an appropriate, yet strong, immune response in the brain. This particular study investigates the interactions between cells in the brain that we do not normally consider immune cells, but they talk all the time, and I thought it was important to determine if such communication was interrupted or altered due to infection.”

For their study, the researchers cultured neurons from mouse embryos in the lab and infected them with the Toxoplasma parasite. After allowing time for the cysts to form inside neurons, they collected the extracellular vesicles released by the infected cells. These vesicles were then analyzed using a combination of imaging, protein analysis, RNA sequencing, and mass spectrometry. In a separate set of experiments, the team exposed cultured astrocytes to these vesicles to examine how they responded at both the genetic and protein levels.

The study was led by Emily Tabaie in collaboration with other members of the Wilson Lab, with support from core facilities at UC Riverside and guidance from Wenwan Zhong of the Department of Chemistry, who assisted in the isolation of extracellular vesicles.

The researchers found that neurons infected with Toxoplasma produced fewer extracellular vesicles compared to uninfected neurons. This decrease was consistent across multiple measurements, including electron microscopy and a specialized ELISA assay that detects a surface protein common to vesicles. The reduction in vesicle production was not due to cell death, as most of the infected neurons remained healthy in culture, suggesting that the parasite was interfering with vesicle release.

The contents of the vesicles from infected neurons were markedly different. Using mass spectrometry, the researchers found that these vesicles contained altered levels of both host- and parasite-derived proteins. Several host proteins involved in inflammation, immune signaling, and structural support were increased, while others linked to neuron growth and synaptic communication were decreased.

In particular, the team detected nine parasite proteins—including GRA7, a known Toxoplasma effector protein—in vesicles from infected neurons. These proteins are usually secreted by the parasite to manipulate the host cell and were now being carried inside vesicles to other parts of the brain.

When these parasite-altered vesicles were introduced to astrocytes, the astrocytes absorbed them and responded with significant changes in gene expression. Many of the genes that were activated were involved in inflammation and immune defense.

The researchers also observed that the vesicles triggered a decrease in GLT-1 protein levels in the astrocytes, suggesting that this communication pathway could directly affect how well the brain clears excess glutamate. The vesicles did not change the gene expression of GLT-1 itself, pointing to possible post-translational modifications or other regulatory mechanisms.

Notably, the researchers saw that the vesicle-induced gene expression changes in astrocytes grown in the lab matched patterns observed in astrocytes from mice infected with Toxoplasma. This parallel suggests that the effects seen in vitro are likely to reflect real processes occurring in the living brain during infection.

The findings suggest that Toxoplasma gondii has developed a sophisticated way to influence its host’s brain function without relying on traditional immune responses. By changing the content of vesicles released by infected neurons, the parasite can indirectly alter the behavior of nearby astrocytes, potentially shifting the chemical environment of the brain in a way that favors its survival.

“You should not be concerned that a third of the world has this parasite in their brain because we are able to deal with it very well,” Wilson told PsyPost. “Our work suggests that this is partly through the ability of neurons to communicate to other cells in the brain that they are infected.”

One of the striking observations from the study was the presence of parasite proteins in the nuclei of astrocytes. This implies that materials carried by the vesicles may be able to reach the control centers of recipient cells and directly influence gene regulation. While the exact mechanisms by which these proteins affect host cells remain unknown, their presence in astrocyte nuclei adds another layer of complexity to the parasite’s impact on brain function.

“The mechanism of communication that we investigated between neurons and astrocytes was the secretion of extracellular vesicles, which are relatively tiny packages from cells,” Wilson said. “As an immunologist, we normally deal with strict rules about how cells pass on information with lots of checks and balances, so I was amazed that these small blobs of cell membrane could pass on so much information so effectively.”

“In addition, Toxoplasma is clever, as it injects proteins into cells that can alter cell mechanisms and change their behavior. We found some of these proteins in astrocytes after the addition of extracellular vesicles from infected neurons—so parasite proteins were transported to cells it has never been near thanks to this mechanism of cell-to-cell communication.”

The researchers noted that these effects occurred even though only about half of the neurons in their cultures were infected. This suggests that even a relatively small number of infected cells could have broad effects on the surrounding brain tissue.

Despite these findings, the researchers acknowledge some limitations. The experiments were conducted using mouse cells and brain tissue grown in a laboratory setting, which may not fully capture the complexity of a living brain. In addition, while the study identified changes in vesicle content and astrocyte responses, the long-term consequences of these changes for behavior or cognition remain unclear. The team did not explore whether these molecular shifts lead to symptoms or changes in brain activity in infected animals or humans.

Looking ahead, the researchers hope to investigate how this altered vesicle signaling contributes to the brain’s immune response and whether it might be possible to detect infection-specific vesicles in human blood samples. If so, extracellular vesicles could potentially serve as biomarkers for diagnosing brain infections or monitoring their effects over time. This would represent a major advance, since current diagnostic tools only detect antibodies and cannot determine whether parasites are active in the brain.

“I would like to determine how vital this communication is to generating a balanced and protective immune response in the brain by manipulating the parasite and the process in a natural infection,” Wilson said. “It also may be possible to determine the prevalence of Toxoplasma in the brain during human infection by using these EVs from infected neurons for diagnosis. There have been some suggestions that having a chronic Toxoplasma infection can alter human behavior—make us less risk-averse or make us more or less susceptible to other neurological disease.”

“These studies are limited because we really do not know the extent of parasite infection in the brain—we only know whether someone is infected or not. Diagnosis of the likely presence of parasites in the brain may help us to be more definitive about the ability of the parasite to alter the physiology and brain chemistry in humans.”

The study, “Toxoplasma gondii infection of neurons alters the production and content of extracellular vesicles directing astrocyte phenotype and contributing to the loss of GLT-1 in the infected brain,” was authored by Emily Z. Tabaie, Ziting Gao, Nala Kachour, Arzu Ulu, Stacey Gomez, Zoe A. Figueroa, Kristina V. Bergersen, Wenwan Zhong, and Emma H. Wilson.