Toxoplasma gondii: More than 30 million Americans are infected with a brain parasite


Toxoplasma gondii infections are common in humans and animals worldwide. Toxoplasma gondii infection in pigs continues to be of public health concern.

Pigs are important for the economy of many countries, particularly, USA, China, and European countries.

Among the many food animals, pigs are considered the most important for T. gondii transmission in USA and China because viable parasite have rarely been isolated from beef or indoor raised chickens. Besides public health issues, T. gondii causes outbreaks of clinical toxoplasmosis in pigs in China, associated with a unique genotype of T. gondii (ToxoDB genotype #9 or Chinese 1), rarely found in other countries.

The safety of ready to eat pork products with respect to T. gondii infection is a matter of recent debate. 

More than 30 million Americans are infected with a brain parasite spread by cats and contaminated meat, but most will never show symptoms.

A new discovery from the University of Virginia School of Medicine explains why, and that finding could have important implications for brain infections, neurodegenerative diseases and autoimmune disorders.

The UVA researchers found that the parasite, Toxoplasma gondii, is kept in check by brain defenders called microglia.

These microglia release a unique immune molecule, IL-1α, that recruits immune cells from the blood to control the parasite in the brain, the scientists discovered.

This process works so well that very few people develop symptomatic toxoplasmosis, the disease the parasite causes.

Understanding the role of microglia is essential because they are normally the only immune cells inside the brain.

The new finding reveals how they recruit help when needed, and that discovery could apply to any brain condition with an immunological component – including brain injury, neurodegenerative disease, stroke, multiple sclerosis and more.

“Microglia must die to save the brain from this infection,” said researcher Tajie Harris, PhD, of UVA’s Department of Neuroscience and the interim director of the Center for Brain Immunology and Glia (BIG).

“Otherwise the IL-1α remains stuck inside the microglia and wouldn’t alert the immune system that something is wrong.”

The Brain and the Immune System

UVA’s Department of Neuroscience and BIG center have in recent years completely rewritten our understanding of the brain’s relationship with the body’s immune system.

For decades, textbooks taught that the brain was disconnected from the immune system. UVA research, however, showed that was not the case, to the shock of the scientific community. Many researchers are now exploring the implications of that major discovery.

One area of focus is microglia and their role in defending the brain. This has been a difficult question to answer because microglia are closely related to other immune cells elsewhere in the body.

Until recently, laboratory tools made to target microglia have also targeted these other cells, making it hard to distinguish between the two.

UVA researcher Samantha J. Batista, a graduate student in Harris’ lab, used an elegant approach that leveraged the long-lived nature of microglia to understand their role in brain infection.

She and her colleagues found that infection caused microglia to die in an inflammatory fashion – a way that the closely related immune cells do not.

The microglia burst, the researchers determined, to recruit immune cells called macrophages to control the Toxoplasma gondii infection.

This finding helps explain why most people have no trouble controlling the parasite, while some – especially people who are immunocompromised – can become very sick.

“Understanding pathways like this could be beneficial for other diseases involving neuroinflammation,” Batista 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.

Targeting one specific pathway like this one could have less off-target effects than targeting inflammation more broadly.”

In the future, Harris, Batista and their collaborators are interested in understanding how microglia detect the parasites in the brain.

Microglia could recognize the parasite’s presence directly, or they could recognize damage to brain tissue, a phenomenon that occurs in many diseases.

“The immune system must enter the brain to fight dangerous infections,” said Harris, who is part of UVA’s Carter Immunology Center.

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

Findings Published

The researchers have published their findings in the scientific journal Nature Communications. The research team consisted of Batista, Katherine M. Still, David Johanson, Jeremy A. Thompson, Carleigh A. O’Brien, John R. Lukens and Harris.

Funding: The research was supported by the National Institutes of Health grants R01NS091067, R56NS106028, R01NS112516, R01NS106383, T32AI007046, T32GM008328 and T32AI007496; a Carter Immunology Center Collaborative Research Grant; Alzheimer’s Association grant AARG-18-566113; the Owens Family Foundation; and a University of Virginia Research & Development Award.

Numerous brain infections cause significant morbidity and mortality worldwide. Many of these pathogens persist in a chronic latent form in the brain and require constant immune pressure to prevent symptomatic disease.

As the only resident immune cell, microglia are widely assumed to play an integral role in controlling CNS infections, but in many contexts their specific role remains poorly understood.

One CNS-tropic pathogen is Toxoplasma gondii, a eukaryotic parasite with a broad host range that infects a large portion of the human population.1–6 T. gondii establishes chronic infections by encysting in immune privileged organs, including the brain.7, 8 

Without sufficient immune pressure, an often fatal neurological manifestation of this disease toxoplasmic encephalitis can occur.2, 5, 6

Studies done in mice, a natural host of this parasite, have elucidated many aspects of the immune response that are essential for maintaining control of the parasite during chronic stages of infection.

T cell-derived IFN-γ is one essential element.9–11 IFN-γ acts on target cells to induce an anti-parasitic state, allowing for the destruction of the parasite through a number of mechanisms including the recruitment of immunity-related GTPases (IRGs) and guanylate binding proteins (GBPs) to the parasitophorous vacuole, as well as the production of nitric oxide (NO).12–17 

Large numbers of monocytes and monocyte-derived macrophages, a target population for IFN-γ signaling,13 are recruited into the brain parenchyma during chronic T. gondii infection in mice, and these cells are also necessary for maintaining control of the parasite and host survival.18 

Though microglia occupy the same environment as these cells in the infected brain, have an activated morphology, their role in chronic T. gondii infection has not been fully elucidated.

Indeed, whether microglia and recruited macrophages respond in similar ways to brain infection is an open question.

In this work, we have focused on IL-1, its expression by microglia and macrophages, as well as its role in the brain during chronic T. gondii infection.

IL-1 molecules include two main cytokines: IL-1α and IL-1β. IL-1α can function as a canonical alarmin, which is a pre-stored molecule that does not require processing and can be released upon cell death or damage, making it an ideal candidate for an early initiator of inflammation.19, 20 

In contrast, IL-1β is produced first as a pro-form that requires cleavage by caspase-1 in order for it to be biologically active, rendering IL-1β dependent on the inflammasome as a platform for caspase-1 activation.21–23 

Both of these cytokines signal through the same receptor (IL-1R), a heterodimer of IL-1R1 and IL-1RAcP, with similar affinity.24 

They also lack signal sequences and thus require a loss of membrane integrity to be released. Caspase-mediate cleavage of gasdermin molecules has been identified as a major pathway leading to pore formation and IL-1 release.

The role of IL-1β and inflammasome pathways in T. gondii infection has been studied in vitro as well as in rodent models of acute infection. In sum, these studies suggest roles for IL-1β, IL18, IL-1R, NLRP1 and/or NLPR3 inflammasome sensors, the inflammasome adaptor protein ASC, and inflammatory caspases-1 and −11.25–28 

However, the role of IL-1 signaling in the brain during chronic infection has not been addressed.

Here, we show that though they are present in the same tissue microenvironment in the brain during T. gondii infection, monocyte-derived macrophages in the brain have a stronger NF-κB signature than brain-resident microglia.

Interestingly, we also find that while IL-1α is enriched in microglia, IL-1β is overrepresented in macrophages, suggesting that these two cell types are able to contribute to IL-1-driven inflammation in different ways.

We go on to show that IL-1 signaling is, indeed, important in this model as Il1r1-/- mice chronically infected with T. gondii are less able to control parasite in the brain, and additionally, these mice have deficits in the recruitment of inflammatory monocytes and macrophages into the brain in comparison to wild-type mice.

We find IL-1R1 expression predominantly on blood vasculature in the brain, and observe IL-1-dependent activation of the vasculature during infection.

Further, IL-1-dependent control of T. gondii is mediated though IL-1R1 expression on a radio-resistant cell population. Interestingly, the pro-inflammatory effect of IL-1 signaling is mediated via the alarmin IL-1α, not IL-1β.

We show that microglia, but not infiltrating macrophages, release IL-1α ex vivo in an infection- and gasdermin-D-dependent manner. We propose that one specific function of microglia during T. gondii infection is to release the alarmin IL-1α to promote protective neuroinflammation and parasite control.


Toxoplasma gondii establishes a chronic brain infection in its host, necessitating long-term neuroinflammation.5, 6, 39 Much is known about the immune response to this parasite, but the role of the brain-resident microglia is still largely unknown.

Early studies using culture systems of murine and human microglia showed that IFN-γ and LPS treatment prior to infection inhibited parasite replication.40–42 However, understanding of microglia-specific functions in brain infections has been hindered by the fact that microglia rapidly lose their identity in culture.43

Moreover, culture techniques do not recapitulate the complex interactions microglia have during infection with other cells or the tissue architecture of the brain. Thus, we aimed to examine microglia and macrophages within the brain to begin to uncover their function.

Through RNA-seq analysis as well as staining of infected brain tissue, we find that there is an NF-κB signature present in brain-infiltrating monocytes/macrophages, that is largely absent in microglia in the same environment.

These two cell types are likely exposed to the same signals within the brain, which suggests that the ontogeny of these cells has long lasting implications for their functional capacity.

Transcription factors, including Sall1, that have been accepted as defining microglia identity may be shaping the transcriptional landscape, repressing certain loci that could potentially lead to damaging inflammation in the brain.44

We suggest that these differences are evidence of a division of labor, with microglia and blood-derived macrophages contributing in different ways to inflammation in the brain during infection with T. gondii.

While blood-derived cells display a classic inflammation associated NF-κB response, microglia may be better suited to contributing to inflammation through the release of alarmins, rather than through upregulation of a broader NF-κB-dependent program that may be injurious to the local tissue.

We find the alarmin IL-1α expressed in microglia, though they notably lack expression of IL-1β which is found in infiltrating myeloid cells. This suggests that both of these cell types may be able to participate in an IL-1 response, but in fundamentally different ways. Importantly, we show that host immunity is dependent on the activity of IL-1α rather than IL-1β, and that IL-1α is released ex vivo from microglia but not from infiltrating macrophages.

In general, IL-1β has been the subject of more study than IL-1α, and has a history of being implicated when IL-1 signaling is discussed. More recently, IL-1α has been shown to contribute to certain inflammatory environments.

IL-1α release from lymph node macrophages in an inflammasome-independent death event has been shown to enhance antigen presentation and humoral responses to influenza vaccination.45

IL-1α has been shown to initiate lung inflammation in a model of sterile inflammation using silica.46 Recently, some reports have suggested IL-1α rather than IL-1β drives sepsis pathology.47

IL-1α activity in the CNS has begun to be studied, with a deleterious role for the cytokine shown in spinal cord injury.48 IL-1β has been implicated in some infection models, but IL-1α activity in brain infection has not previously been reported.

As an alarmin expressed in the brain at baseline, IL-1α is ideally placed to initiate inflammation in response to early damage caused by the parasite before there is robust immune infiltration.

In this work, we also show that IL-1α likely signals on brain vasculature, promoting the infiltration of immune cells. We found that IL-1R1 expression on brain vasculature displays a mosaic pattern.

This could suggest that there are functionally distinct sub-populations of endothelial cells capable of becoming activated in response to different signals.49

There is ample evidence in the literature to support IL-1R1 expression on endothelial cells as well as the responsiveness of CNS vasculature to IL-1.50–55

However, IL-1 has also been shown to signal on immune cells.56–59 We found that IL-1R1 expression on radio-resistant cells is what is important in our model, which is supportive of endothelial cells being the relevant responders, but there has also been evidence put forth that other brain resident cells can respond to IL-1.

It has been suggested that microglial IL-1R1 expression plays a role in self-renewal after ablation.60 Microglia are partially radio-resistant and do experience some turnover after irradiation and repopulation.

It has also been suggested that IL-1 can act on neurons, though it should be noted that it has also been reported that neurons express a unique form of IL-1RAcP which affects downstream signaling.61

It is unclear whether astrocytes express IL-1R1, but astrocytes represent another radio-resistant cell population in the brain that has the ability to affect immune cell infiltration through chemokine production.29, 62

Infiltrating immune cells express pro-IL-1β but we have not detected a role for IL-1β in promoting inflammation in this model. We have also shown that they do not release IL-1α ex vivo even though they express it, suggesting that they may die in an immunologically quiet way such as apoptosis, while microglia may undergo a more inflammatory form of cell death, including pyroptosis.

If these two cell types do in fact undergo different forms of cell death, it is of great interest how microglia activate gasdermin-D to release inflammatory factors. It is possible that microglia in an area of parasite reactivation in the brain become infected, sense parasite products in the cytoplasm, and undergo death to eliminate this niche for parasite replication.

NLRP1 and NLRP3 have both been shown to recognize T. gondii25–27 and could be the potential sensors in microglia. AIM2 is another inflammasome sensor that can recognize DNA63 and could therefore be activated if parasite DNA becomes exposed to the cytosol.

However, we and others7 have not been able to observe direct infection of microglia in chronically infected mice. On the other hand, microglia migrate to sites of parasite reactivation and may recognize products resulting from host cell death or damage, such as ATP, and undergo death that will promote inflammation.

The presence of ASC specks in infected brains suggests the formation of caspase-1-dependent canonical inflammasome, but it remains unclear if the ASC specks are directly linked to IL-1α release in microglia.

Moreover, the canonical inflammasome can even be activated downstream of non-canonical inflammasome driven gasdermin-D pores.64 Thus, the sensors upstream of caspase-dependent cleavage of gasdermin-D in microglia are of great interest.

reference link :

University of Virginia


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