Understanding the immune response to a persistent pathogen

(Press-News.org) Most humans have long-lived infections in various tissues—including in the nervous system—that typically do not result in disease. The microbes associated with these infections enter a latent stage during which they quietly hide in cells, playing the long game to evade capture and ensure their own survival. But a lack of natural models to study these quiescent stages has led to gaps in scientists’ understanding of how latency contributes to pathogen persistence and whether these stages can be targeted by the immune system.

Now, a team led by University of Pennsylvania School of Veterinary Medicine researchers shows that the immune system indeed recognizes the latent stage of the parasite Toxoplasma gondii, which causes toxoplasmosis—challenging some common assumptions about how the immune system deals with infections in the brain. Penn Vet professor Christopher A. Hunter, the paper’s senior author, says this knowledge supports the idea that Toxoplasma gondii cysts can be targeted and perhaps even cleared, and the findings have implications for other infections and potential future therapies. The paper also demonstrates how cysts promote the mutual survival of the parasite and host.

In its latent stage, Toxoplasma gondii forms long-lived cysts in neurons in the brain, which helps the parasite evade the host’s immune response. However, in this study, the researchers found that certain T cells can target neurons containing cysts, thereby promoting parasite control. But there’s a tradeoff: They also found that when cysts are not formed, there is an even higher parasite burden and increased damage to the brain. The study is published in Nature Microbiology.

“There’s this balance of the pathogen needing to take hold in the host but not expand so much that it’s detrimental to the host, because if the host dies, the pathogen may not survive,” says author Lindsey A. Shallberg, who at the time of the research was a doctoral student in Hunter's lab.

Toxoplasma gondii causes toxoplasmosis, an infection that is asymptomatic for most healthy people but poses a greater risk for those who are immunocompromised or pregnant. It is caused by eating contaminated, poorly cooked meat and by exposure to infected cat feces, as felines are the only animal in which the parasite can sexually reproduce.

Co-author Julia N. Eberhard, an immunology doctoral student, points to two findings that run counter to preexisting literature and common notions among immunologists. She says scientists long thought that Toxoplasma gondii cysts could hide out in neurons to prevent immune recognition, but this study showed that “neurons aren’t this complete refuge for pathogens.”

Eberhard says another commonly held belief was that the parasite needs to form cysts to be able to persist, but in looking at a parasite strain that couldn’t convert to the cyst stage, the researchers found that the immune system did not clear the parasite. They could still identify parasites in mice six months later, which Eberhard found very surprising.

Mathematical modeling independently confirmed experimental findings and indicated that immune pressure on the latent stage of Toxoplasma gondii could explain the observed rise and fall in cyst numbers. This was done by Aaron Winn, a doctoral student in the Department of Physics and Astronomy in the School of Arts & Sciences.

Shallberg says this paper came about because co-author Sebastian Lourido, an associate professor of biology at MIT, had identified the key molecular mechanism that allows the parasite to become latent and wanted to know what would happen if the parasite could not form cysts. In addition, co-author Anita Koshy, a neurologist and scientist at the University of Arizona, had evidence that some neurons could rid themselves of this infection. 

While Toxoplasma gondii is a relevant microorganism to study in and of itself, it is also useful in furthering scientists’ understanding of nervous system infections with latent stages in humans that don’t have mouse models, such as cytomegalovirus. “What makes it special is the fact that it’s a tractable model that we can use in the lab and then apply what we’ve learned to other infections,” Shallberg says.

Looking ahead, Hunter says that his laboratory continues to investigate whether T cells directly recognize the neurons and to study the T cell response in more detail.

Christopher A. Hunter is the Mindy Halikman Heyer Distinguished Professor of Pathobiology at the University of Pennsylvania School of Veterinary Medicine.

Lindsey A. Shallberg was an immunology doctoral student in the University of Pennsylvania Perelman School of Medicine at the time of this research. 

Aaron Winn is a sixth-year doctoral student in the Department of Physics and Astronomy in the School of Arts & Sciences.

Julia N. Eberhard is a fifth-year immunology doctoral student at Penn Medicine.

Other co-authors are Penn Vet’s Daniel L. Aldridge, Molly Bunkofske, David A. Christian, Maxime Jacquet, and Elinor Wilis; Penn Arts & Science’s Eleni Katifori; Massachusetts Institute of Technology and Whitehead Institute for Biomedical Research’s Christopher J. Giuliano and Sebastian Lourido; University of Arizona’s Anita A. Koshy, Sambamurthy Chandrasekaran, and Emily F. Merritt; and the Royal Ottawa Mental Health Center’s Florence Dzierszinski.

This research was supported by the National Institutes of Health (grants AI157247, AI160664, AI161962, CA009140, AI158501, and AI157247); the Commonwealth of Pennsylvania; and institutional funding from the College of Medicine and BIO5 Institute of the University of Arizona.

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