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Many individuals carry long-term infections in various body tissues, including the nervous system, which usually do not lead to illness. The microorganisms causing these infections often enter a dormant state, enabling them to evade the immune system and persist within the host. However, the limited availability of natural models to investigate these dormant phases has hindered scientists’ understanding of how these latent infections endure and whether they can be effectively targeted by the immune response.
A recent study led by researchers at the University of Pennsylvania School of Veterinary Medicine reveals that the immune system can recognize the dormant form of the parasite Toxoplasma gondii, the agent responsible for toxoplasmosis. This finding challenges several prevalent theories regarding the immune system’s management of infections situated within the brain. Christopher A. Hunter, a professor at Penn Vet and the study’s senior author, remarks that these discoveries indicate the potential for targeting and possibly eliminating Toxoplasma gondii cysts, which could inform strategies for treating other infections as well. The research sheds light on the symbiotic relationship between the parasite and its host.
During its dormant phase, Toxoplasma gondii forms resilient cysts within neurons of the brain, strategically allowing it to evade immune detection. The research team found that specific T cells are capable of identifying neurons harboring cysts, facilitating the management of the parasite. However, they also noted a significant catch: when cysts are absent, there is a notable increase in parasite load coupled with greater brain damage. The study has been published in Nature Microbiology.
“There’s a delicate balance whereby the pathogen must establish itself within the host without overwhelming it,” observes Lindsey A. Shallberg, a co-author and a former doctoral student in Hunter’s laboratory.
The infection caused by Toxoplasma gondii, known as toxoplasmosis, typically remains asymptomatic in most healthy individuals, yet poses serious health risks for those whose immune systems are compromised or who are pregnant. The infection is primarily contracted through the consumption of undercooked, contaminated meat and exposure to infected cat feces, as felines are the only animals where the parasite undergoes sexual reproduction.
Co-author Julia N. Eberhard, an immunology doctoral student, highlights two critical findings that contradict established literature and prevailing assumptions in immunology. Historically, it was believed that Toxoplasma gondii cysts could entirely conceal themselves within neurons, thereby avoiding immune detection. However, this study demonstrated that “neurons aren’t an absolute sanctuary for pathogens.”
Eberhard also addresses a widely accepted notion suggesting that the parasite must form cysts for enduring persistence. The research team examined a strain of the parasite that could not develop into cysts and discovered that the immune system did not eradicate the infection; parasites remained detectable in the mice up to six months following initial exposure, a finding that surprised Eberhard.
To bolster their experimental results, mathematical modeling conducted by Aaron Winn, a doctoral student in the Department of Physics and Astronomy within the School of Arts & Sciences, corroborated the findings. The modeling suggested that immune pressure on the latent phase of Toxoplasma gondii could account for the fluctuations in cyst numbers observed during the study.
This research emerged from a collaborative effort sparked by Sebastian Lourido, a biology associate professor at MIT, who identified the critical molecular pathways enabling the parasite to enter a dormant state and sought to explore the consequences if cyst formation were inhibited. Additionally, Anita Koshy, a neurologist and scientist at the University of Arizona, provided evidence that certain neurons possess the capability to eliminate the infection.
Beyond its significance in understanding Toxoplasma gondii, this research holds potential implications for grasping latent infections in the human nervous system, such as cytomegalovirus, for which there are no effective mouse models. “What sets this study apart is its tractable model that we can experiment with in the lab and subsequently apply our findings to other infectious diseases,” Shallberg explains.
Looking toward the future, Hunter indicates that his laboratory will continue to explore whether T cells can directly recognize infected neurons and will delve deeper into the intricacies of the T cell response.
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