Watch Dr Prasad Paradkar accept the research grant award on behalf of Dr Mujun Sun and hear a bit about the project.
Watch Dr Mujun Sun explain more about the research she is doing as a result of the funding provided by the Brain Foundation.
Project Summary:
Infection with Toxoplasma gondii (T. gondii) is one of the most prevalent infections in humans (i.e., ~30-50% of the global population). T. gondii is a parasite that permanently resides in the brain tissue of infected mammals. T. gondii infection has traditionally been viewed as benign, however recent studies suggest that T. gondii infection in itself may cause subtle behavioural abnormalities, and is associated with neurodegenerative diseases, such as Parkinson’s diseases, Alzheimer’s disease, as well as neuropsychiatric disorders. Notably, T. gondii infection also results in inflammation in the brain.
Traumatic brain injury (TBI) and stroke are common forms of brain injury that affect millions of people worldwide each year, and both lack effective treatments to improve long-term outcomes. The difficulty in developing effective treatments for brain injuries is in large part due to their heterogeneous nature, as there are factors that can modify how the brain responds to injury. For example, T. gondii infection could result in pre-existing inflammation in the brain, and therefore when the brain is injured the outcomes could be worse. This would affect the optimal treatment strategy required for such patients, and could account for some of the past translational failures in developing interventions for these conditions.
Despite the high prevalence of T. gondii, TBI, and stroke worldwide, how the presence of T. gondii affects TBI or stroke has never been investigated. Therefore, this study will evaluate the possibility that the presence of T. gondii infection modifies TBI and stroke outcomes in rats. Findings from this novel and innovative project will significantly improve our understanding of these prevalent conditions and will provide a foundation for future studies to develop optimized treatment strategies to improve brain injury outcomes.
Outcomes:
Our hypothesis was that T. gondii infection will exacerbate neuropathophysiological mechanisms in rodents that given an acquired brain injury, and there will be worse brain damage and functional outcomes in these animals. Although the project was delayed due to the impact of the COVID-19, we were able to complete a substantial study which examined the effects of T. gondii infection on TBI in mice, while leaving the stroke element as unanswered questions.
The mouse model of TBI and T. gondii infection compared four groups: TBI and T. gondii infection, TBI only, T. gondii infection only, and healthy controls. We found that there were synergistic effects between T. gondii and TBI at 24 hours post-injury (7 weeks post-infection), that the T. gondii infection amplified the neuroinflammation induced by the TBI. We also found that:
- TBI and T. gondii effects were evident on neuroinflammatory and immune cell markers at 2 hours post-injury and 7 days post-injury, respectively.
- At 24 hours, TBI + T. gondii resulted in increased neuronal damage, compared to T. gondii or TBI alone.
- TBI + T. gondii exacerbated excitotoxicity, as GLT-1 was decreased compared to T. gondii or TBI alone.
Overall, our findings suggested that a history of T. gondii infection could worsen neuroinflammation, excitotoxicity, and neuronal damage, during the acute stage of TBI.
The mechanisms underlying the development of post-traumatic epilepsy (PTE) currently remain unclear. To test whether the effects of excessive neuroinflammation, excitotoxicity, and neuronal damage induced by T. gondii + TBI may manifest chronically and impact seizure susceptibility in the long-term, mice underwent seizure susceptibility at 3.5 months after TBI. We found that a preexisting T. gondii infection is an important modifier of seizure susceptibility independent of TBI in mice. We also performed a battery of behavioural testing at 3.5 months after the TBI to examine motor ability, sociability, anxiety, depression, and cognition in these mice, and the data analysis is still ongoing. MRI brain structure analysis and immunohistochemistry analysis of brain samples from these mice (18 weeks post-injury) is also on-going.
Outcomes submitted August 2022.
The Brain Foundation is dedicated to funding the next generation of Australian research into brain disorders, diseases, and injuries, with the ultimate goal of advancing diagnoses, treatments, and patient outcomes.