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Long-term effects of early systemic immune challenge on CNS function

Subject Area Molecular and Cellular Neurology and Neuropathology
Term from 2011 to 2022
Project identifier Deutsche Forschungsgemeinschaft (DFG) - Project number 190888409
 
Final Report Year 2024

Final Report Abstract

Type I interferons (IFNs) are important antiviral cytokines that also act in the central nervous system (CNS). They are released during CNS viral infections and high-dose IFN therapy, and can lead to a variety of symptoms, including fatigue, irritability, cognitive impairment, malaise, anorexia, and insomnia. In the first funding period, we investigated the mechanism by which Type I IFNs produce these symptoms. We demonstrated that IFNs induce the production and release of the chemokine CXCL10. CXCL10 binds to the chemokine receptor CXCR3, which is expressed on central nervous system neurons. This binding impairs synaptic plasticity, an essential function for learning and memory. These results suggest that Type I IFNs are causally linked to the described affective, cognitive, and neurovegetative symptoms. They open new possibilities for the development of therapies that can alleviate these symptoms in CNS viral infections or high-dose IFN therapy. In the second funding period, we expanded our research to investigate whether a viral infection immediately after birth increases the vulnerability for later neuropsychiatric and cognitive impairment. The acute course of the disease after virus exposure is initially similar in both sexes in mice. However, after early immune stimulation, male mice had higher levels of Type II IFNs in the blood than female mice. Once the animals reached adolescence, male mice showed longlasting concentration and social behavior disorders after an early, resolved viral infection. Female mice, on the other hand, did not show these neuropsychological changes. Sexspecific changes were also observed at the cellular level. Male mice had increased numbers of T cells in the hippocampus. Microglial cells, also known as phagocytes, increased the breakdown of dendritic spines from nerve cells in the hippocampus of male mice after early immune stimulation. These spines play an important role in learning and memory formation. The molecular changes and neuropsychological abnormalities could not only be detected in a real viral infection. Even after administration of a viral mimic, the long-lasting cognitive and behavioral disorders occurred only in male mice. The findings that the response of the male and female immune system differs significantly should have clinical significance in the future. This includes the treatment of early infections in humans, which can cause long-term CNS sequelae in male newborns, or the possible different response to immunotherapy in men and women.

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