A role for maternal helminth treatment to alter central inflammation and to reduce lifelong offspring inflammation

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PROJECT SUMMARY Neuroinflammation is correlated with a broad spectrum of disorders, including cognitive and mental health disorders. Treating and reducing neuroinflammation remains a medical challenge. The purpose of this research is to determine the effects of maternal helminth colonization on her neonatal and adult offspring, specifically focused on the effects on microglia function and inflammation across the lifespan as well as hippocampal-dependent behavior in adulthood. As previous work has shown, neonatal infection alters neuroinflammation via changes in microglial function and has an enduring, negative effect on adult learning and memory. Current work in patient populations suffering from non- communicable inflammatory disorders, such as multiple sclerosis, shows that treatment with commensalist parasites may be a new form of intervention beyond pharmaceutical treatments. Commensalist organisms emit anti-inflammatory signals in order to survive, and these signals may have potential benefits by reducing inflammation within their hosts. Previous work has shown that maternal helminth colonization attenuates neuroinflammation in the offspring following a neonatal infection with Escherichia coli. The same work showed that the combination of maternal and weanling offspring helminth colonization rescues learning deficits on a hippocampal-dependent contextual fear conditioning task. Further research is needed to understand the effects on the offspring of maternal helminth colonization alone as well as to define the duration and time course of the effects of maternal helminth colonization in our neonatal infection model. This proposal will test the hypothesis that maternal helminth colonization alone is sufficient to protect offspring from the lifelong effects of neonatal infection by reducing inflammation within the hippocampus throughout the lifespan. It will also characterize the effects of maternal helminth colonization on the offspring to explore possible mechanisms, including mRNA-sequencing of isolated cell populations (microglia, astrocytes and neurons) from the central nervous system. Importantly, this project proposes to engage and train approximately 8 undergraduates working in the lab each year with rodents on behavioral task analysis as well as cellular and molecular analysis techniques, such as immunohistochemistry and real-time quantitative PCR as well as bioinformatics projects with NextGen RNAsequencing. These studies will elucidate potential mechanisms for the effects of maternal helminths that can be further explored as interventions for populations susceptible to immune-mediated inflammatory diseases.