Inflammation, Iron, and Cognition in S. japonicum

点击翻译按钮获取中文摘要

DESCRIPTION (provided by applicant): The overall objective of this proposal is to prospectively investigate the mechanisms of Schistosomiasis japonicum associated cognitive impairment. We will use changes in S. japonicum infection status as a model for understanding mechanisms of cognitive impairment observed in a range of parasitic infections. The hypotheses addressed in this proposal have broader implications for a host of diseases of childhood that promote an exuberant pro-inflammatory cytokine response. We propose to explore the biologic mechanisms underlying the known causal relationship between S. japonicum and decreased cognitive function. We will utilize the changes in levels of pro-inflammatory cytokines (TNF-alpha and IL-6) which occur with S. japonicum re-infection during an 18 month period of follow-up to investigate their role as mediators of cognitive impairment. A fuller understanding of the mechanisms underlying the relationship between parasitic infections and morbidity is fundamental to our conceptualization of interventions for childhood diseases. The aims of this study are: 1) to prospectively determine the relationship between pro-inflammatory cytokines made in response to S. japonicum and cognitive function. Using a longitudinal design, we will establish the relationship between proinflammatory cytokines and cognitive function as subjects move from a post-treatment, uninfected state (six weeks after chemotherapeutic cure) to an increasingly re-infected state at five time points over an 18 month period of follow-up. We hypothesize that performance on tests of cognitive function will be inversely related to levels of pro-inflammatory cytokines made in response to S. japonicum re-infection and be mediated by the direct toxic effects of these cytokines on the central nervous system. 2) To prospectively determine the relationship between host iron status and cognitive function in the context of parasitic diseases. We will investigate the role of anemia of inflammation in cognitive impairment related to host pro-inflammatory immune response to parasitic diseases. Specifically, we will investigate the role of decreased bio-available iron as measured by serum transferrin receptor levels in the pathogenesis of parasitic disease related cognitive impairment. We hypothesize that host's pro-inflammatory immune responses to parasitic diseases decrease the bioavailability of iron through anemia of inflammation, which, in turn, negatively impacts cognitive function.