The goal of this proposal is to define the contribution of host genetics to co-infection with S. mansoni and N. americanus. In preliminary data, I have determined that nearly half of the variance in egg counts for both helminthes can be explained by additive genetic effects. An even larger additive genetic component determines their co-infection status. Strong additive genetic components were also found to influence the isotype responses to crude and defined antigens from these helminths. Bi-variate genetic analyses further suggested that a substantial proportion of these additive genetic components were due to common sets of genes (pleiotropic effects). Especially strong pleiotropic effects were found between the isotype responses to adult stage antigens from S. mansoni and N. americanus, indicating that the immune responses to these two helminths may derive from a common set of genes. The current proposal will focus on the contribution of host genetics to the alterations in the isotype responses that occur after chemotherapy and are associated with re-infection. Chemotherapy has been well documented to dramatically alter the antibody responses already initiated and possibly accelerate the immune response toward conferring resistance to re-infection. I will test the hypotheses that additive host genetics contribute significantly to the variation in the humoral immune response after chemotherapy for S. mansoni and N. americanus infection and that a substantial proportion of this additive genetic component is due to the pleiotropic effects of underlying genes. I will continue to use the extended, multi-household pedigrees assembled during the first three years of the IRSDA and from which parasitological data have been acquired and biological specimens banked for the last three years. Using maximum likelihood variance component analysis, I will partition the variance of the traits as they relate to re-infection into genetic and non-genetic (systemic and random) components. ! will also perform bi-variate covariance decomposition analysis to examine the genetic correlations between all pairs of helminth-related traits. These analyses will quantify the pleiotropic effects of underlying genes via maximum likelihood estimation of genetic correlations. The quantitative genetic methods used in this study invite new ways of understanding the mechanisms that contribute to trait variation during helminth co-infection. It is also necessary to have shown a significant genetic component to co-infection before linkage studies can be undertaken to identify and map specific genes in the host that influence co-infection. The study of the contribution of host genetics to changes in the immune response elicited by chemotherapy are quite timely given the renewed intellectual and financial emphasis on chemotherapy as the means to control helminth infections in developing countries.
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