Host Genetic Correlates of Helminthic Coinfection

描述（由申请人提供）：本提案的目的是确定宿主遗传学对与S. mansoni和N.美国人在初步的数据中，我已经确定，两种蠕虫卵数的近一半方差可以用加性遗传效应来解释。更大的加性遗传成分决定了它们的合并感染状态。强加性遗传成分也被发现影响同种型反应的原油和确定的抗原从这些蠕虫。双变量遗传分析进一步表明，这些加性遗传成分的很大一部分是由于共同的基因集（多效性效应）。特别是在对S. mansoni和N.这表明对这两种蠕虫的免疫反应可能来自一组共同的基因。目前的建议将集中在宿主遗传学的贡献，发生在化疗后的同种型反应的改变，并与再感染。化疗已被充分证明可以显著改变已经启动的抗体应答，并可能加速免疫应答，从而赋予对再感染的抵抗力。我将检验加性宿主遗传学对沙门氏菌化疗后体液免疫反应的变化有显著影响的假设。mansoni和N.因此，我们认为，这种加性遗传成分的很大一部分是由于潜在基因的多效性效应。我将继续使用扩展的，多户系谱收集在第一个三年的IRSDA和寄生虫学数据已被收购和生物标本库在过去三年。使用最大似然方差分量分析，我将划分性状的方差，因为它们涉及到遗传和非遗传（系统性和随机）的组件再感染。!也将进行双变量协方差分解分析，以检查所有对蠕虫相关性状之间的遗传相关性。这些分析将通过遗传相关性的最大似然估计来量化潜在基因的多效性效应。在这项研究中使用的数量遗传学方法邀请新的方式来理解的机制，有助于在蠕虫共感染性状变异。在进行连锁研究以确定和绘制宿主中影响合并感染的特定基因之前，还必须表明合并感染的重要遗传成分。鉴于发展中国家在知识和财政上重新强调化疗是控制蠕虫感染的手段，研究宿主遗传学对化疗引起的免疫反应变化的贡献是非常及时的。

DESCRIPTION (provided by applicant): 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.