Host Genetic Correlates of Helminthic Coinfection

描述(由申请人提供)：本提案的目标是确定宿主遗传学对曼氏葡萄球菌和美洲奈瑟氏菌混合感染的贡献。在初步数据中，我已经确定，两种蠕虫的卵数差异中，近一半可以用加性遗传效应来解释。一个更大的相加遗传成分决定了他们的共同感染状态。强加性遗传成分也被发现影响对这些蠕虫的粗制抗原和定义抗原的同型反应。双变量遗传分析进一步表明，这些加性遗传成分中有相当大一部分是由共同的基因集(多效性效应)造成的。对曼氏血吸虫和美洲按蚊成虫阶段抗原的同型反应之间存在很强的多效性效应，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对化疗后发生的与再感染相关的同型反应变化的贡献。化疗可以显著改变已经启动的抗体反应，并可能加速免疫反应，从而增强对再次感染的抵抗力。我将测试这样的假设：加性宿主遗传学对曼氏葡萄球菌和美洲奈瑟氏菌感染化疗后体液免疫反应的变化有显著贡献，并且这种加性遗传成分的相当大比例是由于潜在基因的多效性作用。我将继续使用在IRSDA的头三年收集的扩展的、多家庭的家谱，从这些家谱中已经获得了寄生虫学数据，并在最后三年保存了生物标本。使用最大似然方差分量分析，我将把与再感染有关的性状的方差划分为遗传和非遗传(系统和随机)分量。好了！还将进行双变量协方差分解分析，以检查所有与蠕虫相关的性状对之间的遗传相关性。这些分析将通过对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。这项研究中使用的数量遗传方法为理解蠕虫合并感染过程中导致特征变化的机制提供了新的途径。在进行连锁研究以确定和定位宿主中影响联合感染的特定基因之前，也有必要证明联合感染具有重要的遗传成分。宿主遗传学对化疗引起的免疫反应变化的贡献的研究是非常及时的，因为在发展中国家，知识和财政上重新重视化疗作为控制蠕虫感染的手段。

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.