The principal objective of this study is the identification and characterization of the major genetic effects that determine the resistance level of mice to the intestinal nematode T. spiralis. Pursuant to this goal we would further develop our analysis of three major components of host resistance; namely the rapid expulsion (RE) of ingested larvae, the rejection of adult worms in the primary infection (Adult lo) and resistance to migratory newborn larvae (anti-NBL). Specifically, we wish to characterize the gene and define linkage for lhe-1, the gene governing RE in mice. We will continue our analysis of genetic control of Adult lo and define the genetic factors that influence anti-NBL immunity. Data to hand indicate that major control of each of these responses is determined by genes that are not linked to the mouse MHC. A strain analysis of responsiveness also suggests that each genetic system is independent of the other. The strength of the Adult lo response is determined by at least two non-MHC. A strain analysis of responsiveness also suggests that each genetic system is independent of the other. The strenght of the Adult lo response is determined by at least two non-MHC genes (AA and BB) which are co-dominant and additive. In this study RE, Adult lo and anti-NBL will be analyzed by single approach that comprises; l) continuing strain survey to phenotypicaly characterize the response pattern of a wide variety of inbred strains, including recently derived wild mouse strains. The objective is to define the phenotypic variation that exists in mice and identify the strongest and weakest responder for further genetic analysis; 2) analysis of selected F1 hybrids to characterize dominance, complementation and autosomal or sex-linked character, followed by a segregation analysis of F2 and backcross to estimate the numbers of loci involved; 3) linkage analysis of major genes; for Adult lo (AA and BB) we will also use recombinant inbred mouse lines; 4) definition of chromosomal position. We will use the following approach to examine function for the AA and BB genes. Antibody responses to adult worm excretion/secretion antigens will be analyzed to determine antibody kinetics, repertoire and class-specificity. Secondly, we will determine whether AA and BB operate through bone-marrow derived cells by using radiation chimeras. Thirdly, we will measure strain-specific delayed hypersensitivity responses to adult antigens. These studies will define the function of the genes that we identify, particulary as it relates to their role in acquired resistance to infection.
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