This project is directed at understanding the role of specific enzyme systems in generating and maintaining host immunity. The approach taken involves the creation of mice with discrete defects in host defenses by using homologous recombination of DNA into the host genome to disrupt relevant genes. Lesions will be introduced that either correspond to previously identified mutations in humans or that incapacitate systems probably involved in host defense. We have used the NADPH oxidase system as a paradigm for creation of mice with a genetic defect similar to one found in humans, chronic granulomatous disease (CGD). To this end, we have cloned, sequenced, and functionally expressed the cDNA of the murine homolog of the human 47(phox) gene. We have isolated genomic fragments from this gene and are characterizing them for disruption and re-insertion into the mouse genome. This will provide the basis for a murine model of the most common form of autosomal recessive CGD. We have also cloned and characterized genomic fragments of the murine homolog of the human 91(phox) gene. This will provide us with a tool for creating a murine model of the predominant, X-linked form of CGD.