We have recently described the existence of the Beg gene located on the chromosome 1 of the murine genome which is the primary regulator of host resistance to infection with intracellular bacterial and protozoal parasites. This gene controls the intrinsic antimicrobial activity of the resident macrophages in the tissues of infected host. Although the mechanism of the Beg gene's action is independent of specific immune responsiveness, the activity of the gene profoundly influences the quality of the acquired cellular responses which develop in the course of infection. We have developed the experimental tools which allow us to attempt the isolation of the Beg gene and the identification of the Beg gene product.
Specific aims of the research proposed in this application are: (1) To identify and clone genomic sequences encoding the Beg gene. This will be achieved by constructing recombinant phage genomic libraries enriched in sequences from mouse chromosome 1 and by using the library to identify the restriction fragment length polymorphisms in the vicinity of the gene. (2) To characterize the Beg gene product at subcellular and molecular level, by analyzing the variability in the antimycobacterial activity of the macrophages derived from pairs of mouse strains which were made congenic for the Beg locus. The search for the gene product will be facilitated by the production of antibodies raised in the Beg-congenic system. (3) To demonstrate the mechanism(s) leading to the modulation, by the Beg gene, of acquired cellular responses (protective versus suppressive) to mycobacterial infection. Long term objectives of this project are to isolate the Beg gene and its product and to attempt the phenotypic conversion from the innate susceptibility to the resistance. Significance: The research program proposed in this application will ultimately lead to the development of methods for an identification of genetic susceptibles in populations and to the devising strategies of their protection from the chronic infectious diseases which still represent the major health hazard.
