All animals, including humans, show differential susceptibility to infection with viruses. Study of the genetics of susceptibility or resistance to specific pathogens is most easily studied in inbred mice. We have been using mouse mammary tumor virus (MMTV), a retrovirus that causes mammary tumors in mice, to study virus/host interactions. These studies have focused on understanding the mechanisms which determine genetic susceptibility to MMTV- induced mammary tumors and the regulation of virus gene expression in vivo. Genetic susceptibility may be determined by the ability of different mouse strains to regulate MMTV expression. Because MMTV infects both the immune system and mammary gland, it has acquired transcriptional regulatory regions that control its expression in these tissues. We will focus on 2 of these regions, the mammary gland enhancer and the STAT (Signal Transducers and Activators of Transcription) recognition element. To determine the role of the STAT family of transcription factors in mammary gland and lymphoid tissue expression of MMTV we will identify the factors that interact with the STAT consensus sequence and elucidate their in tissue-specific and cytokine-, lipopolysaccharide- or prolactin- mediated regulation of MMTV transcription using transfection studies and transgenic mice. We will also identify, characterize and clone the transcription factor that controls mammary gland-specific expression. Finally, we have found a genetic locus in C3H/HeN mice that confers dominant susceptibility to MMTV infection. We will determine what step in the infection pathway is controlled by this locus, perform genetic linkage analysis using PCR-based microsatellite markers to determine its chromosomal location, establish a physical map of the region and use cloned large genomic fragments (YAC/BAC) to create transgenic mice as a functional means to test candidate loci and clone the susceptibility gene. The results obtained from these studies will greatly increase our understanding of the genetic mechanisms which viruses use to infect their hosts and how genetic resistance to such viruses in the hosts occurs.
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