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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA045954-17
Application #
2871721
Study Section
Mammalian Genetics Study Section (MGN)
Program Officer
Cole, John S
Project Start
1987-05-15
Project End
2002-01-31
Budget Start
1999-02-01
Budget End
2000-01-31
Support Year
17
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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Burzyn, Dalia; Rassa, John C; Kim, David et al. (2004) Toll-like receptor 4-dependent activation of dendritic cells by a retrovirus. J Virol 78:576-84
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Rassa, John C; Meyers, Jennifer L; Zhang, Yuanming et al. (2002) Murine retroviruses activate B cells via interaction with toll-like receptor 4. Proc Natl Acad Sci U S A 99:2281-6
Czarneski, Jennifer; Berguer, Paula; Bekinschtein, Pedro et al. (2002) Neonatal infection with a milk-borne virus is independent of beta7 integrin- and L-selectin-expressing lymphocytes. Eur J Immunol 32:945-56
Czarneski, J; Meyers, J; Peng, T et al. (2001) Interleukin-4 up-regulates mouse mammary tumor virus expression yet is not required for in vivo virus spread. J Virol 75:11886-90
Hook, L M; Agafonova, Y; Ross, S R et al. (2000) Genetics of mouse mammary tumor virus-induced mammary tumors: linkage of tumor induction to the gag gene. J Virol 74:8876-83

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