The goals of the parent grant are to understand how MMTV uses its host to establish infection and to determine why some mice are genetically resistant to infection. MMTV has evolved to take advantage of the transcription factors that regulate gene expression in the cell types that it infects, namely, lymphocytes and mammary gland. Our preliminary data, derived from experiments performed as a result of the parent grant, indicate that various cytokines such as IL-2 and IL-4 induce MMTV transcription. Because the superantigen encoded by MMTV causes the production of these cytokines during the infection process, a by-product of this process would be increased virus production. In mice that lack the ability to fully respond to cytokines due to naturally occurring or induced genetic alterations, virus infection should be abrogated or reduced. Several types of genetically altered mice will be used: transcription and response to superantigen-stimulation will be compared in C3H/HeJ (Ipsr) and C3H/HeN (Ipss) mice to determine the role of the lipopolysaccharide sensitivity gene in regulating MMTV transcription; MMTV infection and transcription in Stat5a and 5b knockout mice will be tested, to examine the role of cytokines such as IL-2 and prolactin; IL-4 and Stat6 knockout mice will be examined for their ability to be infected with MMTV, to test the role of IL-4.
Three aims are proposed: 1. Examine the transcription of endogenous proviruses in the different mice. 2. Determine the course of MMTV infection in vivo in the C3H substrains and knockout mice. 3. Test the C3H substrains and knockout mice for immune responses to MMTV. The research that will be performed in this joint FIRCA project will allow us to address the role of cytokine induction on virus infection in vivo. Moreover, they will greatly expand the studies in my lab on how host genetic variation affects susceptibility or resistance to infection.
| Courreges, Maria Cecilia; Burzyn, Dalia; Nepomnaschy, Irene et al. (2007) Critical role of dendritic cells in mouse mammary tumor virus in vivo infection. J Virol 81:3769-77 |
| 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 |
| 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 |
