Immunology Graduate Group
Susan R. Ross, Ph.D.
Professor, Microbiology
Address: 313 BRB II/III
Office Phone: 215-898-9764
Lab Phone: 215-898-2986
Fax: 215-898-2028
Email: rosss@mail.med.upenn.edu
Education:
Postdoctoral fellow, Wistar Institute
Postdoctoral fellow, University of California at San Francisco
Ph.D., Princeton University
B.A., University of Pennsylvania
Research Interests
Host/virus interactions; genetics of susceptibility to virus infection; immune response to virus infection
Research Summary
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| Pathway of MMTV infection. B cells first acquire the virus and present superantigen (SAG) to T cells, which are activated and cause bystander cell division. Both types of lymphocytes divide and become infected. At puberty, mammary gland cell (MG) division occurs and these cells become MMTV infected. Pregnancy stimulates mammary glad cell division and virus production. |
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 are using mouse mammary tumor virus (MMTV) to study virus/host interactions. MMTV is a retrovirus that causes breast cancer in mice. It is both inherited through the germ line and passed as an infectious virus from mothers to offspring through milk. The ultimate target tissue for MMTV is the mammary gland. However, MMTV encodes a superantigen that allows it to use cells of the immune system in its journey from milk to the mammary gland of offspring. An ongoing project is to determine which type of lymphocytes are important for delivering MMTV to the mammary cell and how infected lymphocytes traffic to this tissue.
Although most retroviruses require activated cells as their targets for infection, it is not known how this is achieved in vivo. A candidate protein for the activation of B cells by MMTV is the toll-like receptor 4 (TLR4), a component of the innate immune system. We recently showed that B cells from mice with mutations in their TLR4 gene were not activated by MMTV, in contrast to those from wild type mice. We also determined that the MMTV envelope protein binds TLR4. Our current focus is on understanding the outcome on viral infection of signaling through TLR pathways.
A better understanding of how MMTV infects these different cell types and reaches its target tissue is dependent on identifying the cell surface receptor that the virus uses to infect cells. We recently found that mouse transferrin receptor 1 (TfR1) is the MMTV cell entry receptor. TfR1 is the major means by which most cells take up iron and it is a lymphocyte activation marker. We are currently studying the physical interaction between the MMTV envelope protein and TrfR1 and how lymphocyte activation by the virus affects receptor levels. We are also determining why the human TrfR1 does not function as a virus receptor. This is important to determine because several labs have recently implicated MMTV-like elements in human breast cancer.
Recent Publications
Czarneski, J., Meyers, J.L., Peng, T., Abraham, V. and Ross, S.R. (2001). Interleukin-4 up-regulates MMTV expression but is not required for in vivo virus spread. J. Virol. 5:11886-11890.
Rassa, J.C., Meyers, J.L., Zhang, Y., Kudaravalli, R. and Ross, S.R. (2002). Murine retroviruses activate B cells via interaction with the Toll-like receptor 4. Proc. Natl. Acad. Sci. USA 99:2281-2286.
Czarneski, J., Berguer, P., Bekinschtein, P., Kim, D.C., Hakimpour, P., Wagner, N., Nepomnaschy, I., Piazzon, I. and Ross, S.R. (2002). Neonatal infection with mouse mammary tumor virus is independent of 7 integrin- or L-selectin-expressing lymphocytes. Eur. J. Immunol. 32:945-956.
Lee, J.D., Kim, D.C., Gee, M.S., Saunder, H.M., Sehgal, C.M., Ross, S.R. and Lee, W.M.F. (2002). Interleukin-12 inhibits angiogenesis and growth of transplanted but not in situ mouse mammary tumor virus (MMTV)-induced mammary carcinomas. Canc. Res. 62: 747-755.
Ross, S.R., Schofield, J., Farr, C. and Bucan, M. (2002). Mouse tranferrin receptor 1 is the cell entry receptor for mouse mammary tumor virus. Proc. Natl. Acad. Sci. USA 99:12386-12390.
Rassa, J. and Ross, S.R. (2003). Viruses and Toll-like receptors. Microbes and Infection, 5:961-968.
Zhang, Y., Rassa, J.C., deObaldia, E.M., Albritton, L.M. and Ross, S.R. (2003). Identification of the mouse mammary tumor virus envelope receptor-binding domain. J Virol. 77: 10468-10478.
Burzyn, D., Rassa, J.C., Kim, D.C., Nepomnaschy, I., Ross, S.R. and Piazzon, I. MMTV activates dendritic cells through toll- like receptors. J. Virol., in press.
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