Susan R. Ross, Ph.D.

Professor of Microbiology

Office Address:
University of Pennsylvania School of Medicine
313 BRBII/III
421 Curie Blvd
Philadelphia, PA 19104-6141

TEL 215-898-9764
LAB 215-898-2986
FAX 215-573-2028
rosss@mail.med.upenn.edu

RESEARCH SUMMARY

The use of both genetic and molecular approaches to the study of virus-host interactions in vivo provides us with insight into the processes that determine the susceptibility and resistance of individuals to viral infection and virus-induced cancer (approximately 20% of human cancers). Our interests lie in determining why viruses infect specific hosts and how in turn, host genes confer resistance to this infection.

The genetics of susceptibility is easily studied with naturally-occurring pathogens in inbred and genetically-manipulated mice. One virus that we study is mouse mammary tumor virus (MMTV), an endemic oncogenic retrovirus that has been an infectious agent in mice for > 20 million years. Infectious MMTV is passed from mothers to offspring through milk and first spreads in lymphoid cells before infecting mammary epithelial cells. This route of transmission makes the study of MMTV a good model for the human milk-borne retroviruses HIV-1 and HTLV1. MMTV causes breast cancer when the viral genome inserts next to cellular oncogenes, thereby activating their expression. Our studies focus on understanding the mechanisms that determine susceptibility to MMTV infection and virus-induced mammary tumors and we have identified a number of genes and mechanisms that confer resistance to infection by MMTV.

One gene which we recently discovered is involved in the control of MMTV infection is apobec3. The genomes of all mammals encode apobec3 genes which play a role in intrinsic cellular immunity to a number of viruses, including human immunodeficiency virus type 1. APOBEC3 proteins are packaged into virions and inhibit retroviral replication in newly infected cells, at least in part by deaminating cytosine on the negative strand DNA intermediates. We found that mouse APOBEC3 protein is packaged into MMTV particles in vitro and dramatically reduces viral titers. Most importantly, APOBEC3 knockout mice are more susceptible to MMTV infection compared to their wild type littermates. These findings indicate that the APOBEC3 provides protection to mice against MMTV infection and represent the first demonstration that it functions during retroviral infection in vivo. We are currently studying how genetic variation in the mouse APOBEC3 genes affects their ability to inhibit MMTV infection, whether APOBEC3 can be used as an anti-retroviral therapeutic target and whether packaging of APOBEC3 in viruses that are vertically transmitted from mother to offspring limits this transmission.

We are also interested in how MMTV causes breast cancer and recently found that the MMTV envelope protein plays a role in this process. We found that ectopic expression of the MMTV envelope protein in normal mammary epithelial cells resulted in phenotypic transformation and that an immuno-tyrosine based activation motif (ITAM) in this protein was critical to this activity. Moreover, mutation of the ITAM motif in an infectious MMTV dramatically attenuated its ability to cause mammary tumors, without affecting its infectivity in vivo. ITAMs are commonly found in receptors expressed in hematopoietic cells and are negatively regulated by cell-type specific modulators. We speculate that uncontrolled signaling by the envelope protein in epithelial cells, which lack such negative modulators, is an early step in the MMTV transformation process. Because ITAMs are found both in viral and cellular proteins, inappropriate expression of such signaling molecules represents a novel mechanism of transformation and is of potential importance in developing new treatment paradigms for breast and other cancers, especially those associated with viruses that encode proteins that activate ITAM-mediated signaling.

A final area of research in the lab is on virus entry and how it affects tropism and pathogenesis. Numerous reports in recent years have implicated a virus highly related to MMTV in human breast cancer and patients with primary biliary cirrhosis, an autoimmune disease, making it important to determine whether the MMTV can infect human cells. We showed that the mouse mammary tumor virus cell entry receptor is mouse transferrin receptor 1 (TfR1) and that mouse and rat but not human, hamster, dog or cat TfR1 function as MMTV entry receptors. By constructing hybrid mouse/human TfR1s we mapped the segments of the mouse receptor important for virus infection, thus confirming that human TfR1 does not function as an MMTV entry receptor. This led us to a new area of investigation on how New World hemorrhagic fever arenaviruses (NWA) like Junin and Machupo virus infect cells, because these viruses show the opposite species tropism, using human but not mouse TfR1 as an entry receptor. We are currently studying how MMTV and the NWA use TfR1 to enter cells, how the iron metabolic pathway intersects with infection by these viruses and whether there are additional molecules involved in cell- and disease-tropism.

RECENT PUBLICATIONS





Current Lab Members:

Chioma Okeoma, Ph.D. Postdoc
Pieter van den Heuvel, Ph.D., Postdoc
Lavanya Madakasira, Ph.D., Postdoc
Christian Cuevas, Ph.D., Postdoc
Alyssa Huegel, B.A., Graduate Student
Andrew Zodda, M.S., Lab Manager

 


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