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 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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