Transgenic mice susceptible to poliovirus

Yesterday I terminated the last remaining mice in my small colony, including the line of poliovirus receptor transgenic mice that we established here in 1990. Remarkably, I had never written about this animal model for poliomyelitis which has played an important role in the work done in my laboratory.

While I was still working on poliovirus as a postdoctoral fellow with David Baltimore, I became interested in how the virus causes disease. There were no convenient animal models to study poliovirus pathogenesis, so I began to think about the cellular receptor for the virus and how it could be used to make a mouse model for infection. When I moved to Columbia University Medical Center in 1982, I decided to identify the cellular gene for the poliovirus receptor. This work was carried out by the second graduate student in my lab, Cathy Mendelsohn. She identified a gene from human cells that encoded a protein which we believed to be the cellular receptor for poliovirus. When this human gene was expressed in mouse cells, it made them susceptible* to poliovirus infection (the mouse cells were already permissive for poliovirus replication). The gene encodes a transmembrane glycoprotein (illustrated) that we called the poliovirus receptor (PVR), later renamed CD155. Over the years we worked extensively on PVR, with the goals of understanding its interaction with poliovirus during entry into the cell. In one project we collaborated with Jim Hogle, David Belnap, and Alasdair Steven to solve the structure of poliovirus bound to a soluble form of PVR. The image of that complex decorates the banner at virology blog and twiv.tv.

Shortly after identifying PVR as the cellular receptor for poliovirus, a new student, Ruibao Ren, joined my lab. For his project I suggested he create transgenic mice with the human gene for PVR. We already knew that synthesis of PVR in mouse cells allowed the complete poliovirus replication cycle. Together with Frank Costantini and JJ Lee, Ruibao produced PVR transgenic mice and showed that they were susceptible to poliovirus infection. The illustration at top left shows a PVR transgenic mouse with a paralyzed left hind limb after poliovirus inoculation.

Poliovirus transgenic mice were used for many years in my laboratory to study how the virus causes disease, and to identify the mutations that attenuate the neurovirulence of the Sabin vaccine strains. A good summary of this work can be found in my review, ‘One hundred years of poliovirus pathogenesis‘. But there is a dark side of this story that I wish to briefly recount. When we first developed PVR transgenic mice, my employer decided to patent the animals. Until the patent issued, we could not share the transgenic mice with other researchers. As a consequence, others developed their own lines of PVR transgenic mice. One of these lines has been qualified by the World Health Organization to determine the neurovirulence of the Sabin vaccine strains. However, Columbia University realized little income from the PVR transgenic mice – such animals cannot be patented in Europe. By patenting the mice, we simply delayed research progress. Because of this experience I am personally very wary about patenting biological discoveries.

There are several reasons why I decided to stop doing research with mice. The cost of housing and breeding mice is very high, nearly $1.00 US per cage per day, and I simply don’t have the funds to support such work. More importantly, no one in my laboratory has any interest in working with mice: the last student to do mouse work left years ago. Although there are many interesting experiments to be done using viruses and mice, that line of work ended for the Racaniello lab on 11 July 2011.

*A susceptible cell bears the receptor for the virus; a permissive cell allows viral replication. A susceptible and permissive cell allows the complete viral replication cycle.

 Ren, R., Costantini, F., Gorgacz, E., Lee, J., & Racaniello, V. (1990). Transgenic mice expressing a human poliovirus receptor: A new model for poliomyelitis Cell, 63 (2), 353-362 DOI: 10.1016/0092-8674(90)90168-E