Sep 5, 2011

Transgenic mice susceptible to poliovirus

pvr transgenic mouseYesterday 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 madepvr modelthem susceptible* to poliovirus infection (the mouse cells were alreadypermissive 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.
Figure 1
(a) Cryomicrographs of poliovirus particles complexed with (Top) and without (Bottom) sPvr. Bar = 300 Å. Image reconstructions are shown of virion + sPvr [in stereo (b)] and, for comparison, of the virion (c) (from ref. 9). The two reconstructions were overlaid in d with the respective contour levels adjusted to clarify the interaction of sPvr with the virion. Bar = 100 Å. (e) Two views of a single sPvr molecule extracted from the difference map. Domain boundaries are marked. Bar = 25 Å.
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, The pathogenesis of poliomyelitis: what we don't .


Source

Department of Microbiology and Neurology, School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.

Abstract

Poliomyelitis has long served as a model for studies of viral pathogenesis, but there remain many important gaps in our understanding of this disease. It is the intent of this review to highlight these residual but important questions, in light of a possible future moratorium on research with polioviruses. Salient questions include: 
(1) What cells in the gastrointestinal tract are initially infected and act as the source of excreted virus?
 (2) What is the receptor used by mouse-adapted strains of poliovirus and how can some polioviruses use both mouse and primate receptors? 
(3) What determines species differences in susceptibility of the gastrointestinal tract to polioviruses? Why cannot PVR transgenic mice be infected by the natural enteric route? 
(4) Why are neuroadapted polioviruses unable to infect nonneural cells?
 (5) What is the role of postentry blocks in replication as determinants of neurovirulence?
 (6) What route(s) does poliovirus take to enter the central nervous system and how does it cross the blood-brain barrier?
 (7) Why does poliovirus preferentially attack lower motor neurons in contrast to many other neuronal types within the central nervous system? 
(8) Does cellular immunity play any role in recovery from acute infection or in vaccine-induced protection? 
(9) In which cells does poliovirus persist in patients with gamma-globulin deficiencies? 
(10) Is there any evidence that poliovirus genomes can persist in immunocompetent hosts? 
(11) Why has type 2 poliovirus been eradicated while types 1 and 3 have not?
 (12) Can transmission of vaccine-derived polioviruses be prevented with inactivated poliovirus vaccine?
 (13) What is the best strategy to control and eliminate vaccine-derived polioviruses?
PMID:


18585526
[PubMed - indexed for MEDLINE]

Aug 30, 2011

3 Casos de Polio Post Vacunal en Peru

Lunes, 29 de Agosto 2011  |  2:24 pm


Director general de Salud asegura que no hay rebrote de polio

Lunes, 29 de Agosto 2011  |  2:24 pm
/Director afirmó que a diferencia de la polio tradicional que 
se presentaba de manera crítica, los casos de los tres niños son diferentes
 y que tienen la opción de rehabilitarse.

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