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The cotton rat is considered the model of choice for Respiratory
Syncytial Virus (RSV) studies because it recapitulates several characteristic features
in the human disease. The cotton rat model accurately predicted the success of immunoglobulin
prophylaxis (RespiGam®, MedImmune Inc.) against RSV bronchiolitis in the newborn
population. Clinical trials of a second, more potent generation of immunoprophylactic
therapy against RSV (Synagis®, MedImmune Inc.) were consented by FDA relying on
preclinical data solely generated in the cotton rat . In theses clinical trials,
Synagis® decreased the rate of hospitalization of high risk-infants up to 80%. In
addition, the cotton rat closely recapitulated the devastating pathological outcome
associated with the RSV-vaccine failure in the 1960’s. These achievements place
the RSV cotton rat model as the “gold standard” for testing vaccines, antivirals
and anti-inflammatory therapies against RSV.
The first use of the cotton rat in biomedical research occurred in 1937 and was related to poliovirus, rather
than to RSV. At that time paralytic poliomyelitis had been produced in experimentally
infected monkeys. However, scarcity and cost of these animals had severely limited their
utility as a model for vaccine development. In an effort to identify a small-animal
model, Dr. Charles Armstrong of the National Institute of Health dispatched his
assistants to Florida and Georgia, with instructions to live-trap wild rodents.
They returned with a wide variety of animals and injected them with a homogenate
of spinal cord from an 18-year-old who had died of polio. Amongst all the species,
only the cotton rat developed paralytic disease.
Over the ensuing decades the cotton rat has been shown to be a preferred model of
an impressive list of human pathogens: RSV, influenza (A and B serotypes), adenoviruses
(several serotypes), parainfluenza virus (type 3), measles, herpes simplex (types
1 and 2), human metapneumovirus, Staphylococcus species, Streptococcus species,
and Mycobacterium tuberculosis. The permissiveness of a single, small laboratory
animal for such a wide array of human pathogens is unprecedented. A few general
observations may provide clues to the cotton rat’s unique utility:
- Unlike the laboratory mouse, which either lacks or
has defective Mx genes that are of great importance in the host response to infection,
the cotton rat has fully functional Mx genes that appear to respond to infection
in the same manner as human Mx genes.
- The intracellular machinery of cotton rats differs
markedly from that of laboratory mice, as evidenced by the fact that human immunodeficiency
virus (HIV-1) productively infects cotton rat cells, yet is blocked by post-entry
mechanisms in mouse cells.
- RNA from RSV-infected cotton rat lungs reacts with
double (about 600) the number of genes on a human gene chip as on a mouse chip (about
300).
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