Why we use the calf as a model for human disease:
Innate
immune recognition of microbes in the intestine is a pivotal step during host
pathogen interactions that result in disease. The rationale for studying
innate immune recognition is that a better understanding of the underlying
molecular mechanisms will be required for developing innovative approaches for
treatment or prevention of infections such as inflammatory diarrhea.
Furthermore, detailed knowledge about the mechanisms involved in the normal
regulation of intestinal inflammation will be required to fully understand
disease states of uncontrolled inflammation, such as inflammatory bowel
disease.
A
current limitation for studying innate immunity is that the host response to
infection observed in the most commonly used animal model, the mouse, differs
dramatically from that observed in the human. For example, mice infected with Mycobacterium
avium paratuberculosis develop a systemic infection while cattle develop a
localized enteric infection that resembles inflammatory bowel disease (this
pathogen has also been isolated from a subset of patients with Crohn's
disease). Oral S. Typhimurium infection in mice results in intestinal
inflammation characterized by a slowly developing mononuclear infiltrate which
develops in the absence of diarrhea. In contrast, S. Typhimurium
infections in calves and humans are characterized by a rapidly developing
neutrophil infiltrate in the intestine that is always associated with diarrhea.
These data show that mice and humans exhibit
strikingly different disease manifestations and host responses during infection
with invasive enteric pathogens. Due to these limitations it is difficult to
extrapolate data on the host response to enteric pathogens obtained using
rodent models to human disease. In contrast, the striking similarities in the
host responses of calf and human illustrate that the bovine host is an
excellent model for studying responses observed in the intestine. Although the
calf will not likely become a model used as widely as the mouse,
characterization of the host response in calves is significant because it will
provide insights into responses that cannot be studied using mice.
The bovine ligated ileal loop model allows the
collection of samples at defined time points of up to 12 hours after infection,
thereby providing a powerful tool for studying host pathogen interaction in
vivo using a variety of techniques, including in situ hybridization,
immunohistochemistry, histopathology, ultrastructural analysis and gene
expression analysis using real-time polymerase chain reaction (RT-PCR), DNA
microarrays or massive parallel signature sequencing
(MPSS). With highly developed linkage and Riation
Hybrid (HR) maps, a nearly completed whole-genome Bacterial Artificial Chromosome (BAC) map, sequences
being available for genes involved in innate immunity and complete sequencing
of its genome as a high priority at the NHGRI, the bovine is among the better
genetically defined mammals, aside from humans and laboratory rodents.
Transmission Electron Micrograph of Brucella entering a macrophage
Massive proliferation of Brucella in a bovine macrophage
