Multicellular living organisms and unmodified parts thereof and – Nonhuman animal
Reexamination Certificate
1998-09-18
2002-03-12
Clark, Deborah J. R. (Department: 1632)
Multicellular living organisms and unmodified parts thereof and
Nonhuman animal
C536S023100, C536S023500, C424S009100
Reexamination Certificate
active
06355859
ABSTRACT:
BACKGROUND OF THE INVENTION
This invention relates interactions between genotype and diet in swine that prevent
E. coli
associated intestinal disease. Methods and compositions are provided for identifying swine which are genetically able to utilize low cost feed stuffs and feed compositions to prevent intestinal disorders after weaning.
Disease caused by F18
+E. coli
can be prevented by reducing the amount of soy bean meal (SBM) and total protein in the diet; however, this decrease in the total protein content of the pig's diet results in decreased quality e.g. weight (Bosworth et al., 1996; Bertschinger et al., 1979). Therefore, this treatment for F18
+E. coli
is not economical. Diets that prevent disease due to F18
+E. coli
but still contain high enough protein levels to allow swine to gain weight rapidly after weaning would be desirable.
Reduction of costs in swine production is a goal of breeders. Two of the most significant costs associated with swine production relate to food and disease, especially in the postweaning period. Intestinal diseases reduce weight gain, hence decrease the value of the swine. Treatment costs also occur. Swine weaned early require a high amount of protein in their diet in order to gain weight adequately, and the source of the protein is a major food diet cost. Plant-based sources high in protein content, typically soy bean meal (SBM), are common ingredients in most swine diets and are cheaper than animal-based sources, such as fish meal and blood meal. However, swine fed diets with high levels of SBM frequently have a reduced rate of weight gain relative to swine fed nursery diets postweaning in which a portion of the SBM is replaced with animal byproducts, such as whey and plasma (Li et al., 1991). The mechanisms responsible for this reduced rate of gain in recently weaned swine are not defined, but it could be that SBM acts as a food allergen in recently weaned swine who have just been removed from a diet high in animal protein (i.e., sows' milk).
A major problem in breeding swine is to keep them disease-free. Intestinal disorders postweaning are a particular problem. Intestinal disease is manifest in swine infected with F18
E. coli
who may get either diarrhea and/or edema disease after weaning. Newborn swine are resistant to disease due to F18
E. coli
because they do not express intestinal receptors for this
E. coli
and thus, the
E. coli
is unable to adhere to and grow (colonize) the intestine of newborn swine (Nagy et al, 1992). F18
E. coli
can also cause a mild subclinical disease, which results in a decreased rate of gain after weaning, but may cause no other detectable clinical signs (Bosworth et al., 1996). Swine suffering from subclinical disease also have very mild vascular damage in the brain and intestines, problems only detectable by thorough histologic examination performed by an experienced investigator.
A limited number of serotypes of toxigenic
Escherichia
(
E.
)
coli
strains are the causative agents of oedema disease and postweaning diarrhea in swine which induce serious economic losses, especially among piglets aged 4 to 12 weeks, in swine breeding farms all over the world. The typical clinical symptoms of oedema disease are neurological signs such as ataxia, convulsions and/or diarrhea. At post mortem examination, oedema is typically present at characteristic sites such as eyelids and forehead, stomach wall and mesocolon. The diseases are caused by Shiga-like toxin-II variant and enterotoxins LT, STa, STb respectively, produced by
E. coli
that colonize the surface of the small intestine without effecting major morphological changes of the enterocytes (cells in the intestine). Types of bacterial
E. coli
strains, such as F4, F18 and K88 are major lethal villains in this regard. “Oedema disease of swine is an enterotoxaemia characterized by generalized vascular damage. The latter is caused by a toxin, Shiga-like toxin II variant, produced by certain strains of
E. coli
” (Bertschinger et al., 1993). The
E. coli
are distinguished by their pili types, a group of adhesive fimbriae that are related are designated e.g., K88 or F18 (Vögeli et al., 1996).
Not all swine succumb to
E. coli
infections. Colonization depends on adherence of the bacteria to the enterocytes which is mediated by the bacterial fimbriae designated e.g., K88 or F18. Susceptibility to adhesion, i.e. expression of receptors in swine for binding the fimbriae, has been shown to be genetically controlled by the host and is inherited as a dominant trait with, in the case of F18, B being the susceptibility allele and b the resistance allele. (Vögeli et al., 1996; Meijerink et al., 1996). The genetic locus for this
E. coli
F18-receptor (ECF18R) has been mapped to porcine chromosome 6 (SSC6), based on its close genetic linkage to the S locus and other loci of the halothane (HAL) linkage group on chromosome 6. The receptor for K88
E. coli
is on chromosome 13.
The mechanism for resistance appears to be that intestinal borders in resistant animals are not colonized by
E. coli,
i.e., the bacteria do not adhere to intestinal walls of resistant swine. Glycoprotein receptors in the brush border membrane of the intestine were shown to be responsible for the differences between adhesive and non-adhesive phenotypes related to some
E. coli,
therefore, the genotype of the host swine determines resistance. The fimbriated bacteria also have been studied. (WO 9413811)
Current methods of identifying swine that are resistant to F18
E. coli
associated diseases are either to 1) collect intestinal samples from swine at slaughter and perform the microscopic adhesion test, (see Example 2 herein) 2) challenge the animals with virulent
E. coli
(“colonization test”), or 3) perform blood typing of the A-O(S) blood group system. The first two methods are not practical for identifying resistant animals for use as breeding stock. Although the blood typing method does identify resistant animals, the test is unable to determine whether susceptible animals are homozygous or heterozygous for susceptibility. At least two alleles (condition of a gene) at the receptor locus control either susceptibility (dominant) or resistance (recessive). Knowledge of the genotype of animals with regard to these alleles is essential to develop a successful breeding program. The purpose of the breeding program is to produce swine that are resistant to F18
E. coli
associated diseases that decimate stock post-weaning.
In one publication the authors stated, in reference to oedema disease in swine, that “Searches are underway for appropriate genetic markers . . . ” (Bertschinger et al., 1993, page 87) and, citing Walters and Sellwood, 1982:
Breeding resistant swine is an attractive method for prevention of diseases for which an effective prophylaxis is not available. The feasibility of this approach will depend on the prevalence of the gene(s) encoding resistance in the pig population, improved methods for the detection of resistant swine, and absence of negative genetic traits co-selected with this resistance.
A genetic “marker” locus is a coding or non-coding locus that is close to a genetic locus of interest, but is not necessarily the locus itself. Detectable phenotypes include restriction length fragment polymorphisms, colorimetric or enzymatic reactions, and antibiotic resistance. The S locus controls expression of the A and O blood group antigens. Swine homozygous recessive at the S locus do not express either A or O blood group antigens. A similar condition exists in humans and is due to mutations in the alpha (1,2) fucosyltransferase gene which encodes the human blood group H (Kelly et al., 1994; see also WO 9628967). The porcine alpha (1,2) fucosyltransferase gene of swine has recently been sequenced (Cohney et al., 1996). This gene is very likely the gene present at the S locus in swine.
The blood group H and Se loci have been mapped genetically and physically to human chromosome 19q13.3. This region is evolutionarily conserved, containing genes hom
Bosworth Brad
Ridpath Julia
Wiseman Barry
Barnes & Thornburg
Biotechnology Research and Development Corporation
Clark Deborah J. R.
Martin Alice O.
Paras, Jr. Peter
LandOfFree
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