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Title: GENETICALLY ENHANCED COWS RESIST INTRAMAMMARY STAPHYLOCOCCUS AUREUS INFECTION

Author
item Wall, Robert
item Powell, Anne
item Paape, Max
item KERR, D - UNIV OF VERMONT
item Bannerman, Douglas
item PURSEL, V - ARS-RETIRED
item WELLS, K - REVIVICOR, INC.
item Talbot, Neil
item HAWK, H - ARS-RETIRED

Submitted to: Nature Biotechnology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 2/2/2005
Publication Date: 4/3/2005
Citation: Wall, R.J., Powell, A.M., Paape, M.J., Kerr, D.E., Bannerman, D.D., Pursel, V.G., Wells, K.D., Talbot, N.C., Hawk, H.W. 2005. Genetically enhanced cows resist intramammary staphylococcus aureus infection. Nature Biotechnology. 23(4):445-451.

Interpretive Summary: Mastitis, a bacterial infection of the mammary gland, has been reported to cost the US dairy industry $2 billion a year. Antibiotics are only moderately affective at curing mastitis and no effective vaccine has been developed. In this study we evaluated a genetic engineering solution by testing cows carrying a new gene (lysostaphin) designed to protect them from Staphylococcus aureus, the most tenacious of the bacteria that causes mastitis. In the laboratory we were able to show the milk from those transgenic animals killed S. aureus and the effectiveness of killing was related to the concentration of lysostaphin in the milk. We then infused S. aureus into the mammary glands of 3 transgenic and 10 non-transgenic cows. Thirty-four of 48 glands (71%) in non-transgenic animals became infected compared to 3 of 21 glands (14%) in transgenic animals. Typical immune system responses to mastitis, such as infiltration of white blood cells into mammary glands, elevated body temperature and acute phase proteins were observed in the non-transgenic animals, but not in the transgenic cows. Cows that were producing relatively low levels of lysostaphin exhibited increased resistance to infection while the cow producing more lysostaphin was completely protected against infection. This is the first example of improving animal well-being through genetic engineering. Products made from the milk of these animals should have public health benefits as well.

Technical Abstract: Mastitis, the most consequential disease in dairy cattle, costs the US dairy industry billions of dollars annually. To test the feasibility of protecting animals through genetic engineering, a transgene encoding the endopeptidase, lysostaphin, was introduced into cattle. Transgenic cows produced lysostaphin at concentrations ranging from 0.9 to 14 ug/ml in their milk. In vitro assays demonstrated the milk's ability to kill Staphylococcus aureus, exhibiting bioequivalence of approximately 15% of recombinant lysostaphin produced in bacteria. Intramammary infusions of S. aureus were administered at peak, mid- and late stages of lactation to three transgenic and 10 non-transgenic cows. Milk somatic cell increases, indicative of infection, were observed in all of the challenged non-transgenic cows but in none of the transgenic animals. Measures of innate immune responses such as a rise in body temperature and induction of hepatically-derived acute phase proteins were observed in non-transgenic animals but not in the transgenics. Protection appeared to be dose dependent, with a predicted threshold of expression of 3 ug/ml of milk required for complete protection. Genetic engineering appears to be a viable tool for protecting against debilitating disease and improving animal well-being in livestock.