Stimulating innate immune reponse to prevent pneumonia in beef cattle
The goal of this work is to develop a method to stimulate immune responses in beef calves that are immunosuppressed by stress or viral infection, as a method to prevent bacterial pneumonia such as shipping fever. We previously showed that these innate immune responses can be effective in killing the bacteria that cause pneumonia in cattle, but that these responses fail during stress and viral infection. This is one reason that these factors predispose to bacterial pneumonia, but is also an opportunity to stimulate this response to prevent disease.
As a first step, we examined molecular pathways that stimulate production of tracheal antimicrobial peptide (a “natural antibiotic” produced in the calf’s airways that kills the bacteria causing pneumonia in cattle), using tracheal epithelial cells grown in vitro. Synthesis of tracheal antimicrobial peptide by these cells has long been known to be stimulated by lipopolysaccharide, a component of Gram-negative bacteria. We looked at a panel of 8 other stimuli, selected to target known receptors on the cell surface, to identify any that gave an earlier response. We found two stimuli that induced earlier responses than lipopolysaccharide: Pam3CSK4, an agonist of a surface receptor called Toll-like receptor 2/1 that detects other cell wall products of bacteria; and interleukin-17A, a calf protein that has been recently identified in humans as important to defence against bacterial infection on body surfaces including the respiratory tract. These findings are critical, because they will help in selecting drug candidates that are already known to affect these specific pathways, and may therefore be able to stimulate this immune response.
We next examined the signalling pathways within the cell that are necessary for Pam3CSK4, lipopolysaccharide and IL-17A to stimulate production of tracheal antimicrobial peptide. The results, using two different experimental approaches, showed that Pam3CSK4 and lipopolysaccharide both require a pathway called NF-κB, whereas IL-17A is less dependent on this pathway. As above, these findings are important because they will allow us to identify specific drug candidates that are already known to affect this pathway.
We developed a method to transiently stimulate innate immune responses in calves that seems to be effective. Some additional refinement of the method and characterization of the resulting innate immune responses are pending. The next steps are to test Page 2 of 6 whether stimulating these responses does indeed increase the resistance to infection and disease, in experimental and in natural disease settings. These studies are planned for later this year, as the project continues with support from Zoetis, NSERC and OMAFRA that was stimulated by this early funding from OCA/BFO.
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