Grants and Contributions:

Grant or Award spanning more than one fiscal year. (2017-2018 to 2018-2019)

The innate immune system serves as a front line defense against microbial pathogens. Activation of innate immunity occurs through pattern recognition receptors which detect pathogen-associated molecular patterns to the initiation of the immediate cellular responses required for management of the pathogen while communicating the occurrence of this threat, and potential need for higher-order responses, to the adaptive immune system. The Toll-like receptors (TLRs) are among the most important pattern recognition receptors of the innate immune system. While the various TLRs are activated by diverse ligands, the ensuing responses are classically associated with a conserved pathway of signal transduction to a common cellular response. This model is consistent with the belief that that innate immune system, and the responses that it governs, are generally non-specific. There is emerging evidence, however, that challenges this perspective with the suggestion of a higher degree of specialization of signalling, and responses, from individual TLRs as well as synergies that exist between different TLRs that enable responses that are customized to specific situations of TLR activation. That is to say that the innate immune response is not binary in its activation, but rather capable of specialization depending on the specific nature of activation of its sensory receptors. Similarly, there is emerging appreciation that biological processes, such as immunity and stress, do not exist in the functional isolation of closed systems but rather share considerable functional overlap and multidirectional influence. While there is general awareness among the general public, as well as within the scientific literature, of the relationship between stress and immunity, the precise mechanisms by which stress compromises immunity remain unclear. Dysregulation of TLR signalling may represent a mechanism by which stress compromises immunity. The objectives of this proposal are to apply a novel platform for kinome analysis established by my lab to: a) gain insight into the true biological complexity of TLR signalling, including responses specific to individual TLRs as well as synergies between TLRs, and to b) define changes to TLR signalling within the context of stress, including representation of both branches of the stress response. This investigation will provide a better overall appreciation of the complexities of kinase-mediated signal transduction within a central system of immunity as well as providing information on how stress influences TLR signaling, which is of broad biological interest for understanding how stress compromises immune function. Further, understanding how stress influences the responsiveness of bovine immune cells could have application in the management of infectious diseases within livestock through improved management practices.