Kinomic Evaluation of Toll-like Receptor Signalling: Specialization, Synergies and Stress

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Within both the general public and scientific community there is an overall appreciation that a relationship exists between stress and immunity. 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. The influences often manifest at the level of cellular signalling to influence the ultimate phenotypes. The objective of this proposal is to obtain a detailed picture of innate immune signaling and to define changes to those patterns within the context of acute stress. The ultimate goal is to to define molecular mechanisms by which the different branches of the stress response influence innate immunity with subsequent consequences to susceptibility to infectious disease. We will conduct kinome analysis to precisely define signaling events associated with activation of a central family of innate immune receptors (Toll-like receptors) and subsequently investigate changes to these signalling patterns within the biological context of stress-induced (cortisol and catecholamine) responses. The peptide arrays technology to be employed offers unprecedented opportunity to decipher complex signal transduction events, including identification of points of regulation, signalling intermediates and singling cross-talk. Alterations to innate immune signalling as a consequence of activation of stress-associated responses may include the nature (pathways, proteins, phosphorylation events), magnitude, or duration of signalling responses and may occur in a manner that is unique to specific TLRs. The priorities of the current investigation are to: a) develop a bovine-specific peptide kinome array that is customized to prioritize signalling events associated with TLR and stress-associated signaling, b) precisely describe signaling events associated with activation of different members of the Toll-like receptor family, and c) define changes to these signaling patterns in the context of stress. This refined perspective on innate immune signaling, including the influences of stress, will be of both immunological interest and practical importance for understanding and treating inflammation and infections, including limiting infectious disease in livestock through improved recognition and management of animal stress. This is critical contribution as infectious diseases represent the greatest source of economic losses to an industry facing increasing restrictions on the use of antibiotics. Reducing the incidence and severity of infectious diseases in livestock by identifying and minimizing management practices that cause stress, or selecting animals with greater stress tolerance, is a highly desirable outcome from the perspectives of animal health and welfare, as well as industry perception.