Symposium review: Targeting antimicrobial defenses of the udder through an intrinsic cellular pathway

The bovine innate immune system has a strong repertoire of antimicrobial defenses to rapidly attack infectious pathogens that evade physical barriers of the udder. Exploration of the intracrine vitamin D pathway of bovine macrophages has improved understanding of the signals that initiate antimicrobial defenses that protect the udder. In the intracrine vitamin D pathway, pathogen recognition receptors upregulate CYP27B1 mRNA that encodes for the enzyme that converts 25-hydroxyvitamin D [25(OH)D₃] to the active vitamin D hormone, 1,25-dihydroxyvitamin D₃ [1,25(OH)₂D₃]. The 1,25(OH)₂D₃, in turn, is generally known to increase antimicrobial activity and decrease inflammatory responses of immune cells. In cattle specifically, 1,25(OH)₂D₃ increases nitric oxide and β-defensin antimicrobial responses of bovine monocytes. Immune activation of the intracrine vitamin D pathway, including induction of inducible nitric oxide synthase and β-defensin gene expression by 1,25(OH)₂D₃, has been documented in the mammary glands of lactating dairy cows. Furthermore, intramammary 25(OH)D₃ treatment decreased bacteria counts and indicators of mastitis severity in cows experimentally infected with Streptococcus uberis. We propose that vitamin D signaling in the udder contributes to containment of bacterial pathogens and inflammatory responses of the udder. Verification of vitamin D-mediated defenses of the mammary gland potentially provides a path for development of alternative solutions (i.e., nutritional, genetic, therapeutic) to increase mastitis resistance of dairy cows. Continued exploration of the intrinsic cellular pathways that specifically promote antimicrobial defenses of the udder, such as the vitamin D pathway, is needed to support mastitis control efforts for dairy cows.