Bovine Immunity and Vitamin D3: An Emerging Association in Johne's Disease

Abstract

Mycobacterium avium subspecies paratuberculosis (MAP) is an environmentally hardy pathogen of ruminants that plagues the dairy industry. Hallmark clinical symptoms include granulomatous enteritis, watery diarrhea, and significant loss of body condition. Transition from subclinical to clinical infection is a dynamic process led by MAP which resides in host macrophages. Clinical stage disease is accompanied by dysfunctional immune responses and a reduction in circulating vitamin D₃. The immunomodulatory role of vitamin D₃ in infectious disease has been well established in humans, particularly in Mycobacterium tuberculosis infection. However, significant species differences exist between the immune system of humans and bovines, including effects induced by vitamin D₃. This fact highlights the need for continued study of the relationship between vitamin D₃ and bovine immunity, especially during different stages of paratuberculosis.

Keywords: Mycobacterium avium subsp. paratuberculosis; PBMC; cattle; endosomal trafficking; macrophage; vitamin D.

Figure 1

Vitamin D is synthesized in the skin or obtained from the diet. The most common and more potent form, vitamin D₃, is focused on in this review. Vitamin D₃ is converted to 25(OH)D₃ in the liver. Classical effects on calcium homeostasis begin in the kidney, where 25(OH)D₃ is converted to bioactive 1,25(OH)₂D₃. 1,25(OH)₂D₃ increases osteoclast differentiation and activation, and upregulates calcium and phosphate absorption in the gut. Concurrently with 1,25(OH)₂D₃, parathyroid hormone stimulates osteoclasts. It additionally upregulates 1α–OHase (CYP27B1) activity and calcium reabsorption in the kidney. 25(OH)D₃ and 1,25(OH)₂D₃ are both inactivated by 24–OHase (CYP24A1) and are excreted in the bile. Non-classical signaling of vitamin D₃ involves local activation of 25(OH)D₃ to 1,25(OH)₂D₃ by 1α–OHase (CYP27B1) in cells of the immune system. Figure created using BioRender.com (accessed on 28 July 2022).

Figure 2

25(OH)D₃ and 1,25(OH)₂D₃ travel in the circulation mainly bound to vitamin D binding protein (DBP). They are taken up by caveolae mediated endocytosis, where DBP then disassociates. Free 25(OH)D₃ and 1,25(OH)₂D₃ are lipophilic and can diffuse across the cell membrane. 25(OH)D₃ is activated by 1α-OHase (CYP27B1) in the mitochondria. Activated 1,25(OH)₂D₃ binds the vitamin D receptor (VDR) and forms a complex with retinoid X receptor (RXR). Together, they bind vitamin D response elements (VDREs) in vitamin D target gene promoters to facilitate gene expression. Additionally, alternate receptors at the cell membrane have been shown to bind 1,25(OH)₂D₃. One such receptor, protein disulphide isomerase family A member 3 (PDIA3) can bind 1,25(OH)₂D₃ and interact with NF-κB and STAT1–3 pathways, showing 1,25(OH)₂D₃ can also indirectly influence gene expression outside of VDR target genes. PDIA3 is also expressed in the mitochondria, but its full role is currently unknown. Figure created using BioRender.com (accessed on 28 July 2022).