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Intracellular bacteria may alter innate immune response


Patients with chronic, non-granulomatous diseases have elevated 1alpha,25-dihydroxyvitamin-D3 [1a,25(OH)2D3] and low 25-hydroxyvitamin-D [25(OH)D]. The absence of hypercalcemia, hypercalciuria, elevated parathyroid hormone, and chronic kidney disease suggests extra-renal production of excess 1a,25(OH)2D3.

Extra-renal 1alpha-hydroxylase (CYP27B1) catalyzes 25(OH)D to 1a,25(OH)2D3 in immune cells, leading to transcription of antimicrobial peptides (AMPs) via the vitamin D receptor (VDR). 1a,25(OH)2D3 production is down-regulated by 1alpha,25-dihydroxyvitamin D3 24-hydroxylase (CYP24A1) via hydroxylation of 1a,25(OH)2D3 to 1,24,25(OH)3D3. CYP27B1 transcription in macrophages is regulated by cytokines (e.g., Interferon-y [INF-y]). 1a,25(OH)2D3 also interacts with VDR-expressing helper (Th1) and suppressor (Th2) cells to reduce IFN-y production.

L-form bacteria (cell-wall-deficient variants that are ubiquitous but difficult to culture) invade immune cells and must use strategies to avoid phagocytosis. Parasitization of macrophages by these pathogens may be the stimulus for persistent production of cytokines which induce CYP27B1 activity and excess 1a,25(OH)2D3 production.

Down-regulation of the VDR by intracellular bacteria would interfere with 1a,25(OH)2D3 production regulatory processes and thus, prevent transcription of AMPs to allow bacterial persistence. Bacterial interference with enzymatic traffic patterns could allow production of excess 1a,25(OH)2D3 and prevent normal 1a,25(OH)2D3 functions which inhibit the expression of inflammatory cytokines.

Evidence for persistent intracellular bacterial infection and vitamin D metabolism dysfunction has been seen in natural experiments that suggest increased bacterial killing following reduction in elevated 1a,25(OH)2D3.

Non-resolving inflammation associated with many common chronic diseases may be caused by survival strategies of intracellular bacteria and is evidenced by elevated 1a,25(OH)2D3 and depleted 25(OH)D as markers of an infectious disease process.