Vitamin D3 activates the autolysosomal degradation function against Helicobacter pylori through the PDIA3 receptor in gastric epithelial cells. Hu Wei,Zhang Lin,Li Ming Xing,Shen Jing,Liu Xiao Dong,Xiao Zhan Gang,Wu Ding Lan,Ho Idy H T,Wu Justin C Y,Cheung Cynthia K Y,Zhang Yu Chen,Lau Alaster H Y,Ashktorab Hassan,Smoot Duane T,Fang Evandro F,Chan Matthew T V,Gin Tony,Gong Wei,Wu William K K,Cho Chi Hin Autophagy Helicobacter pylori (H. pylori) is a common human pathogenic bacterium. Once infected, it is difficult for the host to clear this organism using the innate immune system. Increased antibiotic resistance further makes it challenging for effective eradication. However, the mechanisms of immune evasion still remain obscure, and novel strategies should be developed to efficiently eliminate H. pylori infection in stomachs. Here we uncovered desirable anti-H. pylori effect of vitamin D3 both in vitro and in vivo, even against antibiotic-resistant strains. We showed that H. pylori can invade into the gastric epithelium where they became sequestered and survived in autophagosomes with impaired lysosomal acidification. Vitamin D3 treatment caused a restored lysosomal degradation function by activating the PDIA3 receptor, thereby promoting the nuclear translocation of PDIA3-STAT3 protein complex and the subsequent upregulation of MCOLN3 channels, resulting in an enhanced Ca release from lysosomes and normalized lysosomal acidification. The recovered lysosomal degradation function drives H. pylori to be eliminated through the autolysosomal pathway. These findings provide a novel pathogenic mechanism on how H. pylori can survive in the gastric epithelium, and a unique pathway for vitamin D3 to reactivate the autolysosomal degradation function, which is critical for the antibacterial action of vitamin D3 both in cells and in animals, and perhaps further in humans. Abbreviations: 1,25D3: 1α, 25-dihydroxyvitamin D3; ATG5: autophagy related 5; Baf A1: bafilomycin A; BECN1: beclin 1; CagA: cytotoxin-associated gene A; CFU: colony-forming unit; ChIP-PCR: chromatin immunoprecipitation-polymerase chain reaction; Con A: concanamycin A; CQ: chloroquine; CRISPR: clustered regularly interspaced short palindromic repeats; CTSD: cathepsin D; GPN: Gly-Phe-β-naphthylamide; H. pylori: Helicobacter pylori; LAMP1: lysosomal associated membrane protein 1; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MCOLN1: mucolipin 1; MCOLN3: mucolipin 3; MCU: mitochondrial calcium uniporter; MOI: multiplicity of infection; NAGLU: N-acetyl-alpha-glucosaminidase; PDIA3: protein disulfide isomerase family A member 3; PMA: phorbol 12-myristate 13-acetate; PRKC: protein kinase C; SQSTM1: sequestosome 1; STAT3: signal transducer and activator of transcription 3; SS1: Sydney Strain 1; TRP: transient receptor potential; VacA: vacuolating cytotoxin; VD3: vitamin D3; VDR: vitamin D receptor. 10.1080/15548627.2018.1557835
    Therapeutic implications of the TLR and VDR partnership. Liu Philip T,Krutzik Stephan R,Modlin Robert L Trends in molecular medicine The innate immune system provides the host with an immediate and rapid defense against invading microbes. Detection of foreign invaders is mediated by a class of receptors that are known as the pattern recognition receptors, such as the family of Toll-like receptors (TLRs). In humans, ten functional TLRs have been identified and they respond to conserved pathogen-associated molecular patterns derived from bacteria, mycoplasma, fungi and viruses. TLR activation leads to direct antimicrobial activity against both intracellular and extracellular bacteria, and induces an antiviral gene program. Recently, it was reported that TLR2 activation leads to the use of vitamin D3 as a mechanism to combat Mycobacterium tuberculosis. Here, we focus on recent findings concerning the TLR-induced antimicrobial mechanisms in humans and the therapeutic implications of these findings. Owing to their capability to combat a wide array of pathogens, TLRs are attractive therapeutic targets. However, additional knowledge about their antimicrobial mechanisms is needed. 10.1016/j.molmed.2007.01.006
    Hypercalcaemia and hypokalaemia in tuberculosis. Bradley G W,Sterling G M Thorax In two patients with extensive pulmonary tuberculosis who developed hypercalcaemia and hypokalaemia the hypercalcaemia appeared related to the use of small doses of vitamin D, which suggested patients with tuberculosis were hypersensitive to vitamin D. They were thus similar to patients with sarcoidosis, and it is interesting that the Kveim test result was positive in both cases. The hypercalcaemia was quickly suppressed with steroids. Hyperparathyroidism, thyrotoxicosis, Addison's disease, and multiple myeloma were excluded on clinical grounds and by the appropriate tests. The hypokalaemia was associated with increased renal excretion of potassium, and was probably due to distal tubular damage from hypercalcaemia. 10.1136/thx.33.4.464
    Transpleural gradient of 1,25-dihydroxyvitamin D in tuberculous pleuritis. Barnes P F,Modlin R L,Bikle D D,Adams J S The Journal of clinical investigation We used tuberculous pleuritis as a model to study the compartmentalization and potential immunoregulatory role of 1,25-dihydroxyvitamin D [1,25-(OH)2-D] in human granulomatous disease. In tuberculous pleuritis, mean concentrations of total 1,25-(OH)2-D were elevated in pleural fluid, compared to blood (67 pg/ml vs. 35 pg/ml). Concentrations of albumin, protein and 25-hydroxyvitamin D (25-OH-D) were lower in pleural fluid than blood, suggesting that accumulation of binding proteins does not explain the transpleural gradient of 1,25-(OH)2-D. The mean free 1,25-(OH)2-D concentration in pleural fluid was increased 5.3-fold over that in serum. 1,25-(OH)2-D3 inhibited PPD-induced proliferation of pleural fluid mononuclear cells, antigen-reactive lines and T lymphocyte clones derived from a single cell. Patient-derived PPD-reactive lines expressed a high-affinity intracellular binding moiety for 1,25-(OH)2-D3. Pleural fluid mononuclear cells and PPD-reactive lines did not metabolize 25-OH-D3 to 1,25-(OH)2-D3. The sum of these data suggests that concentration of 1,25-(OH)2-D in pleural fluid of tuberculosis patients is probably due to local hormone production by pleural tissue-based inflammatory cells that are not present in significant numbers in pleural fluid. Elevated concentrations of 1,25-(OH)2-D in pleural fluid may exert receptor-mediated inhibition of antigen-induced proliferation by pleural fluid lymphocytes. Inhibition of lymphocyte proliferation and lymphokine production may prevent tissue destruction from an uncontrolled inflammatory response. 10.1172/JCI114048
    Toll-like receptor triggering of a vitamin D-mediated human antimicrobial response. Liu Philip T,Stenger Steffen,Li Huiying,Wenzel Linda,Tan Belinda H,Krutzik Stephan R,Ochoa Maria Teresa,Schauber Jürgen,Wu Kent,Meinken Christoph,Kamen Diane L,Wagner Manfred,Bals Robert,Steinmeyer Andreas,Zügel Ulrich,Gallo Richard L,Eisenberg David,Hewison Martin,Hollis Bruce W,Adams John S,Bloom Barry R,Modlin Robert L Science (New York, N.Y.) In innate immune responses, activation of Toll-like receptors (TLRs) triggers direct antimicrobial activity against intracellular bacteria, which in murine, but not human, monocytes and macrophages is mediated principally by nitric oxide. We report here that TLR activation of human macrophages up-regulated expression of the vitamin D receptor and the vitamin D-1-hydroxylase genes, leading to induction of the antimicrobial peptide cathelicidin and killing of intracellular Mycobacterium tuberculosis. We also observed that sera from African-American individuals, known to have increased susceptibility to tuberculosis, had low 25-hydroxyvitamin D and were inefficient in supporting cathelicidin messenger RNA induction. These data support a link between TLRs and vitamin D-mediated innate immunity and suggest that differences in ability of human populations to produce vitamin D may contribute to susceptibility to microbial infection. 10.1126/science.1123933