Research - Vitamin A
All-Trans Retinoic Acid–Triggered Antimicrobial Activity against Mycobacterium tuberculosis Is Dependent on NPC2
- Matthew Wheelwright*,1,
- Elliot W. Kim*,1,
- Megan S. Inkeles†,
- Avelino De Leon‡,
- Matteo Pellegrini†,
- Stephan R. Krutzik* and
- Philip T. Liu*,‡
- *Division of Dermatology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095;
- †Department of Molecular, Cell, and Developmental Biology, University of California, Los Angeles, Los Angeles, CA 90095; and
- ‡University of California, Los Angeles and Orthopaedic Hospital Department of Orthopaedic Surgery and the Orthopaedic Hospital Research Center, Los Angeles, CA 90095
Abstract
A role for vitamin A in host defense against Mycobacterium tuberculosis has been suggested through epidemiological and in vitro studies; however, the mechanism is unclear. In this study, we demonstrate that vitamin A–triggered antimicrobial activity against M. tuberculosis requires expression of NPC2. Comparison of monocytes stimulated with all-trans retinoic acid (ATRA) or 1,25-dihydroxyvitamin D3 (1,25D3), the biologically active forms of vitamin A and vitamin D, respectively, indicates that ATRA and 1,25D3 induce mechanistically distinct antimicrobial activities. Stimulation of primary human monocytes with ATRA did not result in expression of the antimicrobial peptide cathelicidin, which is required for 1,25D3 antimicrobial activity. In contrast, ATRA triggered a reduction in the total cellular cholesterol concentration, whereas 1,25D3 did not. Blocking ATRA-induced cellular cholesterol reduction inhibits antimicrobial activity as well. Bioinformatic analysis of ATRA- and 1,25D3-induced gene profiles suggests that NPC2 is a key gene in ATRA-induced cholesterol regulation. Knockdown experiments demonstrate that ATRA-mediated decrease in total cellular cholesterol content and increase in lysosomal acidification are both dependent upon expression of NPC2. Expression of NPC2 was lower in caseous tuberculosis granulomas and M. tuberculosis–infected monocytes compared with normal lung and uninfected cells, respectively. Loss of NPC2 expression ablated ATRA-induced antimicrobial activity. Taken together, these results suggest that the vitamin A–mediated antimicrobial mechanism against M. tuberculosis requires NPC2-dependent expression and function, indicating a key role for cellular cholesterol regulation in the innate immune response.
Source : Journal of Immunology
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Vitamin A Deficiency Is Associated with Gastrointestinal and Respiratory Morbidity in School-Age Children1,2,3
- 4Department of Epidemiology and Biostatistics, Michigan State University, East Lansing, MI
- 5Foundation for Research in Nutrition and Health (FINUSAD), Bogotá, Colombia; and
- 6Department of Epidemiology, University of Michigan School of Public Health, Ann Arbor, MI
Abstract
Infection is an important cause of morbidity throughout childhood. Poor micronutrient status is a risk factor for infection-related morbidity in young children, but it is not clear whether these associations persist during school-age years. We examined the relation between blood concentrations of micronutrient status biomarkers and risk of gastrointestinal and respiratory morbidity in a prospective study of 2774 children aged 5–12 y from public schools in Bogotá, Colombia. Retinol, zinc, ferritin, mean corpuscular volume, hemoglobin, erythrocyte folate, and vitamin B-12 concentrations were measured in blood at enrollment into the cohort. Children were followed for 1 academic year for incidence of morbidity, including diarrhea with vomiting, cough with fever, earache or ear discharge with fever, and doctor visits. Compared with adequate vitamin A status (≥30.0 μg/dL), vitamin A deficiency (<10.0 μg/dL) was associated with increased risk of diarrhea with vomiting [unadjusted incidence rate ratio (IRR): 2.17; 95% CI: 0.95, 4.96; P-trend = 0.03] and cough with fever (unadjusted IRR: 2.36; 95% CI: 1.30, 4.31; P-trend = 0.05). After adjustment for several sociodemographic characteristics and hemoglobin concentrations, every 10 μg/dL plasma retinol was associated with 18% fewer days of diarrhea with vomiting (P < 0.001), 10% fewer days of cough with fever (P < 0.001), and 6% fewer doctor visits (P = 0.01). Every 1 g/dL of hemoglobin was related to 17% fewer days with ear infection symptoms (P < 0.001) and 5% fewer doctor visits (P = 0.009) after controlling for sociodemographic factors and retinol concentrations. Zinc, ferritin, mean corpuscular volume, erythrocyte folate, and vitamin B-12 status were not associated with morbidity or doctor visits. Vitamin A and hemoglobin concentrations were inversely related to rates of morbidity in school-age children. Whether vitamin A supplementation reduces the risk or severity of infection in children over 5 y of age needs to be determined.
Source : The Journal of Nutrition
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