All-Trans Retinoic Acid-Triggered Antimicrobial Activity against Mycobacterium tuberculosis Is Dependent on NPC2
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.
- SourceAvailable from: Surajit Chakraborty[Show abstract] [Hide abstract]
ABSTRACT: Tuberculosis is continuing as a problem of mankind. With evolution, MDR and XDR forms of tuberculosis have emerged from drug sensitive strain. MDR and XDR strains are resistant to most of the antibiotics, making the management more difficult. BCG vaccine is not providing complete protection against tuberculosis. Therefore new infections are spreading at a tremendous rate. At the present moment there is experimental evidence to believe that Vitamin A and Vitamin D has anti-mycobacterial property. It is in this context, we have hypothesized a host based approach using the above vitamins that can cause possible prevention and cure of tuberculosis with minimal chance of resistance or toxicity.Medical Hypotheses 01/2015; 84(3). DOI:10.1016/j.mehy.2014.12.022 · 1.15 Impact Factor
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ABSTRACT: Rationale: Myeloid cells encompass distinct populations with unique functions during homeostasis and disease. Recently, a novel subset of innate cells, namely myeloid-derived suppressor cells (MDSCs), has been described in cancer, which suppresses T-cell responses and fosters disease progression. The role of MDSCs in infection is insufficiently addressed. Objectives: To examine the presence and function of MDSCs during experimental pulmonary tuberculosis (TB) and further understand the immunological consequences of direct interactions between MDSCs and lung bacterial pathogens. Measurements and Main Results: Using cell-based approaches and experimental mouse models for pulmonary TB we characterized MDSCs as novel myeloid populations directly interacting with Mycobacterium tuberculosis (Mtb). MDSCs readily phagocytosed Mtb, released pro-inflammatory (IL-6, IL-1α) and immunomodulatory (IL-10) cytokines while retaining their suppressive capacity. MDSCs were identified at the site of infection in the lung in disease-resistant and -susceptible mice during pulmonary TB. Excessive MDSC accumulation in lungs correlated with elevated surface expression of IL-4Rα and heightened TB lethality, whereas targeted depletion of MDSCs ameliorated disease. Conclusion: Our data reveal that MDSCs provide a niche for pathogen survival and tailor immunity in TB. These findings suggest MDSCs as amenable targets for host-directed therapies and emphasize them as cellular-immune regulators during chronic inflammatory conditions, including chronic infections and microbial complications of neoplastic disorders.American Journal of Respiratory and Critical Care Medicine 10/2014; 190(9). DOI:10.1164/rccm.201405-0828OC · 11.99 Impact Factor
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ABSTRACT: Tuberculosis is a leading cause of infectious disease-related death worldwide; however, only 10% of people infected with Mycobacterium tuberculosis develop disease. Factors that contribute to protection could prove to be promising targets for M. tuberculosis therapies. Analysis of peripheral blood gene expression profiles of active tuberculosis patients has identified correlates of risk for disease or pathogenesis. We sought to identify potential human candidate markers of host defense by studying gene expression profiles of macrophages, cells that, upon infection by M. tuberculosis, can mount an antimicrobial response. Weighted gene coexpression network analysis revealed an association between the cytokine interleukin-32 (IL-32) and the vitamin D antimicrobial pathway in a network of interferon-γ- and IL-15-induced "defense response" genes. IL-32 induced the vitamin D-dependent antimicrobial peptides cathelicidin and DEFB4 and to generate antimicrobial activity in vitro, dependent on the presence of adequate 25-hydroxyvitamin D. In addition, the IL-15-induced defense response macrophage gene network was integrated with ranked pairwise comparisons of gene expression from five different clinical data sets of latent compared with active tuberculosis or healthy controls and a coexpression network derived from gene expression in patients with tuberculosis undergoing chemotherapy. Together, these analyses identified eight common genes, including IL-32, as molecular markers of latent tuberculosis and the IL-15-induced gene network. As maintaining M. tuberculosis in a latent state and preventing transition to active disease may represent a form of host resistance, these results identify IL-32 as one functional marker and potential correlate of protection against active tuberculosis.Science translational medicine 08/2014; 6(250):250ra114. DOI:10.1126/scitranslmed.3009546 · 14.41 Impact Factor