All-trans Retinoic Acid Augments Autophagy during Intracellular Bacterial Infection
| Autor: | Sharee A. Basdeo, Joseph Keane, Anne Marie McLaughlin, Cliona Ni Cheallaigh, Celia Peral de Castro, Amy M. Coleman, James Harris, Michelle Coleman, Pádraic J. Dunne |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Pulmonary and Respiratory Medicine Tuberculosis Clinical Biochemistry Retinoic acid Antitubercular Agents Antineoplastic Agents Tretinoin Microbiology Mycobacterium tuberculosis 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Macrophages Alveolar Autophagy Medicine Humans Molecular Biology Cells Cultured biology business.industry All trans Cell Biology medicine.disease biology.organism_classification Vitamin A deficiency 030104 developmental biology chemistry 030220 oncology & carcinogenesis business Intracellular |
| Zdroj: | American journal of respiratory cell and molecular biology. 59(5) |
| ISSN: | 1535-4989 |
| Popis: | Vitamin A deficiency strongly predicts the risk of developing tuberculosis (TB) in individuals exposed to Mycobacterium tuberculosis (Mtb). The burden of antibiotic-resistant TB is increasing globally; therefore, there is an urgent need to develop host-directed adjunctive therapies to treat TB. Alveolar macrophages, the niche cell for Mtb, metabolize vitamin A to all-trans retinoic acid (atRA), which influences host immune responses. We sought to determine the mechanistic effects of atRA on the host immune response to intracellular bacterial infection in primary human and murine macrophages. In this study, atRA promoted autophagy resulting in a reduced bacterial burden in human macrophages infected with Mtb and Bordetella pertussis, but not bacillus Calmette-Guérin (BCG). Autophagy is induced by cytosolic sensing of double-stranded DNA via the STING/TBK1/IRF3 axis; however, BCG is known to evade cytosolic DNA sensors. atRA enhanced colocalization of Mtb, but not BCG, with autophagic vesicles and acidified lysosomes. This enhancement was inhibited by blocking TBK1. Our data indicate that atRA augments the autophagy of intracellular bacteria that trigger cytosolic DNA-sensing pathways but does not affect bacteria that evade these sensors. The finding that BCG evades the beneficial effects of atRA has implications for vaccine design and global health nutritional supplementation strategies. The ability of atRA to promote autophagy and aid bacterial clearance of Mtb and B. pertussis highlights a potential role for atRA as a host-directed adjunctive therapy. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|