All-trans Retinoic Acid Augments Autophagy during Intracellular Bacterial Infection

American Journal of Respiratory Cell and Molecular Biology
Michelle M ColemanJoseph Keane

Abstract

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...Continue Reading

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Citations

Aug 11, 2018·American Journal of Respiratory Cell and Molecular Biology·Saurabh Aggarwal, Jennifer DeBerry
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Methods Mentioned

BETA
density-gradient centrifugation
flow cytometry

Software Mentioned

GraphPadPrism5
GE IN Cell Analyzer 1000 Workstation

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