All-trans retinoic acid augments autophagy during intracellular bacterial infection

Michelle M Coleman, Sharee A Basdeo, Amy M Coleman, Cliona Ni Cheallaigh, Celia Peral de Castro, Anne Marie McLaughlin, Pedriac J Dunne, James Harris, Joseph Keane

Research output: Contribution to journalArticleResearchpeer-review

16 Citations (Scopus)

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 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.

Original languageEnglish
Pages (from-to)548-556
Number of pages9
JournalAmerican Journal of Respiratory Cell and Molecular Biology
Volume59
Issue number5
DOIs
Publication statusPublished - 1 Nov 2018

Keywords

  • Autophagy
  • Human alveolar macrophages
  • Tuberculosis
  • Vitamin A

Cite this