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

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

Coleman, M. M., Basdeo, S. A., Coleman, A. M., Ni Cheallaigh, C., Peral de Castro, C., McLaughlin, A. M., ... Keane, J. (2018). All-trans retinoic acid augments autophagy during intracellular bacterial infection. American Journal of Respiratory Cell and Molecular Biology, 59(5), 548-556. https://doi.org/10.1165/rcmb.2017-0382OC
Coleman, Michelle M ; Basdeo, Sharee A ; Coleman, Amy M ; Ni Cheallaigh, Cliona ; Peral de Castro, Celia ; McLaughlin, Anne Marie ; Dunne, Pedriac J ; Harris, James ; Keane, Joseph. / All-trans retinoic acid augments autophagy during intracellular bacterial infection. In: American Journal of Respiratory Cell and Molecular Biology. 2018 ; Vol. 59, No. 5. pp. 548-556.
@article{31ff43a764d24501975b4e5e09e95dcb,
title = "All-trans retinoic acid augments autophagy during intracellular bacterial infection",
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-Gu{\'e}rin (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.",
keywords = "Autophagy, Human alveolar macrophages, Tuberculosis, Vitamin A",
author = "Coleman, {Michelle M} and Basdeo, {Sharee A} and Coleman, {Amy M} and {Ni Cheallaigh}, Cliona and {Peral de Castro}, Celia and McLaughlin, {Anne Marie} and Dunne, {Pedriac J} and James Harris and Joseph Keane",
year = "2018",
month = "11",
day = "1",
doi = "10.1165/rcmb.2017-0382OC",
language = "English",
volume = "59",
pages = "548--556",
journal = "American Journal of Respiratory Cell and Molecular Biology",
issn = "1044-1549",
publisher = "American Thoracic Society",
number = "5",

}

Coleman, MM, Basdeo, SA, Coleman, AM, Ni Cheallaigh, C, Peral de Castro, C, McLaughlin, AM, Dunne, PJ, Harris, J & Keane, J 2018, 'All-trans retinoic acid augments autophagy during intracellular bacterial infection', American Journal of Respiratory Cell and Molecular Biology, vol. 59, no. 5, pp. 548-556. https://doi.org/10.1165/rcmb.2017-0382OC

All-trans retinoic acid augments autophagy during intracellular bacterial infection. / Coleman, Michelle M; Basdeo, Sharee A; Coleman, Amy M; Ni Cheallaigh, Cliona; Peral de Castro, Celia; McLaughlin, Anne Marie; Dunne, Pedriac J; Harris, James; Keane, Joseph.

In: American Journal of Respiratory Cell and Molecular Biology, Vol. 59, No. 5, 01.11.2018, p. 548-556.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - All-trans retinoic acid augments autophagy during intracellular bacterial infection

AU - Coleman, Michelle M

AU - Basdeo, Sharee A

AU - Coleman, Amy M

AU - Ni Cheallaigh, Cliona

AU - Peral de Castro, Celia

AU - McLaughlin, Anne Marie

AU - Dunne, Pedriac J

AU - Harris, James

AU - Keane, Joseph

PY - 2018/11/1

Y1 - 2018/11/1

N2 - 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.

AB - 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.

KW - Autophagy

KW - Human alveolar macrophages

KW - Tuberculosis

KW - Vitamin A

UR - http://www.scopus.com/inward/record.url?scp=85055108987&partnerID=8YFLogxK

U2 - 10.1165/rcmb.2017-0382OC

DO - 10.1165/rcmb.2017-0382OC

M3 - Article

VL - 59

SP - 548

EP - 556

JO - American Journal of Respiratory Cell and Molecular Biology

JF - American Journal of Respiratory Cell and Molecular Biology

SN - 1044-1549

IS - 5

ER -

Coleman MM, Basdeo SA, Coleman AM, Ni Cheallaigh C, Peral de Castro C, McLaughlin AM et al. All-trans retinoic acid augments autophagy during intracellular bacterial infection. American Journal of Respiratory Cell and Molecular Biology. 2018 Nov 1;59(5):548-556. https://doi.org/10.1165/rcmb.2017-0382OC