Statins mediate protection against Mycobacterium tuberculosis infection by enhancing phagosomal maturation and autophagy
-
1
International Centre for Genetic Engineering & Biotechnology (ICGEB) - University of Cape Town, Immunology, South Africa
-
2
Council for Scientific & Industrial Research (CSIR), Biosciences, South Africa
-
3
University of Cape Town, Human Biology, South Africa
-
4
RIKEN, Omics Science Center (OSC), Japan
-
5
University of Cape Town, Chemical Pathology, South Africa
Statins are effective pharmacological inhibitors of the HMG-CoA reductase, a rate-limiting enzyme for cholesterol biosynthesis, and have been shown to reduce bacteremia in statin-users.
We aimed to investigate the effect of statins on M. tuberculosis infected monocytes/macrophages isolated from statin-treated patients and uncovered the possible biological mechanisms in macrophages and mice.
Peripheral blood mononuclear cells (PBMCs) and monocyte-derived macrophages (MDMs) were isolated from patients with familial hypercholesterolemia (FH) on statin therapy. Cells were then infected with Mtb and their bacterial burden determined in comparison to cells from healthy controls. In addition, mice were treated with statins prior to aerosol infection with Mtb and disease progression in infected mice was monitored in comparison to sham-treated mice.
PBMCs and macrophages from FH patients displayed reduced M. tuberculosis burdens compared to cells from healthy non-statin users. Statin treatment also reduced bacterial growth in both Mycobacterium-infected PBMCs isolated from healthy human subjects and murine macrophages. Statin treatment reduced mycobacterial burden in lungs and improved pathology as compared to sham-treated infected mice. Mechanistically, statins counteracted Mycobacterium-induced inhibition of phagosomal maturation and increased host-protective autophagy of infected macrophages.
Human patients on statin therapy show increased protection against Mtb infection. In addition, statin treatment led to increased protection against Mtb in infected mice as shown by reduced bacterial burdens and dissemination of bacteria to peripheral organs. Murine bone marrow-derived macrophages (BMDMs) displayed reduced mycobacterium loads following statin treatment. We found that statins inhibited bacterial growth by enhancing phagosomal maturation and autophagy in infected BMDMs.
Acknowledgements
We thank Wendy Green, Rayaana Fredericks, Fadwah Booley for maintaining mice and Faried Abbass, Rodney Lucas, Hylton Bunting for their valuable technical assistance. We are grateful to Lizette Fick, Marilyn Tyler and Zoë Lotz for their excellent histology services. We thank Susan Cooper for excellent confocal microscope (Zeiss LSM 510) facility. We also thank research nurses Jenny Ross (Lipid Clinic) and Phyllisty Smith Murphy (Desmond Tutu HIV foundation) for the collection of blood samples.
Keywords:
Statins,
Cholesterol,
Tuberculosis,
Human PBMC,
Human and Mouse macrophages
Conference:
15th International Congress of Immunology (ICI), Milan, Italy, 22 Aug - 27 Aug, 2013.
Presentation Type:
Abstract
Topic:
Host-pathogen interactions
Citation:
Parihar
SP,
Guler
R,
Khutlang
R,
Lang
DM,
Mhlanga
MM,
Suzuki
H,
Marais
AD and
Brombacher
F
(2013). Statins mediate protection against Mycobacterium tuberculosis infection by enhancing phagosomal maturation and autophagy.
Front. Immunol.
Conference Abstract:
15th International Congress of Immunology (ICI).
doi: 10.3389/conf.fimmu.2013.02.00149
Copyright:
The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers.
They are made available through the Frontiers publishing platform as a service to conference organizers and presenters.
The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated.
Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed.
For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions.
Received:
11 Mar 2013;
Published Online:
22 Aug 2013.
*
Correspondence:
Prof. Frank Brombacher, International Centre for Genetic Engineering & Biotechnology (ICGEB) - University of Cape Town, Immunology, Cape Town, South Africa, brombacherfrank@gmail.com