Immunomodulatory effects of atorvastatin on peripheral blood mononuclear cells infected with Mycobacterium tuberculosis
Author(s)
Type
Journal Article
Abstract
Background: Tuberculosis (TB) remains a major global health threat, contributing substantially to high morbidity and mortality rates. This underscores the urgent need for more effective interventions. Recent studies highlight the potential of host-directed therapy approaches to enhance immune defences against TB. Atorvastatin, recognized for both its lipid-lowering properties and its immunomodulatory effects, has emerged as a compelling candidate for host-directed therapy against TB. Here, we investigated the ex vivo efficacy of atorvastatin in inducing immunomodulatory activities (phagosome maturation, autophagy, and apoptosis) and enhancing the mycobacterial killing capacity in Mycobacterium tuberculosis (Mtb)-infected peripheral blood mononuclear cells (PBMCs).
Method: Blood samples from healthy donors were collected for PBMC isolation. PBMCs were then treated overnight with or without atorvastatin, followed by infection with Mtb strains (H37Rv, HN878, and CDC1551) to evaluate intracellular mycobacterial growth by colony-forming units enumeration. Furthermore, co-localization of late endosomal marker (Rab-7), lysosomal markers (Cathepsin-D and LAMP-3), and autophagy marker (LC3B) with GFP-Mtb was investigated in infected PBMCs using laser scanning confocal microscopy. Moreover, multiple apoptotic assays were performed, including the TUNEL assay for DNA fragmentation, quantification of caspase-3 activity, and the expression levels of the pro-apoptotic gene (Bax) and anti-apoptotic gene (Bcl2).
Results: Treatment with atorvastatin significantly reduced intracellular mycobacterial replication compared to untreated controls in Mtb-infected PBMCs. Moreover, atorvastatin enhanced co-localization between Mtb and late endosomal marker (Rab-7), lysosomal markers (Cathepsin-D and LAMP-3), and autophagy marker (LC3B) in Mtb-infected PBMCs. Furthermore, atorvastatin robustly promoted apoptosis in Mtb-infected PBMCs, as demonstrated by TUNEL assay and caspase-3 activation.
Conclusion: Our findings highlight atorvastatin’s potential as a crucial modulator of the immune response in Mtb-infected PBMCs, supporting its role in host-directed therapy.
Method: Blood samples from healthy donors were collected for PBMC isolation. PBMCs were then treated overnight with or without atorvastatin, followed by infection with Mtb strains (H37Rv, HN878, and CDC1551) to evaluate intracellular mycobacterial growth by colony-forming units enumeration. Furthermore, co-localization of late endosomal marker (Rab-7), lysosomal markers (Cathepsin-D and LAMP-3), and autophagy marker (LC3B) with GFP-Mtb was investigated in infected PBMCs using laser scanning confocal microscopy. Moreover, multiple apoptotic assays were performed, including the TUNEL assay for DNA fragmentation, quantification of caspase-3 activity, and the expression levels of the pro-apoptotic gene (Bax) and anti-apoptotic gene (Bcl2).
Results: Treatment with atorvastatin significantly reduced intracellular mycobacterial replication compared to untreated controls in Mtb-infected PBMCs. Moreover, atorvastatin enhanced co-localization between Mtb and late endosomal marker (Rab-7), lysosomal markers (Cathepsin-D and LAMP-3), and autophagy marker (LC3B) in Mtb-infected PBMCs. Furthermore, atorvastatin robustly promoted apoptosis in Mtb-infected PBMCs, as demonstrated by TUNEL assay and caspase-3 activation.
Conclusion: Our findings highlight atorvastatin’s potential as a crucial modulator of the immune response in Mtb-infected PBMCs, supporting its role in host-directed therapy.
Date Issued
2025-07-03
Date Acceptance
2025-06-16
Citation
Frontiers in Immunology, 2025, 16
ISSN
1664-3224
Publisher
Frontiers Media S.A.
Journal / Book Title
Frontiers in Immunology
Volume
16
Copyright Statement
© 2025 Sabeel, Motaung, Ozturk, Mafu, Wilkinson, Thienemann and Guler. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
License URL
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/40677706
Subjects
<italic>Mycobacterium tuberculosis</italic>
apoptosis
APOPTOSIS
atorvastatin
AUTOPHAGY
FARNESYLTRANSFERASE INHIBITORS
GROWTH-INHIBITION
HUMAN MACROPHAGES
IMMUNE-RESPONSE
Immunology
Life Sciences & Biomedicine
MECHANISM
mevalonate
peripheral blood mononuclear cells
RANDOMIZED CONTROLLED-TRIAL
Science & Technology
SIMVASTATIN
STATIN ADJUNCTIVE THERAPY
Publication Status
Published
Coverage Spatial
Switzerland
Article Number
1597534
Date Publish Online
2025-07-03