Pharmacological Poly (ADP-Ribose) Polymerase Inhibitors Decrease Mycobacterium tuberculosis Survival in Human Macrophages

Diabetes mellites (DM) is correlated with increased susceptibility to and disease progression of tuberculosis (TB), and strongly impairs effective global TB control measures. To better control the TB-DM co-epidemic, unravelling the bidirectional interactivity between DM-associated molecular processes and immune responses to Mycobacterium tuberculosis (Mtb) is urgently required. Since poly (ADP-ribose) polymerase (PARP) activation has been associated with DM and with Mtb infection in mouse models, we have investigated whether PARP inhibition by pharmacological compounds can interfere with host protection against Mtb in human macrophage subsets, the predominant target cell of Mtb. Pharmacological inhibition of PARP decreased intracellular Mtb and MDR-Mtb levels in human macrophages, identifying PARP as a potential target for host-directed therapy against Mtb. PARP inhibition was associated with modified chemokine secretion and upregulation of cell surface activation markers by human macrophages. Targeting LDH, a secondary target of the PARP inhibitor rucaparib, resulted in decreased intracellular Mtb, suggesting a metabolic role in rucaparib-induced control of Mtb. We conclude that pharmacological inhibition of PARP is a potential novel strategy in developing innovative host-directed therapies against intracellular bacterial infections.

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The human macrophage mannose receptor directs Mycobacterium tuberculosis lipoarabinomannan-mediated phagosome biogenesis

Journal of Experimental Medicine ◽

10.1084/jem.20051239 ◽

2005 ◽

Vol 202 (7) ◽

pp. 987-999 ◽

Cited By ~ 311

Author(s):

Peter B. Kang ◽

Abul K. Azad ◽

Jordi B. Torrelles ◽

Thomas M. Kaufman ◽

Alison Beharka ◽

...

Keyword(s):

Mycobacterium Tuberculosis ◽

Mannose Receptor ◽

Human Macrophage ◽

Phagosome Maturation ◽

Human Macrophages ◽

Phagocytic Process ◽

Fusion Inhibition ◽

Macrophage Mannose Receptor ◽

Intracellular Adhesion Molecule ◽

Intact Molecule

Mycobacterium tuberculosis (M.tb) survives in macrophages in part by limiting phagosome–lysosome (P-L) fusion. M.tb mannose-capped lipoarabinomannan (ManLAM) blocks phagosome maturation. The pattern recognition mannose receptor (MR) binds to the ManLAM mannose caps and mediates phagocytosis of bacilli by human macrophages. Using quantitative electron and confocal microscopy, we report that engagement of the MR by ManLAM during the phagocytic process is a key step in limiting P-L fusion. P-L fusion of ManLAM microspheres was significantly reduced in human macrophages and an MR-expressing cell line but not in monocytes that lack the receptor. Moreover, reversal of P-L fusion inhibition occurred with MR blockade. Inhibition of P-L fusion did not occur with entry via Fcγ receptors or dendritic cell–specific intracellular adhesion molecule 3 grabbing nonintegrin, or with phosphatidylinositol-capped lipoarabinomannan. The ManLAM mannose cap structures were necessary in limiting P-L fusion, and the intact molecule was required to maintain this phenotype. Finally, MR blockade during phagocytosis of virulent M.tb led to a reversal of P-L fusion inhibition in human macrophages (84.0 ± 5.1% vs. 38.6 ± 0.6%). Thus, engagement of the MR by ManLAM during the phagocytic process directs M.tb to its initial phagosomal niche, thereby enhancing survival in human macrophages.

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Integrative Analysis of Human Macrophage Inflammatory Response Related to Mycobacterium tuberculosis Virulence

Frontiers in Immunology ◽

10.3389/fimmu.2021.668060 ◽

2021 ◽

Vol 12 ◽

Author(s):

Pauline Bade ◽

Fabrizio Simonetti ◽

Stephanie Sans ◽

Patricia Laboudie ◽

Khadija Kissane ◽

...

Keyword(s):

Mycobacterium Tuberculosis ◽

Inflammatory Response ◽

Genetic Networks ◽

Host Cells ◽

Human Macrophage ◽

Human Macrophages ◽

Adaptive Immune ◽

Adaptive Immune Cells ◽

Main Host ◽

Host Inflammatory Response

Mycobacterium tuberculosis (Mtb), the etiological agent of tuberculosis, kills 1.5 to 1.7 million people every year. Macrophages are Mtb’s main host cells and their inflammatory response is an essential component of the host defense against Mtb. However, Mtb is able to circumvent the macrophages’ defenses by triggering an inappropriate inflammatory response. The ability of Mtb to hinder phagolysosome maturation and acidification, and to escape the phagosome into the cytosol, is closely linked to its virulence. The modulation of the host inflammatory response relies on Mtb virulence factors, but remains poorly studied. Understanding macrophage interactions with Mtb is crucial to develop strategies to control tuberculosis. The present study aims to determine the inflammatory response transcriptome and miRNome of human macrophages infected with the virulent H37Rv Mtb strain, to identify macrophage genetic networks specifically modulated by Mtb virulence. Using human macrophages infected with two different live strains of mycobacteria (live or heat-inactivated Mtb H37Rv and M. marinum), we quantified and analyzed 184 inflammatory mRNAs and 765 micro(mi)RNAs. Transcripts and miRNAs differently modulated by H37Rv in comparison with the two other conditions were analyzed using in silico approaches. We identified 30 host inflammatory response genes and 37 miRNAs specific for H37Rv virulence, and highlight evidence suggesting that Mtb intracellular-linked virulence depends on the inhibition of IL-1β-dependent pro-inflammatory response, the repression of apoptosis and the delay of the recruitment and activation of adaptive immune cells. Our findings provide new potential targets for the development of macrophage-based therapeutic strategies against TB.

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Fluoroquinolone Action against Clinical Isolates ofMycobacterium tuberculosis: Effects of a C-8 Methoxyl Group on Survival in Liquid Media and in Human Macrophages

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.43.3.661 ◽

1999 ◽

Vol 43 (3) ◽

pp. 661-666 ◽

Cited By ~ 74

Author(s):

Ben Yang Zhao ◽

Richard Pine ◽

John Domagala ◽

Karl Drlica

Keyword(s):

Mycobacterium Tuberculosis ◽

Mycobacterium Bovis ◽

Lethal Dose ◽

Clinical Isolates ◽

Methoxyl Group ◽

Human Macrophage ◽

Wild Type ◽

Liquid Media ◽

Human Macrophages ◽

Resistant Strains

ABSTRACT When the lethal action of a C-8 methoxyl fluoroquinolone against clinical isolates of Mycobacterium tuberculosis in liquid medium was measured, the compound was found to be three to four times more effective (as determined by measuring the 90% lethal dose) than a C-8-H control fluoroquinolone or ciprofloxacin against cells having a wild-type gyrA (gyrase) gene. Against ciprofloxacin-resistant strains, the C-8 methoxyl group enhanced lethality when alanine was replaced by valine at position 90 of the GyrA protein or when aspartic acid 94 was replaced by glycine, histidine, or tyrosine. During infection of a human macrophage model by wild-type Mycobacterium bovis BCG, the C-8 methoxyl group lowered survival 20- to 100-fold compared with the same concentration of a C-8-H fluoroquinolone. The C-8 methoxyl fluoroquinolone was also more effective than ciprofloxacin against a gyrA Asn94 mutant of M. bovis BCG. In an M. tuberculosis-macrophage system the C-8 methoxyl group improved fluoroquinolone action against both quinolone-susceptible and quinolone-resistant clinical isolates. Thus, a C-8 methoxyl group enhances the bactericidal activity of quinolones with N1-cyclopropyl substitutions; these data encourage further refinement of fluoroquinolones as antituberculosis agents.

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Macrophage Migration Inhibitory Factor Reduces the Growth of Virulent Mycobacterium tuberculosis in Human Macrophages

Infection and Immunity ◽

10.1128/iai.73.6.3783-3786.2005 ◽

2005 ◽

Vol 73 (6) ◽

pp. 3783-3786 ◽

Cited By ~ 33

Author(s):

Mauro Oddo ◽

Thierry Calandra ◽

Richard Bucala ◽

Pascal R. A. Meylan

Keyword(s):

Mycobacterium Tuberculosis ◽

Migration Inhibitory Factor ◽

Innate Immune System ◽

Host Response ◽

Macrophage Migration Inhibitory Factor ◽

Bacterial Infections ◽

Innate Immune ◽

Inhibitory Factor ◽

Macrophage Migration ◽

Human Macrophages

ABSTRACT Macrophage migration inhibitory factor (MIF) is a key mediator of the innate immune system and plays a crucial role in the host response to bacterial infections. Its role in immunity to intracellular pathogens has not been well studied. Here, we show that MIF released by infected human macrophages inhibits the growth of virulent Mycobacterium tuberculosis.

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Phage therapy with mycobacteriophage as an alternative against antibiotic resistance produced by Mycobacterium tuberculosis

Bionatura ◽

10.21931/rb/2020.05.01.12 ◽

2020 ◽

Vol 5 (1) ◽

pp. 1078-1081

Author(s):

Pamela Rodríguez H ◽

Angie Changuán C ◽

Lizbeth X. Quiroz

Keyword(s):

Antibiotic Resistance ◽

Mycobacterium Tuberculosis ◽

Antimicrobial Resistance ◽

Bacterial Infections ◽

Phage Therapy ◽

Control Measures ◽

Viral Diversity ◽

Essential Factor ◽

Genetic Modifications ◽

Technological Tool

Bacteriophages are considered a genetic strategy to combat pathogen bacteria that show resistance to antibiotics. Molecular biology has implemented various control measures to deal with bacteria; the application of bacteriophage directly to tuberculosis viruses is a technological tool currently using. Mycobacteriophage is a type of virus that infects mycobacterium hosts. Because most of them have been genetically modified, they are providing insights into viral diversity. Furthermore, phage therapy is potentially a way to improve the treatment of bacterial infections strictly mediated by bacteriophages of lysogenic and lytic type. Genetic modifications are an essential factor for the development of future phage therapy applications to control the diseases caused by Mycobacterium tuberculosis. This review is about the mycobacteriophages to control the antimicrobial resistance caused by Mycobacterium tuberculosis thought some applications of phage therapy.

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Modulation of Cystatin C in Human Macrophages Improves Anti-Mycobacterial Immune Responses to Mycobacterium tuberculosis Infection and Coinfection With HIV

Frontiers in Immunology ◽

10.3389/fimmu.2021.742822 ◽

2021 ◽

Vol 12 ◽

Author(s):

David Pires ◽

Marta Calado ◽

Tomás Velez ◽

Manoj Mandal ◽

Maria João Catalão ◽

...

Keyword(s):

Mycobacterium Tuberculosis ◽

Cystatin C ◽

Human Leukocyte ◽

Multidrug Resistant ◽

Endocytic Pathway ◽

Human Macrophage ◽

Type I ◽

Mycobacterium Tuberculosis Infection ◽

Human Macrophages ◽

T Lymphocyte Proliferation

Tuberculosis owes its resurgence as a major global health threat mostly to the emergence of drug resistance and coinfection with HIV. The synergy between HIV and Mycobacterium tuberculosis (Mtb) modifies the host immune environment to enhance both viral and bacterial replication and spread. In the lung immune context, both pathogens infect macrophages, establishing favorable intracellular niches. Both manipulate the endocytic pathway in order to avoid destruction. Relevant players of the endocytic pathway to control pathogens include endolysosomal proteases, cathepsins, and their natural inhibitors, cystatins. Here, a mapping of the human macrophage transcriptome for type I and II cystatins during Mtb, HIV, or Mtb-HIV infection displayed different profiles of gene expression, revealing cystatin C as a potential target to control mycobacterial infection as well as HIV coinfection. We found that cystatin C silencing in macrophages significantly improves the intracellular killing of Mtb, which was concomitant with an increased general proteolytic activity of cathepsins. In addition, downmodulation of cystatin C led to an improved expression of the human leukocyte antigen (HLA) class II in macrophages and an increased CD4+ T-lymphocyte proliferation along with enhanced IFN-γ secretion. Overall, our results suggest that the targeting of cystatin C in human macrophages represents a promising approach to improve the control of mycobacterial infections including multidrug-resistant (MDR) TB.

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