Tuberculosis: From Pathogenesis to Targeted Therapies

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cellular Pathology".

Deadline for manuscript submissions: 31 August 2024 | Viewed by 5557

Special Issue Editor


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Guest Editor
Research Center Borstel - Leibniz Lung Center, Division of Infection Immunology, 23845 Borstel, Germany
Interests: tuberculosis; immunology; pathology; cell therapy

Special Issue Information

Dear Colleagues,

Most bacterial infections can quickly be cured by antibiotic monotherapy. In contrast, drug-sensitive tuberculosis (TB) must be treated with a combination of  four antibiotics over 6 months. This lengthy, multidrug regimen often confounds compliance, leading to treatment failure, recurrence of TB, and the emergence of antibiotic-resistant mycobacteria. The goal of current TB research is, therefore, not only the development of new antibiotics and identification of novel antibiotic targets but also to find therapies that shorten treatment time. One reason for the need for such a long-term therapy is the development of centrally necrotizing granulomas in TB patients. This hallmark of TB pathogenesis represents not only a physical barrier, which often hinders the efficient penetration of antibiotics into the necrotic lesions. Additionally, within these types of granulomas particular conditions prevail, such as permissive cells, devascularization of the necrotic center, physicochemical peculiarities of the caseous content, and the presence of extracellular, quiescent mycobacteria with special metabolic adaptations that all pose a challenge to the efficacy of compounds. Hence, new drugs and regimens for the therapy of TB must consider the pathogenesis of this complex disease, ensuring that compounds can reach their target and act more effectively within the habitat of centrally necrotizing granulomas. This Special Issue aims to cover new research on the pathogenesis of TB in terms of therapy and novel compounds, as well as present host-directed strategies that mediate better and faster antibiotic treatment through modulation of the pathology.

Dr. Christoph Hölscher
Guest Editor

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Keywords

  • tuberculosis
  • therapy
  • granuloma
  • antibiotics
  • host-directed

Published Papers (3 papers)

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Research

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Article
Fluvastatin Converts Human Macrophages into Foam Cells with Increased Inflammatory Response to Inactivated Mycobacterium tuberculosis H37Ra
by María Teresa Montero-Vega, Joaquín Matilla, Eulalia Bazán, Diana Reimers, Ana De Andrés-Martín, Rafael Gonzalo-Gobernado, Carlos Correa, Francisco Urbano and Diego Gómez-Coronado
Cells 2024, 13(6), 536; https://doi.org/10.3390/cells13060536 - 18 Mar 2024
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Abstract
Cholesterol biosynthesis inhibitors (statins) protect hypercholesterolemic patients against developing active tuberculosis, suggesting that these drugs could help the host to control the pathogen at the initial stages of the disease. This work studies the effect of fluvastatin on the early response of healthy [...] Read more.
Cholesterol biosynthesis inhibitors (statins) protect hypercholesterolemic patients against developing active tuberculosis, suggesting that these drugs could help the host to control the pathogen at the initial stages of the disease. This work studies the effect of fluvastatin on the early response of healthy peripheral blood mononuclear cells (PBMCs) to inactivated Mycobacterium tuberculosis (Mtb) H37Ra. We found that in fluvastatin-treated PBMCs, most monocytes/macrophages became foamy cells that overproduced NLRP3 inflammasome components in the absence of immune stimulation, evidencing important cholesterol metabolism/immunity connections. When both fluvastatin-treated and untreated PBMCs were exposed to Mtb H37Ra, a small subset of macrophages captured large amounts of bacilli and died, concentrating the bacteria in necrotic areas. In fluvastatin-untreated cultures, most of the remaining macrophages became epithelioid cells that isolated these areas of cell death in granulomatous structures that barely produced IFNγ. By contrast, in fluvastatin-treated cultures, foamy macrophages surrounded the accumulated bacteria, degraded them, markedly activated caspase-1 and elicited a potent IFNγ/cytotoxic response. In rabbits immunized with the same bacteria, fluvastatin increased the tuberculin test response. We conclude that statins may enhance macrophage efficacy to control Mtb, with the help of adaptive immunity, offering a promising tool in the design of alternative therapies to fight tuberculosis. Full article
(This article belongs to the Special Issue Tuberculosis: From Pathogenesis to Targeted Therapies)
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12 pages, 2370 KiB  
Article
Comparison of the Single Cell Immune Landscape between Subjects with High Mycobacterium tuberculosis Bacillary Loads during Active Pulmonary Tuberculosis and Household Members with Latent Tuberculosis Infection
by Supitcha Kamolratanakul, Wassawon Ariyanon, Kanyarat Udompornpitak, Thansita Bhunyakarnjanarat, Asada Leelahavanichkul, Jittima Dhitavat, Polrat Wilairatana and Wiwat Chancharoenthana
Cells 2024, 13(4), 362; https://doi.org/10.3390/cells13040362 - 19 Feb 2024
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Abstract
It is unclear how the immune system controls the transition from latent tuberculosis (TB) infection (LTBI) to active pulmonary infection (PTB). Here, we applied mass spectrometry cytometry time-of-flight (CyTOF) analysis of peripheral blood mononuclear cells to compare the immunological landscapes in patients with [...] Read more.
It is unclear how the immune system controls the transition from latent tuberculosis (TB) infection (LTBI) to active pulmonary infection (PTB). Here, we applied mass spectrometry cytometry time-of-flight (CyTOF) analysis of peripheral blood mononuclear cells to compare the immunological landscapes in patients with high tuberculous bacillary load PTB infections and LTBI. A total of 32 subjects (PTB [n = 12], LTBI [n = 17], healthy volunteers [n = 3]) were included. Participants with active PTBs were phlebotomized before administering antituberculosis treatment, whereas participants with LTBI progressed to PTB at the time of household screening. In the present study, CyTOF analysis identified significantly higher percentages of mucosal-associated invariant natural killer T (MAIT NKT) cells in subjects with LTBI than in those with active PTB and healthy controls. Moreover, 6 of 17 (35%) subjects with LTBI progressed to active PTB (LTBI progression) and had higher proportions of MAIT NKT cells and early NKT cells than those without progression (LTBI non-progression). Subjects with LTBI progression also showed a tendency toward low B cell levels relative to other subject groups. In conclusion, MAIT NKT cells were substantially more prevalent in subjects with LTBI, particularly those with progression to active PTB. Full article
(This article belongs to the Special Issue Tuberculosis: From Pathogenesis to Targeted Therapies)
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Review

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16 pages, 2081 KiB  
Review
Antisense Therapy for Infectious Diseases
by Lwanda Abonga Buthelezi, Shandre Pillay, Noxolo Nokukhanya Ntuli, Lorna Gcanga and Reto Guler
Cells 2023, 12(16), 2119; https://doi.org/10.3390/cells12162119 - 21 Aug 2023
Cited by 2 | Viewed by 2471
Abstract
Infectious diseases, particularly Tuberculosis (TB) caused by Mycobacterium tuberculosis, pose a significant global health challenge, with 1.6 million reported deaths in 2021, making it the most fatal disease caused by a single infectious agent. The rise of drug-resistant infectious diseases adds to [...] Read more.
Infectious diseases, particularly Tuberculosis (TB) caused by Mycobacterium tuberculosis, pose a significant global health challenge, with 1.6 million reported deaths in 2021, making it the most fatal disease caused by a single infectious agent. The rise of drug-resistant infectious diseases adds to the urgency of finding effective and safe intervention therapies. Antisense therapy uses antisense oligonucleotides (ASOs) that are short, chemically modified, single-stranded deoxyribonucleotide molecules complementary to their mRNA target. Due to their designed target specificity and inhibition of a disease-causing gene at the mRNA level, antisense therapy has gained interest as a potential therapeutic approach. This type of therapy is currently utilized in numerous diseases, such as cancer and genetic disorders. Currently, there are limited but steadily increasing studies available that report on the use of ASOs as treatment for infectious diseases. This review explores the sustainability of FDA-approved and preclinically tested ASOs as a treatment for infectious diseases and the adaptability of ASOs for chemical modifications resulting in reduced side effects with improved drug delivery; thus, highlighting the potential therapeutic uses of ASOs for treating infectious diseases. Full article
(This article belongs to the Special Issue Tuberculosis: From Pathogenesis to Targeted Therapies)
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