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Cellular and Molecular Mechanisms in Mycobacterial Infection 3.0

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Microbiology".

Deadline for manuscript submissions: closed (31 July 2024) | Viewed by 6765

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Special Issue Editors

Dr. Natalie Nieuwenhuizen

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Guest Editor

Institute for Hygiene and Microbiology, Julius-Maximilians-Universität Würzburg, Josef-Schneider-Str. 2, 97080 Würzburg, Germany
Interests: infectious disease; immunology; host-pathogen interactions; tuberculosis; vaccines; fungal infection; leishmaniasis; helminth infection; IL-4 receptor alpha; TGF-beta; activin A
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Dr. Joanna Evans

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Guest Editor

The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK
Interests: infectious diseases; microbiology; tuberculosis; nontuberculous mycobacteria; drug discovery; molecular biology; bacterial physiology and metabolism
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Mycobacterium tuberculosis (M.tb) caused over 10 million cases of tuberculosis (TB) and 1.3 million deaths in 2022. The current TB vaccine, a live attenuated form of M. bovis named M. bovis Calmette–Guerin (BCG), provides insufficient protection. In addition, the emergence of multiple and extremely drug-resistant strains of M.tb is a growing problem. Novel vaccines and drug therapies are urgently required. The primary host cell of M.tb, the macrophage, serves as the first line of defense. Multiple pattern-recognition receptors sense mycobacterial molecular patterns, triggering intracellular signaling cascades and induction of proinflammatory cytokines, chemokines, and antimicrobial molecules. Macrophage-derived cytokines such as tumor necrosis factor, interleukin-12, IL-1β and IL-18 are critical for host defense against tuberculosis. Adaptive responses, including antigen-specific T cells, are critical in controlling the growth of M. tb by producing interferon-gamma, activating macrophages, and orchestrating granuloma formation.

This Special Issue aims to cover a selection of original research articles, short communications, and current review articles exploring mycobacterial research, including immunity against mycobacteria, signaling transduction in TB, host–pathogen interactions, mycobacterial metabolism, drug resistance mechanisms, biomarkers of disease, and novel drugs and vaccines within the scope of molecular biology.

Dr. Natalie Nieuwenhuizen
Dr. Joanna Evans
Guest Editors

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Keywords

tuberculosis
mycobacteria
bacterial metabolism
bacterial infection
antibiotic resistance
vaccines
biomarkers
signaling pathways
immune system
host-directed therapy
host–pathogen interaction
drug discovery

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Published Papers (5 papers)

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Research

16 pages, 5387 KiB

Open AccessArticle

Characteristics of Pulmonary Inflammation in Patients with Different Forms of Active Tuberculosis

by Galina S. Shepelkova, Vladimir V. Evstifeev, Yuriy S. Berezovskiy, Anush E. Ergeshova, Ruslan V. Tarasov, Mamed A. Bagirov and Vladimir V. Yeremeev

Int. J. Mol. Sci. 2024, 25(21), 11795; https://doi.org/10.3390/ijms252111795 - 2 Nov 2024

Viewed by 666

Abstract

Targeted treatment of tuberculosis-associated lung damage requires an understanding of the precise mechanisms of immunopathology. A major obstacle to the longitudinal study of tuberculosis (TB) immunopathogenesis in humans is the lack of serial lung biopsies during disease progression and treatment, which could be used to characterize local immune pathways involved in tissue damage. Understanding of the immunobiology of lung tissue damage in tuberculosis has largely been based on animal models. Our study looked for signs of inflammation in TB patients’ lung biopsies. Results were compared between a site of infection and relatively healthy tissue outside the site. The most significant differences in the expression of microRNAs (miRs) and cytokine/chemokines were observed between the non-decayed tuberculoma and the surrounding parenchyma. In addition, these parameters showed almost no differences between the cavitary wall and surrounding tissue. This is an indication that the inflammatory process is more prevalent in fibrotic cavitary tuberculosis (FCT). In FCT subjects, no difference was observed between the cavity wall and the parenchyma in the production of key inflammatory factors such as IL-6, IL-11, IL-17, and IFNγ. This is an indication that the limits of the inflammatory response are broader in FCT. The expression levels of miR-191, miR-193a, miR-222, miR-223, miR-18, miR-155, miR-376c, miR-26a, miR-150, and miR-124 were not significantly different between the cavernous wall and lung tissue in patients with FCT, further confirming the spread of inflammatory and destructive processes beyond the focus of infection. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms in Mycobacterial Infection 3.0)

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25 pages, 6695 KiB

Open AccessArticle

Challenge Dose Titration in a Mycobacterium bovis Infection Model in Goats

by Elisabeth M. Liebler-Tenorio, Nadine Wedlich, Julia Figl, Heike Köhler, Reiner Ulrich, Charlotte Schröder, Melanie Rissmann, Leander Grode, Stefan H. E. Kaufmann and Christian Menge

Int. J. Mol. Sci. 2024, 25(18), 9799; https://doi.org/10.3390/ijms25189799 - 10 Sep 2024

Viewed by 1023

Abstract

Goats are natural hosts of Mycobacterium (M.) bovis, and affected herds can be the cause of significant economic losses. Similarites in disease course and lesions of M. bovis infections in goats and M. tuberculosis in humans make goats good models for human tuberculosis. The aim of this investigation was to characterize M. bovis challenge models in goats. For this, goats were endobronchially inoculated with three doses of M. bovis or culture medium. Clinical signs, shedding, and immune responses were monitored until 146 days post inoculation (dpi). At necropsy, lesions were examined by computed tomography, histology, and bacteriological culture. Infected goats did not develop clinical signs. M. bovis was cultured from feces, but never from nasal swabs. IGRAs were positive from 28 dpi onwards, antibodies at 140 dpi, and SICCT at 146 dpi. The increase in CD25⁺, IFN-γ⁺, and IFN-γ-releasing T-cell subpopulations was time-related, but not dose-dependent. All infected goats developed paucibacillary granulomas in the lungs and regional lymph nodes. M. bovis was regularly cultured. Dose-dependent effects included the size of pulmonary lesions, caverns, intestinal lesions, and early generalization in the high-dose group. In summary, reproducible challenge models with dose-dependent differences in lesions were established, which may serve for testing vaccines for veterinary or medical use. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms in Mycobacterial Infection 3.0)

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17 pages, 3313 KiB

Open AccessArticle

Photoinactivation of Mycobacterium tuberculosis and Mycobacterium smegmatis by Near-Infrared Radiation Using a Trehalose-Conjugated Heptamethine Cyanine

by Nataliya V. Kozobkova, Michael P. Samtsov, Anatol P. Lugovski, Nikita V. Bel’ko, Dmitri S. Tarasov, Arseny S. Kaprelyants, Alexander P. Savitsky and Margarita O. Shleeva

Int. J. Mol. Sci. 2024, 25(15), 8505; https://doi.org/10.3390/ijms25158505 - 4 Aug 2024

Viewed by 914

Abstract

The spread of multidrug-resistant mycobacterium strains requires the development of new approaches to combat diseases caused by these pathogens. For that, photodynamic inactivation (PDI) is a promising approach. In this study, a tricarbocyanine (TCC) is used for the first time as a near-infrared (740 nm) activatable PDI photosensitizer to kill mycobacteria with deep light penetration. For better targeting, a novel tricarbocyanine dye functionalized with two trehalose units (TCC2Tre) is developed. The photodynamic effect of the conjugates against mycobacteria, including Mycobacterium tuberculosis, is evaluated. Under irradiation, TCC2Tre causes more effective killing of mycobacteria compared to the photosensitizer without trehalose conjugation, with 99.99% dead vegetative cells of M. tuberculosis and M. smegmatis. In addition, effective photoinactivation of dormant forms of M. smegmatis is observed after incubation with TCC2Tre. Mycobacteria treated with TCC2Tre are more sensitive to 740 nm light than the Gram-positive Micrococcus luteus and the Gram-negative Escherichia coli. For the first time, this study demonstrates the proof of principle of in vitro PDI of mycobacteria including the fast-growing M. smegmatis and the slow-growing M. tuberculosis using near-infrared activatable photosensitizers conjugated with trehalose. These findings are useful for the development of new efficient alternatives to antibiotic therapy. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms in Mycobacterial Infection 3.0)

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18 pages, 1733 KiB

Open AccessArticle

Negative Regulation of Autophagy during Macrophage Infection by Mycobacterium bovis BCG via Protein Kinase C Activation

by Rafael Maldonado-Bravo, Tomás Villaseñor, Martha Pedraza-Escalona, Leonor Pérez-Martínez, Rogelio Hernández-Pando and Gustavo Pedraza-Alva

Int. J. Mol. Sci. 2024, 25(6), 3145; https://doi.org/10.3390/ijms25063145 - 9 Mar 2024

Viewed by 1500

Abstract

Mycobacterium tuberculosis (Mtb) employs various strategies to manipulate the host’s cellular machinery, overriding critical molecular mechanisms such as phagosome-lysosome fusion, which are crucial for its destruction. The Protein Kinase C (PKC) signaling pathways play a key role in regulating phagocytosis. Recent research in Interferon-activated macrophages has unveiled that PKC phosphorylates Coronin-1, leading to a shift from phagocytosis to micropinocytosis, ultimately resulting in Mtb destruction. Therefore, this study aims to identify additional PKC targets that may facilitate Mycobacterium bovis (M. bovis) infection in macrophages. Protein extracts were obtained from THP-1 cells, both unstimulated and mycobacterial-stimulated, in the presence or absence of a general PKC inhibitor. We conducted an enrichment of phosphorylated peptides, followed by their identification through mass spectrometry (LC-MS/MS). Our analysis revealed 736 phosphorylated proteins, among which 153 exhibited alterations in their phosphorylation profiles in response to infection in a PKC-dependent manner. Among these 153 proteins, 55 are involved in various cellular processes, including endocytosis, vesicular traffic, autophagy, and programmed cell death. Importantly, our findings suggest that PKC may negatively regulate autophagy by phosphorylating proteins within the mTORC1 pathway (mTOR2/PKC/Raf-1/Tsc2/Raptor/Sequestosome-1) in response to M. bovis BCG infection, thereby promoting macrophage infection. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms in Mycobacterial Infection 3.0)

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29 pages, 2349 KiB

Open AccessArticle

Drug-Tolerant Mycobacterium tuberculosis Adopt Different Survival Strategies in Alveolar Macrophages of Patients with Pulmonary Tuberculosis

by Elena G. Ufimtseva and Natalya I. Eremeeva

Int. J. Mol. Sci. 2023, 24(19), 14942; https://doi.org/10.3390/ijms241914942 - 6 Oct 2023

Viewed by 1748

Abstract

The rapid spread of drug-resistant M. tuberculosis (Mtb) strains and the phenomenon of phenotypic tolerance to drugs present challenges toward achieving the goal of tuberculosis (TB) elimination worldwide. By using the ex vivo cultures of alveolar macrophages obtained from lung tissues of TB patients after intensive antimicrobial chemotherapy before surgery, different subpopulations of multidrug-tolerant Mtb with a spectrum of phenotypic and growth features were identified in the same TB lesions. Our results are indicative of not only passive mechanisms generating nonheritable resistance of Mtb to antibiotics, which are associated mainly with a lack of Mtb growth, but also some active mechanisms of Mtb persistence, such as cell wall and metabolic pathway remodeling. In one of the subpopulations, non-acid-fast Mtb have undergone significant reprogramming with the restoration of acid-fastness, lipoarabinomannan expression and replication in host cells of some patients after withdrawal of anti-TB drugs. Our data indicate the universal stress protein Rv2623 as a clinically relevant biomarker of Mtb that has lost acid-fastness in human lungs. The studies of Mtb survival, persistence, dormancy, and resumption and the identification of biomarkers characterizing these phenomena are very important concerning the development of vaccines and drug regimens with individualized management of patients for overcoming the resistance/tolerance crisis in anti-TB therapy. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms in Mycobacterial Infection 3.0)

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