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Cellular and Molecular Mechanisms in Mycobacterial Infection

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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 March 2021) | Viewed by 40586

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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

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
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Mycobacterium tuberculosis (M.tb) caused an estimated 10 million cases of tuberculosis (TB) and 1.5 million deaths in 2018. 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 will cover a selection of original research articles, short communications, and current review articles in 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 Eva Nieuwenhuizen

Dr. Joanna Evans
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

Tuberculosis
Mycobacteria
Bacterial metabolism
Bacterial infection
Antibiotic resistance
Vaccines
Biomarkers
Signaling pathways
Immune system
Host-directed therapy
Host-pathogen interaction
Drug discovery

Related Special Issue

Cellular and Molecular Mechanisms in Mycobacterial Infection 2.0 in International Journal of Molecular Sciences (21 articles)

Published Papers (11 papers)

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Editorial

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3 pages, 183 KiB

Open AccessEditorial

Cellular and Molecular Mechanisms in Mycobacterial Infection

by Natalie E. Nieuwenhuizen and Joanna C. Evans

Int. J. Mol. Sci. 2022, 23(13), 7205; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23137205 - 29 Jun 2022

Viewed by 1335

Abstract

Tuberculosis (TB), caused by the bacillus Mycobacterium tuberculosis (Mtb), remains a leading cause of death by infectious disease, overshadowed only recently by the COVID-19 pandemic [...] Full article

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

Research

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16 pages, 18495 KiB

Open AccessArticle

Replication-Deficient Lymphocytic Choriomeningitis Virus-Vectored Vaccine Candidate for the Induction of T Cell Immunity against Mycobacterium tuberculosis

by Elodie Belnoue, Alexis Vogelzang, Natalie E. Nieuwenhuizen, Magdalena A. Krzyzaniak, Stephanie Darbre, Mario Kreutzfeldt, Ingrid Wagner, Doron Merkler, Paul-Henri Lambert, Stefan H. E. Kaufmann, Claire-Anne Siegrist and Daniel D. Pinschewer

Int. J. Mol. Sci. 2022, 23(5), 2700; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23052700 - 28 Feb 2022

Cited by 4 | Viewed by 2357

Abstract

Mycobacterium tuberculosis (Mtb) represents a major burden to global health, and refined vaccines are needed. Replication-deficient lymphocytic choriomeningitis virus (rLCMV)-based vaccine vectors against cytomegalovirus have proven safe for human use and elicited robust T cell responses in a large proportion of vaccine recipients. Here, we developed an rLCMV vaccine expressing the Mtb antigens TB10.4 and Ag85B. In mice, rLCMV elicited high frequencies of polyfunctional Mtb-specific CD8 and CD4 T cell responses. CD8 but not CD4 T cells were efficiently boosted upon vector re-vaccination. High-frequency responses were also observed in neonatally vaccinated mice, and co-administration of rLCMV with Expanded Program of Immunization (EPI) vaccines did not result in substantial reciprocal interference. Importantly, rLCMV immunization significantly reduced the lung Mtb burden upon aerosol challenge, resulting in improved lung ventilation. Protection was associated with increased CD8 T cell recruitment but reduced CD4 T cell infiltration upon Mtb challenge. When combining rLCMV with BCG vaccination in a heterologous prime-boost regimen, responses to the rLCMV-encoded Mtb antigens were further augmented, but protection was not significantly different from rLCMV or BCG vaccination alone. This work suggests that rLCMV may show utility for neonatal and/or adult vaccination efforts against pulmonary tuberculosis. Full article

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

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18 pages, 4287 KiB

Open AccessArticle

Evaluation of Myeloperoxidase as Target for Host-Directed Therapy in Tuberculosis In Vivo

by Lara C. Linnemann, Ulrich E. Schaible and Tobias K. Dallenga

Int. J. Mol. Sci. 2022, 23(5), 2554; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23052554 - 25 Feb 2022

Cited by 5 | Viewed by 2021

Abstract

Due to the rise of tuberculosis cases infected with multi and extensively drug-resistant Mycobacterium tuberculosis strains and the emergence of isolates resistant to antibiotics newly in clinical use, host-directed therapies targeting pathogenesis-associated immune pathways adjunct to antibiotics may ameliorate disease and bacterial clearance. Active tuberculosis is characterized by neutrophil-mediated lung pathology and tissue destruction. Previously, we showed that preventing M. tuberculosis induced necrosis in human neutrophils by inhibition of myeloperoxidase (MPO) promoted default apoptosis and subsequent control of mycobacteria by macrophages taking up the mycobacteria-infected neutrophils. To translate our findings in an in vivo model, we tested the MPO inhibitor 4-aminobenzoic acid hydrazide (ABAH) in C3HeB/FeJ mice, which are highly susceptible to M. tuberculosis infection manifesting in neutrophil-associated necrotic granulomas. MPO inhibition alone or as co-treatment with isoniazid, a first-line antibiotic in tuberculosis treatment, did not result in reduced bacterial burden, improved pathology, or altered infiltrating immune cell compositions. MPO inhibition failed to prevent M. tuberculosis induced neutrophil necrosis in C3Heb/FeJ mice in vivo as well as in murine neutrophils in vitro. In contrast to human neutrophils, murine neutrophils do not respond to M. tuberculosis infection in an MPO-dependent manner. Thus, the murine C3HeB/FeJ model does not fully resemble the pathomechanisms in active human tuberculosis. Consequently, murine infection models of tuberculosis are not necessarily adequate to evaluate host-directed therapies targeting neutrophils in vivo. Full article

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

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18 pages, 3381 KiB

Open AccessArticle

Mycobacterium tuberculosis H37Rv Strain Increases the Frequency of CD3⁺TCR⁺ Macrophages and Affects Their Phenotype, but Not Their Migration Ability

by Lucero A. Ramon-Luing, Claudia Carranza, Norma A. Téllez-Navarrete, Karen Medina-Quero, Yolanda Gonzalez, Martha Torres and Leslie Chavez-Galan

Int. J. Mol. Sci. 2022, 23(1), 329; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23010329 - 28 Dec 2021

Cited by 7 | Viewed by 2450

Abstract

In mycobacterial infections, the number of cells from two newly discovered subpopulations of CD3⁺ myeloid cells are increased at the infection site; one type expresses the T cell receptor (CD3⁺TCRαβ⁺) and the other does not (CD3⁺TCRαβ⁻). The role of Mycobacterium tuberculosis (Mtb) virulence in generating these subpopulations and the ability of these cells to migrate remains unclear. In this study, monocyte-derived macrophages (MDMs) infected in vitro with either a virulent (H37Rv) or an avirulent (H37Ra) Mtb strain were phenotypically characterized based on three MDM phenotypes (CD3⁻, CD3⁺TCRαβ⁺, and CD3⁺TCRαβ⁻); then, their migration ability upon Mtb infection was evaluated. We found no differences in the frequency of CD3⁺ MDMs at 24 h of infection with either Mtb strain. However, H37Rv infection increased the frequency of CD3⁺TCRαβ⁺ MDMs at a multiplicity of infection of 1 and altered the expression of CD1b, CD1c, and TNF on the surface of cells from both the CD3⁺ MDM subpopulations; it also modified the expression of CCR2, CXCR1, and CCR7, thus affecting CCL2 and IL-8 levels. Moreover, H37Rv infection decreased the migration ability of the CD3⁻ MDMs, but not CD3⁺ MDMs. These results confirm that the CD3⁺ macrophage subpopulations express chemokine receptors that respond to chemoattractants, facilitating cell migration. Together, these data suggest that CD3⁺ MDMs are a functional subpopulation involved in the immune response against Mtb. Full article

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

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18 pages, 3346 KiB

Open AccessArticle

PGRS Domain of Rv0297 of Mycobacterium tuberculosis Functions in A Calcium Dependent Manner

by Tarina Sharma, Jasdeep Singh, Sonam Grover, Manjunath P., Firdos Firdos, Anwar Alam, Nasreen Z. Ehtesham and Seyed E. Hasnain

Int. J. Mol. Sci. 2021, 22(17), 9390; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22179390 - 30 Aug 2021

Cited by 8 | Viewed by 2178

Abstract

Mycobacterium tuberculosis (M.tb), the pathogen causing tuberculosis, is a major threat to human health worldwide. Nearly 10% of M.tb genome encodes for a unique family of PE/PPE/PGRS proteins present exclusively in the genus Mycobacterium. The functions of most of these proteins are yet unexplored. The PGRS domains of these proteins have been hypothesized to consist of Ca²⁺ binding motifs that help these intrinsically disordered proteins to modulate the host cellular responses. Ca²⁺ is an important secondary messenger that is involved in the pathogenesis of tuberculosis in diverse ways. This study presents the calcium-dependent function of the PGRS domain of Rv0297 (PE_PGRS5) in M.tb virulence and pathogenesis. Tandem repeat search revealed the presence of repetitive Ca²⁺ binding motifs in the PGRS domain of the Rv0297 protein (Rv0297PGRS). Molecular Dynamics simulations and fluorescence spectroscopy revealed Ca²⁺ dependent stabilization of the Rv0297PGRS protein. Calcium stabilized Rv0297PGRS enhances the interaction of Rv0297PGRS with surface localized Toll like receptor 4 (TLR4) of macrophages. The Ca²⁺ stabilized binding of Rv0297PGRS with the surface receptor of macrophages enhances its downstream consequences in terms of Nitric Oxide (NO) production and cytokine release. Thus, this study points to hitherto unidentified roles of calcium-modulated PE_PGRS proteins in the virulence of M.tb. Understanding the pathogenic potential of Ca²⁺ dependent PE_PGRS proteins can aid in targeting these proteins for therapeutic interventions. Full article

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

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14 pages, 3592 KiB

Open AccessArticle

A Screening of the MMV Pandemic Response Box Reveals Epetraborole as A New Potent Inhibitor against Mycobacterium abscessus

by Taeho Kim, Bui-Thi-Bich Hanh, Boeun Heo, Nguyenthanh Quang, Yujin Park, Jihyeon Shin, Seunghyeon Jeon, June-Woo Park, Kirandeep Samby and Jichan Jang

Int. J. Mol. Sci. 2021, 22(11), 5936; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22115936 - 31 May 2021

Cited by 14 | Viewed by 2808

Abstract

Mycobacterium abscessus is the one of the most feared bacterial respiratory pathogens in the world. Unfortunately, there are many problems with the current M. abscessus therapies available. These problems include misdiagnoses, high drug resistance, poor long-term treatment outcomes, and high costs. Until now, there have only been a few new compounds or drug formulations which are active against M. abscessus, and these are present in preclinical and clinical development only. With that in mind, new and more powerful anti-M. abscessus medicines need to be discovered and developed. In this study, we conducted an in vitro-dual screen against M. abscessus rough (R) and smooth (S) variants using a Pandemic Response Box and identified epetraborole as a new effective candidate for M. abscessus therapy. For further validation, epetraborole showed significant activity against the growth of the M. abscessus wild-type strain, three subspecies, drug-resistant strains and clinical isolates in vitro, while also inhibiting the growth of M. abscessus that reside in macrophages without cytotoxicity. Furthermore, the in vivo efficacy of epetraborole in the zebrafish infection model was greater than that of tigecycline. Thus, we concluded that epetraborole is a potential anti-M. abscessus candidate in the M. abscessus drug search. Full article

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

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16 pages, 1708 KiB

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Super-Resolution Microscopy Reveals a Direct Interaction of Intracellular Mycobacterium tuberculosis with the Antimicrobial Peptide LL-37

by Dhruva Deshpande, Mark Grieshober, Fanny Wondany, Fabian Gerbl, Reiner Noschka, Jens Michaelis and Steffen Stenger

Int. J. Mol. Sci. 2020, 21(18), 6741; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21186741 - 14 Sep 2020

Cited by 18 | Viewed by 4295

Abstract

The antimicrobial peptide LL-37 inhibits the growth of the major human pathogen Mycobacterium tuberculosis (Mtb), but the mechanism of the peptide–pathogen interaction inside human macrophages remains unclear. Super-resolution imaging techniques provide a novel opportunity to visualize these interactions on a molecular level. Here, we adapt the super-resolution technique of stimulated emission depletion (STED) microscopy to study the uptake, intracellular localization and interaction of LL-37 with macrophages and virulent Mtb. We demonstrate that LL-37 is internalized by both uninfected and Mtb infected primary human macrophages. The peptide localizes in the membrane of early endosomes and lysosomes, the compartment in which mycobacteria reside. Functionally, LL-37 disrupts the cell wall of intra- and extracellular Mtb, resulting in the killing of the pathogen. In conclusion, we introduce STED microscopy as an innovative and informative tool for studying host–pathogen–peptide interactions, clearly extending the possibilities of conventional confocal microscopy. Full article

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

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Review

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17 pages, 1993 KiB

Open AccessReview

The Mycobacterium tuberculosis PE_PGRS Protein Family Acts as an Immunological Decoy to Subvert Host Immune Response

by Tarina Sharma, Anwar Alam, Aquib Ehtram, Anshu Rani, Sonam Grover, Nasreen Z. Ehtesham and Seyed E. Hasnain

Int. J. Mol. Sci. 2022, 23(1), 525; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23010525 - 04 Jan 2022

Cited by 18 | Viewed by 7456

Abstract

Mycobacterium tuberculosis (M.tb) is a successful pathogen that can reside within the alveolar macrophages of the host and can survive in a latent stage. The pathogen has evolved and developed multiple strategies to resist the host immune responses. M.tb escapes from host macrophage through evasion or subversion of immune effector functions. M.tb genome codes for PE/PPE/PE_PGRS proteins, which are intrinsically disordered, redundant and antigenic in nature. These proteins perform multiple functions that intensify the virulence competence of M.tb majorly by modulating immune responses, thereby affecting immune mediated clearance of the pathogen. The highly repetitive, redundant and antigenic nature of PE/PPE/PE_PGRS proteins provide a critical edge over other M.tb proteins in terms of imparting a higher level of virulence and also as a decoy molecule that masks the effect of effector molecules, thereby modulating immuno-surveillance. An understanding of how these proteins subvert the host immunological machinery may add to the current knowledge about M.tb virulence and pathogenesis. This can help in redirecting our strategies for tackling M.tb infections. Full article

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

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20 pages, 3538 KiB

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Transmembrane TNF and Its Receptors TNFR1 and TNFR2 in Mycobacterial Infections

by Andy Ruiz, Yadira Palacios, Irene Garcia and Leslie Chavez-Galan

Int. J. Mol. Sci. 2021, 22(11), 5461; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22115461 - 22 May 2021

Cited by 18 | Viewed by 5280

Abstract

Tumor necrosis factor (TNF) is one of the main cytokines regulating a pro-inflammatory environment. It has been related to several cell functions, for instance, phagocytosis, apoptosis, proliferation, mitochondrial dynamic. Moreover, during mycobacterial infections, TNF plays an essential role to maintain granuloma formation. Several effector mechanisms have been implicated according to the interactions of the two active forms, soluble TNF (solTNF) and transmembrane TNF (tmTNF), with their receptors TNFR1 and TNFR2. We review the impact of these interactions in the context of mycobacterial infections. TNF is tightly regulated by binding to receptors, however, during mycobacterial infections, upstream activation signalling pathways may be influenced by key regulatory factors either at the membrane or cytosol level. Detailing the structure and activation pathways used by TNF and its receptors, such as its interaction with solTNF/TNFRs versus tmTNF/TNFRs, may bring a better understanding of the molecular mechanisms involved in activation pathways which can be helpful for the development of new therapies aimed at being more efficient against mycobacterial infections. Full article

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

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24 pages, 923 KiB

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Neutrophils in Tuberculosis: Cell Biology, Cellular Networking and Multitasking in Host Defense

by Rachana R. Borkute, Sören Woelke, Gang Pei and Anca Dorhoi

Int. J. Mol. Sci. 2021, 22(9), 4801; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22094801 - 30 Apr 2021

Cited by 26 | Viewed by 5754

Abstract

Neutrophils readily infiltrate infection foci, phagocytose and usually destroy microbes. In tuberculosis (TB), a chronic pulmonary infection caused by Mycobacterium tuberculosis (Mtb), neutrophils harbor bacilli, are abundant in tissue lesions, and their abundances in blood correlate with poor disease outcomes in patients. The biology of these innate immune cells in TB is complex. Neutrophils have been assigned host-beneficial as well as deleterious roles. The short lifespan of neutrophils purified from blood poses challenges to cell biology studies, leaving intracellular biological processes and the precise consequences of Mtb–neutrophil interactions ill-defined. The phenotypic heterogeneity of neutrophils, and their propensity to engage in cellular cross-talk and to exert various functions during homeostasis and disease, have recently been reported, and such observations are newly emerging in TB. Here, we review the interactions of neutrophils with Mtb, including subcellular events and cell fate upon infection, and summarize the cross-talks between neutrophils and lung-residing and -recruited cells. We highlight the roles of neutrophils in TB pathophysiology, discussing recent findings from distinct models of pulmonary TB, and emphasize technical advances that could facilitate the discovery of novel neutrophil-related disease mechanisms and enrich our knowledge of TB pathogenesis. Full article

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

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26 pages, 4930 KiB

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Addressing Latent Tuberculosis: New Advances in Mimicking the Disease, Discovering Key Targets, and Designing Hit Compounds

by André Campaniço, Shrika G. Harjivan, Digby F. Warner, Rui Moreira and Francisca Lopes

Int. J. Mol. Sci. 2020, 21(22), 8854; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21228854 - 23 Nov 2020

Cited by 9 | Viewed by 3497

Abstract

Despite being discovered and isolated more than one hundred years ago, tuberculosis (TB) remains a global public health concern arch. Our inability to eradicate this bacillus is strongly related with the growing resistance, low compliance to current drugs, and the capacity of the bacteria to coexist in a state of asymptomatic latency. This last state can be sustained for years or even decades, waiting for a breach in the immune system to become active again. Furthermore, most current therapies are not efficacious against this state, failing to completely clear the infection. Over the years, a series of experimental methods have been developed to mimic the latent state, currently used in drug discovery, both in vitro and in vivo. Most of these methods focus in one specific latency inducing factor, with only a few taking into consideration the complexity of the granuloma and the genomic and proteomic consequences of each physiological factor. A series of targets specifically involved in latency have been studied over the years with promising scaffolds being discovered and explored. Taking in account that solving the latency problem is one of the keys to eradicate the disease, herein we compile current therapies and diagnosis techniques, methods to mimic latency and new targets and compounds in the pipeline of drug discovery. Full article

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

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