Special Issue "Mycobacterium tuberculosis Pathogenesis, Infection Prevention and Treatment"

A special issue of Pathogens (ISSN 2076-0817).

Deadline for manuscript submissions: closed (1 March 2020).

Printed Edition Available!
A printed edition of this Special Issue is available here.

Special Issue Editors

Dr. Davide Maria Ferraris
E-Mail Website
Guest Editor
Department of Pharmaceutical Sciences, University of Eastern Piedmont, Novara, Italy
Interests: M. tuberculosis, enzymology, biochemistry, structural biology
Dr. Riccardo Miggiano
E-Mail Website
Guest Editor
Department of Pharmaceutical Sciences, University of Eastern Piedmont, Novara, Italy
Interests: biochemistry; structural biology; M. tuberculosis; DNA repair mechanisms; biochemistry; structural biology
Prof. Dr. Menico Rizzi
E-Mail Website
Guest Editor
Department of Pharmaceutical Sciences, University of Eastern Piedmont, Novara, Italy
Interests: M. tuberculosis; malaria; NAD metabolism; biochemistry; structural biology

Special Issue Information

Dear colleagues,

The global scale and the dramatic number of individuals that succumb to tuberculosis necessitates drastic measures to fight this widespread, debilitating disease. The last data provided by the World Health Organization (WHO) in their annual “Global Tuberculosis Report” [1] maintain tuberculosis as the ninth cause of death worldwide and the leading cause of mortality by a single infectious agent, with the highest rate of infections and death toll rate mostly concentrated in developing and low-income countries.

Tuberculosis is also considered an impairing factor for economic growth and for the improvement of the general public health in those countries, as it drains human and financial resources that would otherwise be invested in the economy [2]. Hence, there is a pressing need to study and develop new prevention protocols and treatments for tuberculosis.

Public health policy makers, supranational organizations, and governing bodies are currently joining efforts in raising awareness in the general population regarding M. tuberculosis contagion and in establishing guidelines and protocols for fighting tuberculosis [3]. At the same time, pharmaceutical companies research new therapies and approaches for finding new antitubercular diagnostics and treatments, the commercial sustainability of which should not be overlooked in order to make antitubercular treatments accessible and inclusive [4].

The aim of the current Special Issue is to collect, update, and harmonize the most recent literature on tuberculosis. We aim to touch herein the most relevant aspects of M. tuberculosis infection as well as its diagnosis and treatments, spanning from the understanding of the molecular mechanisms involved in pathogenesis, to the recapitulation of the host immune responses against tuberculosis, to the analysis of available tools for tuberculosis prevention, and to the latest advancements in antitubercular drug discovery.

Our intent is also to focus the attention not only on the aspects of tuberculosis research (although they are of fundamental importance for advancing antitubercular treatments), but also on the standpoints and the priorities of healthcare policy makers, who are those that contribute in dictating the guidelines to which governments and healthcare providers must adhere to fight tuberculosis.

While mainly dedicated to scientists and to experts in the field, this Special Issue reaches out to a broader audience with the aim of raising awareness not only on the scientific aspects of tuberculosis research, but also with the aim of encouraging the readers to gain a comprehensive vision of the multifaceted aspects of tuberculosis research, management, and treatment.

  1. World Health Organization Global tuberculosis Report WHO 2018; 2018; Vol. 69.
  2. Reid, M.J.A.; Arinaminpathy, N.; Bloom, A.; Bloom, B.R.; Boehme, C.; Chaisson, R.; Chin, D.P.; Churchyard, G.; Cox, H.; Ditiu, L.; et al. Building a tuberculosis-free world: The Lancet Commission on tuberculosis. Lancet 2019, 393, 1331–1384.
  3. Political declaration of the High-Level Meeting of the General Assembly on the Fight Against Tuberculosis : 2018.
  4. Treatment Action Group Tuberculosis Research Funding Trends 2005-2017; 2018;

Dr. Davide Maria Ferraris
Dr. Riccardo Miggiano
Prof. Dr. Menico Rizzi
Guest Editors

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Keywords

  • M. tuberculosis
  • tuberculosis
  • host-pathogen interactions
  • immune response
  • antitubercular drug discovery
  • antitubercular treatments

Published Papers (10 papers)

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Editorial

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Open AccessEditorial
Mycobacterium tuberculosis Pathogenesis, Infection Prevention and Treatment
Pathogens 2020, 9(5), 385; https://doi.org/10.3390/pathogens9050385 - 18 May 2020
Cited by 1 | Viewed by 1498
Abstract
Tuberculosis (TB) is an infectious disease caused by the bacterium Mycobacterium tuberculosis (MTB) and it represents a persistent public health threat for a number of complex biological and sociological reasons. According to the most recent Global Tuberculosis Report (2019) edited by the World [...] Read more.
Tuberculosis (TB) is an infectious disease caused by the bacterium Mycobacterium tuberculosis (MTB) and it represents a persistent public health threat for a number of complex biological and sociological reasons. According to the most recent Global Tuberculosis Report (2019) edited by the World Health Organization (WHO), TB is considered the ninth cause of death worldwide and the leading cause of mortality by a single infectious agent, with the highest rate of infections and death toll rate mostly concentrated in developing and low-income countries. We present here the editorial section to the Special Issue entitled “Mycobacterium tuberculosis Pathogenesis, Infection Prevention and Treatment” that includes 7 research articles and a review. The scientific contributions included in the Special Issue mainly focus on the characterization of MTB strains emerging in TB endemic countries as well as on multiple mechanisms adopted by the bacteria to resist and to adapt to antitubercular therapies. Full article

Research

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Open AccessArticle
Interleukin-18, Functional IL-18 Receptor and IL-18 Binding Protein Expression in Active and Latent Tuberculosis
Pathogens 2020, 9(6), 451; https://doi.org/10.3390/pathogens9060451 - 08 Jun 2020
Viewed by 700
Abstract
A thorough understanding of the processes modulating the innate and acquired immune response to Mycobacterium tuberculosis (M.tb) infection in the context of gene expression is still a scientific and diagnostic problem. The study was aimed to assess IL-18, IL-18 binding protein [...] Read more.
A thorough understanding of the processes modulating the innate and acquired immune response to Mycobacterium tuberculosis (M.tb) infection in the context of gene expression is still a scientific and diagnostic problem. The study was aimed to assess IL-18, IL-18 binding protein (IL-18BP), IL-18R, IFN-γ, and IL-37 mRNA expression in patients with active tuberculosis (ATB) and healthy volunteers with latent M.tb-infection (LTB) or M.tb-uninfected healthy controls (Control). The relative mRNA expression was assessed in the buffy coat blood fraction using the qPCR method. In total, 97 BCG-vaccinated Polish adults were enrolled in the study. The relative expression of IL-18 and IL-18BP mRNA was significantly elevated in the ATB and LTB groups. In ATB, but not LTB individuals, the overexpression of IL-18 and IL-18BP, as well as a significant increase in IFN-γ mRNA expression, might be considered as a manifestation of active tuberculosis disease. No statistically significant differences were observed in the IL-37 mRNA expression among the studied groups. Particularly noteworthy is the outstanding reduction in the relative expression of IL-18R mRNA in the LTB group as compared to the ATB and Control group. Reduced expression of IL-18R in LTB group may, at least partially, prevent the development of a pathological inflammatory reaction and promote the maintenance of homeostatic conditions between host immunity and M.tb. Full article
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Open AccessArticle
Preclinical Evidence of Nanomedicine Formulation to Target Mycobacterium tuberculosis at Its Bone Marrow Niche
Pathogens 2020, 9(5), 372; https://doi.org/10.3390/pathogens9050372 - 13 May 2020
Cited by 2 | Viewed by 841
Abstract
One-third of the world’s population is estimated to be latently infected with Mycobacterium tuberculosis (Mtb). Recently, we found that dormant Mtb hides in bone marrow mesenchymal stem cells (BM-MSCs) post-chemotherapy in mice model and in clinical subjects. It is known that residual Mtb [...] Read more.
One-third of the world’s population is estimated to be latently infected with Mycobacterium tuberculosis (Mtb). Recently, we found that dormant Mtb hides in bone marrow mesenchymal stem cells (BM-MSCs) post-chemotherapy in mice model and in clinical subjects. It is known that residual Mtb post-chemotherapy may be responsible for increased relapse rates. However, strategies for Mtb clearance post-chemotherapy are lacking. In this study, we engineered and formulated novel bone-homing PEGylated liposome nanoparticles (BTL-NPs) which actively targeted the bone microenvironment leading to Mtb clearance. Targeting of BM-resident Mtb was carried out through bone-homing liposomes tagged with alendronate (Ald). BTL characterization using TEM and DLS showed that the size of bone-homing isoniazid (INH) and rifampicin (RIF) BTLs were 100 ± 16.3 nm and 84 ± 18.4 nm, respectively, with the encapsulation efficiency of 69.5% ± 4.2% and 70.6% ± 4.7%. Further characterization of BTLs, displayed by sustained in vitro release patterns, increased in vivo tissue uptake and enhanced internalization of BTLs in RAW cells and CD271+BM-MSCs. The efficacy of isoniazid (INH)- and rifampicin (RIF)-loaded BTLs were shown using a mice model where the relapse rate of the tuberculosis was decreased significantly in targeted versus non-targeted groups. Our findings suggest that BTLs may play an important role in developing a clinical strategy for the clearance of dormant Mtb post-chemotherapy in BM cells. Full article
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Open AccessArticle
Genome Subtraction and Comparison for the Identification of Novel Drug Targets against Mycobacterium avium subsp. hominissuis
Pathogens 2020, 9(5), 368; https://doi.org/10.3390/pathogens9050368 - 12 May 2020
Cited by 2 | Viewed by 881
Abstract
Mycobacterium avium complex (MAC) is a major cause of non-tuberculous pulmonary and disseminated diseases worldwide, inducing bronchiectasis, and affects HIV and immunocompromised patients. In MAC, Mycobacterium avium subsp. hominissuis is a pathogen that infects humans and mammals, and that is why it is [...] Read more.
Mycobacterium avium complex (MAC) is a major cause of non-tuberculous pulmonary and disseminated diseases worldwide, inducing bronchiectasis, and affects HIV and immunocompromised patients. In MAC, Mycobacterium avium subsp. hominissuis is a pathogen that infects humans and mammals, and that is why it is a focus of this study. It is crucial to find essential drug targets to eradicate the infections caused by these virulent microorganisms. The application of bioinformatics and proteomics has made a significant impact on discovering unique drug targets against the deadly pathogens. One successful bioinformatics methodology is the use of in silico subtractive genomics. In this study, the aim was to identify the unique, non-host and essential protein-based drug targets of Mycobacterium avium subsp. hominissuis via in silico a subtractive genomics approach. Therefore, an in silico subtractive genomics approach was applied in which complete proteome is subtracted systematically to shortlist potential drug targets. For this, the complete dataset of proteins of Mycobacterium avium subsp. hominissuis was retrieved. The applied subtractive genomics method, which involves the homology search between the host and the pathogen to subtract the non-druggable proteins, resulted in the identification of a few prioritized potential drug targets against the three strains of M. avium subsp. Hominissuis, i.e., MAH-TH135, OCU466 and A5. In conclusion, the current study resulted in the prioritization of vital drug targets, which opens future avenues to perform structural as well as biochemical studies on predicted drug targets against M. avium subsp. hominissuis. Full article
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Open AccessArticle
Genotyping, Assessment of Virulence and Antibacterial Resistance of the Rostov Strain of Mycobacterium tuberculosis Attributed to the Central Asia Outbreak Clade
Pathogens 2020, 9(5), 335; https://doi.org/10.3390/pathogens9050335 - 30 Apr 2020
Cited by 1 | Viewed by 638
Abstract
The Central Asia Outbreak (CAO) clade is a growing public health problem for Central Asian countries. Members of the clade belong to the narrow branch of the Mycobacterium tuberculosis Beijing genotype and are characterized by multidrug resistance and increased transmissibility. The Rostov strain [...] Read more.
The Central Asia Outbreak (CAO) clade is a growing public health problem for Central Asian countries. Members of the clade belong to the narrow branch of the Mycobacterium tuberculosis Beijing genotype and are characterized by multidrug resistance and increased transmissibility. The Rostov strain of M. tuberculosis isolated in Russia and attributed to the CAO clade based on PCR-assay and whole genome sequencing and the laboratory strain H37Rv were selected to evaluate the virulence on C57Bl/6 mice models by intravenous injection. All mice infected with the Rostov strain succumbed to death within a 48-day period, while more than half of the mice infected by the H37Rv strain survived within a 90-day period. Mice weight analysis revealed irreversible and severe depletion of animals infected with the Rostov strain compared to H37Rv. The histological investigation of lung and liver tissues of mice on the 30th day after injection of mycobacterial bacilli showed that the pattern of pathological changes generated by two strains were different. Moreover, bacterial load in the liver and lungs was higher for the Rostov strain infection. In conclusion, our data demonstrate that the drug-resistant Rostov strain exhibits a highly virulent phenotype which can be partly explained by the CAO-specific mutations. Full article
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Open AccessArticle
Immune Phenotype and Functionality of Mtb-Specific T-Cells in HIV/TB Co-Infected Patients on Antiretroviral Treatment
Pathogens 2020, 9(3), 180; https://doi.org/10.3390/pathogens9030180 - 02 Mar 2020
Cited by 2 | Viewed by 1276
Abstract
The performance of host blood-based biomarkers for tuberculosis (TB) in HIV-infected patients on antiretroviral therapy (ART) has not been fully assessed. We evaluated the immune phenotype and functionality of antigen-specific T-cell responses in HIV positive (+) participants with TB (n = 12) compared [...] Read more.
The performance of host blood-based biomarkers for tuberculosis (TB) in HIV-infected patients on antiretroviral therapy (ART) has not been fully assessed. We evaluated the immune phenotype and functionality of antigen-specific T-cell responses in HIV positive (+) participants with TB (n = 12) compared to HIV negative (−) participants with either TB (n = 9) or latent TB infection (LTBI) (n = 9). We show that the cytokine profile of Mtb-specific CD4+ T-cells in participants with TB, regardless of HIV status, was predominantly single IFN-γ or dual IFN-γ/ TNFα. Whilst ESAT-6/CFP-10 responding T-cells were predominantly of an effector memory (CD27−CD45RA−CCR7−) profile, HIV-specific T-cells were mainly of a central (CD27+CD45RA−CCR7+) and transitional memory (CD27+CD45RA+/−CCR7−) phenotype on both CD4+ and CD8+ T-cells. Using receiving operating characteristic (ROC) curve analysis, co-expression of CD38 and HLA-DR on ESAT-6/CFP-10 responding total cytokine-producing CD4+ T-cells had a high sensitivity for discriminating HIV+TB (100%, 95% CI 70–100) and HIV−TB (100%, 95% CI 70–100) from latent TB with high specificity (100%, 95% CI 68–100 for HIV−TB) at a cut-off value of 5% and 13%, respectively. TB treatment reduced the proportion of Mtb-specific total cytokine+CD38+HLA-DR+ CD4+ T-cells only in HIV−TB (p = 0.001). Our results suggest that co-expression of CD38 and HLA-DR on Mtb-specific CD4+ T-cells could serve as a TB diagnosis tool regardless of HIV status. Full article
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Open AccessArticle
MmpS5-MmpL5 Transporters Provide Mycobacterium smegmatis Resistance to imidazo[1,2-b][1,2,4,5]tetrazines
Pathogens 2020, 9(3), 166; https://doi.org/10.3390/pathogens9030166 - 28 Feb 2020
Cited by 6 | Viewed by 922
Abstract
The emergence and spread of drug-resistant Mycobacterium tuberculosis strains (including MDR, XDR, and TDR) force scientists worldwide to search for new anti-tuberculosis drugs. We have previously reported a number of imidazo[1,2-b][1,2,4,5]tetrazines – putative inhibitors of mycobacterial eukaryotic-type serine-threonine protein-kinases, active against [...] Read more.
The emergence and spread of drug-resistant Mycobacterium tuberculosis strains (including MDR, XDR, and TDR) force scientists worldwide to search for new anti-tuberculosis drugs. We have previously reported a number of imidazo[1,2-b][1,2,4,5]tetrazines – putative inhibitors of mycobacterial eukaryotic-type serine-threonine protein-kinases, active against M. tuberculosis. Whole genomic sequences of spontaneous drug-resistant M. smegmatis mutants revealed four genes possibly involved in imidazo[1,2-b][1,2,4,5]tetrazines resistance; however, the exact mechanism of resistance remain unknown. We used different approaches (construction of targeted mutants, overexpression of the wild-type (w.t.) and mutant genes, and gene-expression studies) to assess the role of the previously identified mutations. We show that mutations in MSMEG_1380 gene lead to overexpression of the mmpS5-mmpL5 operon in M. smegmatis, thus providing resistance to imidazo[1,2-b][1,2,4,5]tetrazines by increased efflux through the MmpS5-MmpL5 system, similarly to the mechanisms of resistance described for M. tuberculosis and M. abscessus. Mycobacterial MmpS5-MmpL5 transporters should be considered as an MDR-efflux system and they should be taken into account at early stages of anti-tuberculosis drug development. Full article
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Open AccessArticle
Metabolic Changes of Mycobacterium tuberculosis during the Anti-Tuberculosis Therapy
Pathogens 2020, 9(2), 131; https://doi.org/10.3390/pathogens9020131 - 18 Feb 2020
Cited by 5 | Viewed by 897
Abstract
Tuberculosis, caused by Mycobacterium tuberculosis complex bacteria, remains one of the most pressing health problems. Despite the general trend towards reduction of the disease incidence rate, the situation remains extremely tense due to the distribution of the resistant forms. Most often, these strains [...] Read more.
Tuberculosis, caused by Mycobacterium tuberculosis complex bacteria, remains one of the most pressing health problems. Despite the general trend towards reduction of the disease incidence rate, the situation remains extremely tense due to the distribution of the resistant forms. Most often, these strains emerge through the intra-host microevolution of the pathogen during treatment failure. In the present study, the focus was on three serial clinical isolates of Mycobacterium tuberculosis Beijing B0/W148 cluster from one patient with pulmonary tuberculosis, to evaluate their changes in metabolism during anti-tuberculosis therapy. Using whole genome sequencing (WGS), 9 polymorphisms were determined, which occurred in a stepwise or transient manner during treatment and were linked to the resistance (GyrA D94A; inhA t-8a) or virulence. The effect of the inhA t-8a mutation was confirmed on both proteomic and transcriptomic levels. Additionally, the amount of RpsL protein, which is a target of anti-tuberculosis drugs, was reduced. At the systemic level, profound changes in metabolism, linked to the evolution of the pathogen in the host and the effects of therapy, were documented. An overabundance of the FAS-II system proteins (HtdX, HtdY) and expression changes in the virulence factors have been observed at the RNA and protein levels. Full article
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Open AccessArticle
Detection of Second Line Drug Resistance among Drug Resistant Mycobacterium Tuberculosis Isolates in Botswana
Pathogens 2019, 8(4), 208; https://doi.org/10.3390/pathogens8040208 - 28 Oct 2019
Cited by 4 | Viewed by 964
Abstract
The emergence and transmission of multidrug resistant (MDR) and extensively drug resistant (XDR) Mycobacterium tuberculosis (M.tb) strains is a threat to global tuberculosis (TB) control. The early detection of drug resistance is critical for patient management. The aim of this study was to [...] Read more.
The emergence and transmission of multidrug resistant (MDR) and extensively drug resistant (XDR) Mycobacterium tuberculosis (M.tb) strains is a threat to global tuberculosis (TB) control. The early detection of drug resistance is critical for patient management. The aim of this study was to determine the proportion of isolates with additional second-line resistance among rifampicin and isoniazid resistant and MDR-TB isolates. A total of 66 M.tb isolates received at the National Tuberculosis Reference Laboratory between March 2012 and October 2013 with resistance to isoniazid, rifampicin or both were analyzed in this study. The genotypes of the M.tb isolates were determined by spoligotyping and second-line drug susceptibility testing was done using the Hain Genotype MTBDRsl line probe assay version 2.0. The treatment outcomes were defined according to the Botswana national and World Health Organization (WHO) guidelines. Of the 57 isolates analyzed, 33 (58%) were MDR-TB, 4 (7%) were additionally resistant to flouroquinolones and 3 (5%) were resistant to both fluoroquinolones and second-line injectable drugs. The most common fluoroquinolone resistance-conferring mutation detected was gyrA A90V. All XDR-TB cases remained smear or culture positive throughout the treatment. Our study findings indicate the importance of monitoring drug resistant TB cases to ensure rapid detection of second-line drug resistance. Full article
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Review

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Open AccessReview
Intelligent Mechanisms of Macrophage Apoptosis Subversion by Mycobacterium
Pathogens 2020, 9(3), 218; https://doi.org/10.3390/pathogens9030218 - 16 Mar 2020
Cited by 2 | Viewed by 1505
Abstract
Macrophages are one of the first innate defense barriers and play an indispensable role in communication between innate and adaptive immune responses, leading to restricted Mycobacterium tuberculosis (Mtb) infection. The macrophages can undergo programmed cell death (apoptosis), which is a crucial [...] Read more.
Macrophages are one of the first innate defense barriers and play an indispensable role in communication between innate and adaptive immune responses, leading to restricted Mycobacterium tuberculosis (Mtb) infection. The macrophages can undergo programmed cell death (apoptosis), which is a crucial step to limit the intracellular growth of bacilli by liberating them into extracellular milieu in the form of apoptotic bodies. These bodies can be taken up by the macrophages for the further degradation of bacilli or by the dendritic cells, thereby leading to the activation of T lymphocytes. However, Mtb has the ability to interplay with complex signaling networks to subvert macrophage apoptosis. Here, we describe the intelligent strategies of Mtb inhibition of macrophages apoptosis. This review provides a platform for the future study of unrevealed Mtb anti-apoptotic mechanisms and the design of therapeutic interventions. Full article
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