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Virulence Identification and Analysis from Pathogenic Mycobacteria of Humans and...
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Virulence Identification and Analysis from Pathogenic Mycobacteria of Humans and Animals

A special issue of Microorganisms (ISSN 2076-2607). This special issue belongs to the section "Medical Microbiology".

Deadline for manuscript submissions: closed (30 September 2019) | Viewed by 80849

Special Issue Editors

Prof. Frederick D. Quinn

E-Mail Website
Guest Editor
Department of Infectious Diseases, University of Georgia, Athens, GA, USA
Interests: tuberculosis; animal models; virulence factors; vaccines
Dr. Kaori Sakamoto

E-Mail Website
Guest Editor
Department of Pathology, College of Veterinary Medicine, University of Georgia, Athens, GA, USA
Interests: tuberculosis; pathology; macrophage; scavenger receptors; veterinary

Special Issue Information

Dear Colleagues,

Mycobacterium tuberculosis is the number one, bacterial cause of human deaths worldwide. Currently available vaccines are effective mainly against childhood tuberculosis, and treatment requires months of multiple antibiotics, which have serious side effects. Despite numerous ongoing vaccine and antibiotic clinical trials, the field is outpaced by the development of antibiotic resistance and vaccine trial failures, and we are no closer to eliminating the disease than we were 20 years ago. Mycobacterial species also infect and cause disease in most other vertebrate species, with the potential for zoonotic transmission. A better understanding of how mycobacteria cause disease, and thwart vaccine and antibiotic efforts, is needed in order to achieve elimination. In this special issue, we invite you to submit a review or original research article related to virulence factors and mechanisms contributing to mycobacterial infection in humans and animals.

Prof. Frederick D. Quinn
Dr. Kaori Sakamoto
Guest Editors

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. Microorganisms is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). 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

  • mycobacterium
  • animal models
  • diagnosis
  • pathology
  • veterinary
  • virulence

Published Papers (17 papers)

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Research

Jump to: Review, Other

14 pages, 3245 KiB  
Article
Cording Mycobacterium tuberculosis Bacilli Have a Key Role in the Progression towards Active Tuberculosis, Which is Stopped by Previous Immune Response
by Lilibeth Arias, Paula Cardona, Martí Català, Víctor Campo-Pérez, Clara Prats, Cristina Vilaplana, Esther Julián and Pere-Joan Cardona
Microorganisms 2020, 8(2), 228; https://doi.org/10.3390/microorganisms8020228 - 08 Feb 2020
Cited by 5 | Viewed by 3075
Abstract
Cording was the first virulence factor identified in Mycobacterium tuberculosis (Mtb). We aimed to ascertain its role in the induction of active tuberculosis (TB) in the mouse strain C3HeB/FeJ by testing the immunopathogenic capacity of the H37Rv strain. We have obtained two batches [...] Read more.
Cording was the first virulence factor identified in Mycobacterium tuberculosis (Mtb). We aimed to ascertain its role in the induction of active tuberculosis (TB) in the mouse strain C3HeB/FeJ by testing the immunopathogenic capacity of the H37Rv strain. We have obtained two batches of the same strain by stopping their growth in Proskauer Beck liquid medium once the mid-log phase was reached, in the noncording Mtb (NCMtb) batch, and two days later in the cording Mtb (CMtb) batch, when cording could be detected by microscopic analysis. Mice were challenged with each batch intravenously and followed-up for 24 days. CMtb caused a significant increase in the bacillary load at an early stage post-challenge (day 17), when a granulomatous response started, generating exudative lesions characterized by neutrophilic infiltration, which promoted extracellular bacillary growth together with cording formation, as shown for the first time in vivo. In contrast, NCMtb experienced slight or no bacillary growth and lesions could barely be detected. Previous Bacillus Calmette-Guérin (BCG) vaccination or low dose aerosol (LDA) Mtb infection were able to delay the progression towards active TB after CMtb challenge. While BCG vaccination also reduced bacillary load when NCMtb was challenged, LDA did not, and its proliferative lesions experienced neutrophil infiltration. Analysis of lung cytokine and chemokine profiles points to their capacity to block the production of CXCL-1 and further amplification of IL-1β, IL-17 and neutrophilic extracellular trap formation, all of which are essential for TB progression. These data highlight the key role of cording formation in the induction of active TB. Full article
(This article belongs to the Special Issue Virulence Identification and Analysis from Pathogenic Mycobacteria of Humans and Animals)
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17 pages, 15621 KiB  
Article
Automatic Detection of Granuloma Necrosis in Pulmonary Tuberculosis Using a Two-Phase Algorithm: 2D-TB
by Pelin Kus, Metin N. Gurcan and Gillian Beamer
Microorganisms 2019, 7(12), 661; https://doi.org/10.3390/microorganisms7120661 - 07 Dec 2019
Cited by 5 | Viewed by 5797
Abstract
Granuloma necrosis occurs in hosts susceptible to pathogenic mycobacteria and is a diagnostic visual feature of pulmonary tuberculosis (TB) in humans and in super-susceptible Diversity Outbred (DO) mice infected with Mycobacterium tuberculosis. Currently, no published automated algorithms can detect granuloma necrosis in pulmonary [...] Read more.
Granuloma necrosis occurs in hosts susceptible to pathogenic mycobacteria and is a diagnostic visual feature of pulmonary tuberculosis (TB) in humans and in super-susceptible Diversity Outbred (DO) mice infected with Mycobacterium tuberculosis. Currently, no published automated algorithms can detect granuloma necrosis in pulmonary TB. However, such a method could reduce variability, and transform visual patterns into quantitative data for statistical and machine learning analyses. Here, we used histopathological images from super-susceptible DO mice to train, validate, and performance test an algorithm to detect regions of cell-poor necrosis. The algorithm, named 2D-TB, works on 2-dimensional histopathological images in 2 phases. In phase 1, granulomas are detected following background elimination. In phase 2, 2D-TB searches within granulomas for regions of cell-poor necrosis. We used 8 lung sections from 8 different super-susceptible DO mice for training and 10-fold cross validation. We used 13 new lung sections from 10 different super-susceptible DO mice for performance testing. 2D-TB reached 100.0% sensitivity and 91.8% positive prediction value. Compared to an expert pathologist, agreement was 95.5% and there was a statistically significant positive correlation for area detected by 2D-TB and the pathologist. These results show the development, validation, and accurate performance of 2D-TB to detect granuloma necrosis. Full article
(This article belongs to the Special Issue Virulence Identification and Analysis from Pathogenic Mycobacteria of Humans and Animals)
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16 pages, 2334 KiB  
Article
Development of a Biocontrol Method Applying Bacteriophage-Containing Aerosol against Mycobacterium tuberculosis Using the Bacteriophage BTCU-1 and M. smegmatis as Models
by Chun-Chieh Tseng, Dan Chi Chang and Kai-Chih Chang
Microorganisms 2019, 7(8), 237; https://doi.org/10.3390/microorganisms7080237 - 03 Aug 2019
Cited by 9 | Viewed by 3635
Abstract
The application of bacteriophages for biocontrol has attracted increasing attention. Here, we applied ϕBTCU-1 as a model phage to develop a method for controlling Mycobacterium tuberculosis (MTB) by using a bacteriophage-containing aerosol in a chamber study. The soil-isolated ϕBTCU-1 can infect both MTB [...] Read more.
The application of bacteriophages for biocontrol has attracted increasing attention. Here, we applied ϕBTCU-1 as a model phage to develop a method for controlling Mycobacterium tuberculosis (MTB) by using a bacteriophage-containing aerosol in a chamber study. The soil-isolated ϕBTCU-1 can infect both MTB and Mycobacterium smegmatis. Our study used M. smegmatis as an MTB surrogate for safety reasons. Among all the evaluated air samplers, the Andersen impactor was chosen to evaluate the bactericidal efficiency of ϕBTCU-1 against M. smegmatis since the recovery rates of the Andersen impactor were 1.5 to 10.6 times higher than those of sampling filters. When airborne ϕBTCU-1 with the highest concentration of 109 PFU/m3 challenged M. smegmatis (105 CFU/m3) for 10 s, no M. smegmatis colony was recovered from the culture medium. For surface decontamination, no colony of M. smegmatis, which started at 1000 CFU/plate (63.6 cm2), was recovered when exposed to higher ϕBTCU-1 concentrations (>109 PFU/m3) for 60 min. Bacteriophages may be useful for reducing MTB contamination in the air or on hard surfaces. The method we have established suggests that the biocontrol method may be an alternative approach or may be combined with other disinfection methods to prevent MTB infection. Full article
(This article belongs to the Special Issue Virulence Identification and Analysis from Pathogenic Mycobacteria of Humans and Animals)
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23 pages, 861 KiB  
Article
Retrospective Analysis of Archived Pyrazinamide Resistant Mycobacterium tuberculosis Complex Isolates from Uganda—Evidence of Interspecies Transmission
by Sylvia I. Wanzala, Jesca Nakavuma, Dominic Travis, Praiscillia Kia, Sam Ogwang, Wade Ray Waters, Tyler Thacker, Timothy Johnson, Syeda Anum Hadi and Srinand Sreevatsan
Microorganisms 2019, 7(8), 221; https://doi.org/10.3390/microorganisms7080221 - 29 Jul 2019
Cited by 4 | Viewed by 3500
Abstract
The contribution of Mycobacterium bovis to the proportion of tuberculosis cases in humans is unknown. A retrospective study was undertaken on archived Mycobacterium tuberculosis complex (MTBC) isolates from a reference laboratory in Uganda to identify the prevalence of human M. bovis infection. A [...] Read more.
The contribution of Mycobacterium bovis to the proportion of tuberculosis cases in humans is unknown. A retrospective study was undertaken on archived Mycobacterium tuberculosis complex (MTBC) isolates from a reference laboratory in Uganda to identify the prevalence of human M. bovis infection. A total of 5676 isolates maintained in this repository were queried and 136 isolates were identified as pyrazinamide resistant, a hallmark phenotype of M. bovis. Of these, 1.5% (n = 2) isolates were confirmed as M. bovis by using regions of difference PCR analysis. The overall size of whole genome sequences (WGSs) of these two M. bovis isolates were ~4.272 Mb (M. bovis Bz_31150 isolated from a captive chimpanzee) and 4.17 Mb (M. bovis B2_7505 from a human patient), respectively. Alignment of these genomes against 15 MTBC genome sequences revealed 7248 single nucleotide polumorphisms (SNPs). Theses SNPs were used for phylogenetic analysis that indicated a strong relationship between M. bovis and the chimpanzee isolate (Bz_31150) while the other M. bovis genome from the human patient (B2_7505) analyzed did not cluster with any M. bovis or M. tuberculosis strains. WGS analysis also revealed multidrug resistance genotypes; these genomes revealed pncA mutations at positions H57D in Bz_31150 and B2_7505. Phenotypically, B2_7505 was an extensively drug-resistant strain and this was confirmed by the presence of mutations in the major resistance-associated proteins for all anti-tuberculosis (TB) drugs, including isoniazid (KatG (S315T) and InhA (S94A)), fluoroquinolones (S95T), streptomycin (rrs (R309C)), and rifampin (D435Y, a rare but disputed mutation in rpoB). The presence of these mutations exclusively in the human M. bovis isolate suggested that these occurred after transmission from cattle. Genome analysis in this study identified M. bovis in humans and great apes, suggesting possible transmission from domesticated ruminants in the area due to a dynamic and changing interface, which has created opportunity for exposure and transmission. Full article
(This article belongs to the Special Issue Virulence Identification and Analysis from Pathogenic Mycobacteria of Humans and Animals)
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7 pages, 775 KiB  
Article
Host Richness Increases Tuberculosis Disease Risk in Game-Managed Areas
by Jose Angel Barasona, Christian Gortázar, José de la Fuente and Joaquín Vicente
Microorganisms 2019, 7(6), 182; https://doi.org/10.3390/microorganisms7060182 - 24 Jun 2019
Cited by 20 | Viewed by 3303
Abstract
Current scientific debate addresses whether species richness in animal communities may negatively moderate pathogen transmission and disease outcome (dilution effect), or to the contrary, if disease emergence benefits from more diverse community assemblages (amplification effect). The result may not depend exclusively on patterns [...] Read more.
Current scientific debate addresses whether species richness in animal communities may negatively moderate pathogen transmission and disease outcome (dilution effect), or to the contrary, if disease emergence benefits from more diverse community assemblages (amplification effect). The result may not depend exclusively on patterns of host species biodiversity but may depend on the specific composition of reservoir hosts and vectors, and their ecology. Host–pathogen interactions have shaped variations in parasite virulence, transmissibility and specificity. In the same way the importance of factors related to host exposure or to life history trade-offs are expected to vary. In this study, we demonstrate that ungulate host species richness correlates with increased community competence to maintain and transmit pathogens of the Mycobacterium tuberculosis complex (MTC) in game-managed areas in Mediterranean Spain. Therefore, we should consider natural and artificial variations in life histories of pathogens and host communities to characterize the impact of biodiversity on the health of diverse assemblages of human and animal communities. Since most approaches assessing epidemiology and transmission of shared pathogens only involve single- or pair-species, further research is needed to better understand the infection dynamics from complete community assemblages, at least in chronic diseases such as tuberculosis and in non-natural animal communities. Full article
(This article belongs to the Special Issue Virulence Identification and Analysis from Pathogenic Mycobacteria of Humans and Animals)
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19 pages, 3487 KiB  
Article
MAV_4644 Interaction with the Host Cathepsin Z Protects Mycobacterium avium subsp. hominissuis from Rapid Macrophage Killing
by Matthew S. Lewis, Lia Danelishvili, Sasha J. Rose and Luiz E. Bermudez
Microorganisms 2019, 7(5), 144; https://doi.org/10.3390/microorganisms7050144 - 21 May 2019
Cited by 5 | Viewed by 3929
Abstract
Mycobacterium avium subspecies hominissuis (MAH) is an opportunistic pathogen that is ubiquitous in the environment and often isolated from faucets and showerheads. MAH mostly infects humans with an underlying disease, such as chronic pulmonary disorder, cystic fibrosis, or individuals that are immunocompromised. In [...] Read more.
Mycobacterium avium subspecies hominissuis (MAH) is an opportunistic pathogen that is ubiquitous in the environment and often isolated from faucets and showerheads. MAH mostly infects humans with an underlying disease, such as chronic pulmonary disorder, cystic fibrosis, or individuals that are immunocompromised. In recent years, MAH infections in patients without concurrent disease are increasing in prevalence as well. This pathogen is resistant to many antibiotics due to the impermeability of its envelope and due to the phenotypic resistance established within the host macrophages, making difficult to treat MAH infections. By screening a MAH transposon library for mutants that are susceptible to killing by reactive nitrogen intermediaries, we identified the MAV_4644 (MAV_4644:Tn) gene knockout clone that was also significantly attenuated in growth within the host macrophages. Complementation of the mutant restored the wild-type phenotype. The MAV_4644 gene encodes a dual-function protein with a putative pore-forming function and ADP-ribosyltransferase activity. Protein binding assay suggests that MAV_4644 interacts with the host lysosomal peptidase cathepsin Z (CTSZ), a key regulator of the cell signaling and inflammation. Pathogenic mycobacteria have been shown to suppress the action of many cathepsins to establish their intracellular niche. Our results demonstrate that knocking-down the cathepsin Z in human macrophages rescues the attenuated phenotype of MAV_4644:Tn clone. Although, the purified cathepsin Z by itself does not have any killing effect on MAH, it contributes to bacterial killing in the presence of the nitric oxide (NO). Our data suggest that the cathepsin Z is involved in early macrophage killing of MAH, and the virulence factor MAV_4644 protects the pathogen from this process. Full article
(This article belongs to the Special Issue Virulence Identification and Analysis from Pathogenic Mycobacteria of Humans and Animals)
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18 pages, 1153 KiB  
Article
Nontuberculous Mycobacteria Persistence in a Cell Model Mimicking Alveolar Macrophages
by Sara Sousa, Vítor Borges, Ines Joao, João Paulo Gomes and Luisa Jordao
Microorganisms 2019, 7(5), 113; https://doi.org/10.3390/microorganisms7050113 - 26 Apr 2019
Cited by 11 | Viewed by 3904
Abstract
Nontuberculous Mycobacteria (NTM) respiratory infections have been gradually increasing. Here, THP-1 cells were used as a model to evaluate intracellular persistence of three NTM species (reference and clinical strains) in human alveolar macrophages. The contribution of phagosome acidification, nitric oxide (NO) production and [...] Read more.
Nontuberculous Mycobacteria (NTM) respiratory infections have been gradually increasing. Here, THP-1 cells were used as a model to evaluate intracellular persistence of three NTM species (reference and clinical strains) in human alveolar macrophages. The contribution of phagosome acidification, nitric oxide (NO) production and cell dead on NTM intracellular fate was assessed. In addition, strains were characterized regarding their repertoire of virulence factors by whole-genome sequencing. NTM experienced different intracellular fates: M. smegmatis and M. fortuitum ATCC 6841 were cleared within 24h. In contrast, M. avium strains (reference/clinical) and M. fortuitum clinical strain were able to replicate. Despite this fact, unexpectedly high percentages of acidified phagosomes were found harbouring rab7, but not CD63. All NTM were able to survive in vitro at acidic pHs, with the exception of M. smegmatis. Our data further suggested a minor role for NO in intracellular persistence and that apoptosis mediated by caspase 8 and 3/7, but not necrosis, is triggered during NTM infection. Insights regarding the bacteria genomic backbone corroborated the virulence potential of M. avium and M. fortuitum. In conclusion, the phenotypic traits detected contrast with those described for M. tuberculosis, pointing out that NTM adopt distinct strategies to manipulate the host immune defense and persist intracellularly. Full article
(This article belongs to the Special Issue Virulence Identification and Analysis from Pathogenic Mycobacteria of Humans and Animals)
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9 pages, 2196 KiB  
Communication
Mycobacterium smegmatis But Not Mycobacterium avium subsp. hominissuis Causes Increased Expression of the Long Non-Coding RNA MEG3 in THP-1-Derived Human Macrophages and Associated Decrease of TGF-β
by Soroush Sharbati, Faustine Ravon, Ralf Einspanier and Jennifer zur Bruegge
Microorganisms 2019, 7(3), 63; https://doi.org/10.3390/microorganisms7030063 - 27 Feb 2019
Cited by 15 | Viewed by 3500
Abstract
Pathogenic mycobacteria are able to persist intracellularly in macrophages, whereas non-pathogenic mycobacteria are effectively combated and eliminated after their phagocytosis. It is known that TGF-β plays an important role in this context. Infection with pathogenic mycobacteria such as Mycobacterium tuberculosis or M. avium [...] Read more.
Pathogenic mycobacteria are able to persist intracellularly in macrophages, whereas non-pathogenic mycobacteria are effectively combated and eliminated after their phagocytosis. It is known that TGF-β plays an important role in this context. Infection with pathogenic mycobacteria such as Mycobacterium tuberculosis or M. avium leads to production of active TGF-β, which blocks the ability of IFN-γ and TNF-α to inhibit intracellular replication. On the other hand, it is known that the long non-coding RNA (lncRNA) maternally expressed 3 (MEG3) is involved in the regulation of TGF-β. In this study, we show how the infection of THP-1-derived human macrophages with the saprophytic M. smegmatis but not with the facultatively pathogenic M. avium subsp. hominissuis leads to increased MEG3 expression. This is associated with the downregulation of DNA methyltransferases (DNMT) 1 and 3b, which are known to regulate MEG3 expression via promoter hypermethylation. Consequently, we observe a significant downregulation of TGF-β in M. smegmatis-infected macrophages but not in M. avium subsp. hominissuis pointing to lncRNAs as novel mediators of host cell response during mycobacterial infections. Full article
(This article belongs to the Special Issue Virulence Identification and Analysis from Pathogenic Mycobacteria of Humans and Animals)
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18 pages, 12777 KiB  
Article
Optimization of In Vitro Mycobacterium avium and Mycobacterium intracellulare Growth Assays for Therapeutic Development
by Lauren Auster, Morgan Sutton, Mary Chandler Gwin, Christopher Nitkin and Tracey L. Bonfield
Microorganisms 2019, 7(2), 42; https://doi.org/10.3390/microorganisms7020042 - 01 Feb 2019
Cited by 7 | Viewed by 4218
Abstract
Infection with nontuberculous mycobacteria (NTM) is a complication of lung disease in immunocompromised patients, including those with human immunodeficiency virus and acquired immune deficiency syndrome (HIV/AIDS), chronic obstructive pulmonary disease (COPD), and cystic fibrosis (CF). The most widespread, disease-causing NTM is Mycobacterium avium [...] Read more.
Infection with nontuberculous mycobacteria (NTM) is a complication of lung disease in immunocompromised patients, including those with human immunodeficiency virus and acquired immune deficiency syndrome (HIV/AIDS), chronic obstructive pulmonary disease (COPD), and cystic fibrosis (CF). The most widespread, disease-causing NTM is Mycobacterium avium complex (MAC), which colonizes the lungs as a combination of Mycobacterium avium, Mycobacterium intracellulare, and other mycobacterial species. While combination drug therapy exists for MAC colonization, there is no cure. Therapeutic development to treat MAC has been difficult because of the slow-growing nature of the bacterial complex, limiting the ability to characterize the bacteria’s growth in response to new therapeutics. The development of a technology that allows observation of both the MAC predominant strains and MAC could provide a means to develop new therapeutics to treat NTM. We have developed a new methodology in which M. avium and M. intracellulare can be optimally grown in short term culture to study each strain independently and in combination, as a monitor of growth kinetics and efficient therapeutic testing protocols. Full article
(This article belongs to the Special Issue Virulence Identification and Analysis from Pathogenic Mycobacteria of Humans and Animals)
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17 pages, 1566 KiB  
Article
Membrane and Cytoplasmic Proteins of Mycobacterium avium subspecies paratuberculosis that Bind to Novel Monoclonal Antibodies
by John P. Bannantine, Judith R. Stabel, John D. Lippolis and Timothy A. Reinhardt
Microorganisms 2018, 6(4), 127; https://doi.org/10.3390/microorganisms6040127 - 11 Dec 2018
Cited by 6 | Viewed by 4585
Abstract
Monoclonal antibodies against Mycobacterium avium subspecies paratuberculosis (Map) proteins are important tools in Johne’s disease research and diagnostics. Johne’s disease is a chronic inflammatory intestinal disease of cattle, sheep, and other ruminant animals. We have previously generated multiple sets of monoclonal antibodies (mAbs) [...] Read more.
Monoclonal antibodies against Mycobacterium avium subspecies paratuberculosis (Map) proteins are important tools in Johne’s disease research and diagnostics. Johne’s disease is a chronic inflammatory intestinal disease of cattle, sheep, and other ruminant animals. We have previously generated multiple sets of monoclonal antibodies (mAbs) in different studies; however, because many were generated and screened against a whole-cell extract of Map, the antigens that bind to these antibodies remained unknown. In this study, we used three different approaches to identify the corresponding Map antigens for 14 mAbs that could not be identified previously. In the first approach, a new Map-lambda phage expression library was screened to identify corresponding antigens for 11 mAbs. This approach revealed that mAbs 7C8, 9H3, 12E4, 3G5, and 11B8 all detect MAP_3404 encoding the biotin carboxylase subunit of acetyl-CoA carboxylase, while mAbs 7A6, 11F8, and 10C12 detect the GroEL2 chaperonin (MAP_3936), 6C9 detects electron transfer flavoprotein (MAP_3060c), and 14G11 detects MAP_3976, a lipoprotein anchoring transpeptidase. The epitopes to a selection of these mAbs were also defined. In a second approach, MAP_2698c bound monoclonal antibody (mAb) 14D4 as determined using protein arrays. When both of these approaches failed to identify the antigen for mAb 12C9, immunoprecipitation, mass spectrometry analysis, and codon optimization was used to identify the membrane protein, MAP_4145, as the reacting antigen. Characterized antibodies were used to quickly interrogate mycobacterial proteomic preps. We conclude by providing a complete catalog of available mAbs to Map proteins, along with their cognate antigens and epitopes, if known. These antibodies are now thoroughly characterized and more useful for research and diagnostic purposes. Full article
(This article belongs to the Special Issue Virulence Identification and Analysis from Pathogenic Mycobacteria of Humans and Animals)
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Review

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16 pages, 606 KiB  
Review
Adjuvant Strategies for More Effective Tuberculosis Vaccine Immunity
by Erica Stewart, James A Triccas and Nikolai Petrovsky
Microorganisms 2019, 7(8), 255; https://doi.org/10.3390/microorganisms7080255 - 12 Aug 2019
Cited by 27 | Viewed by 6797 | Correction
Abstract
Tuberculosis (TB) caused by Mycobacterium tuberculosis infection is responsible for the most deaths by a single infectious agent worldwide, with 1.6 million deaths in 2017 alone. The World Health Organization, through its “End TB” strategy, aims to reduce TB deaths by 95% by [...] Read more.
Tuberculosis (TB) caused by Mycobacterium tuberculosis infection is responsible for the most deaths by a single infectious agent worldwide, with 1.6 million deaths in 2017 alone. The World Health Organization, through its “End TB” strategy, aims to reduce TB deaths by 95% by 2035. In order to reach this goal, a more effective vaccine than the Bacillus Calmette-Guerin (BCG) vaccine currently in use is needed. Subunit TB vaccines are ideal candidates, because they can be used as booster vaccinations for individuals who have already received BCG and would also be safer for use in immunocompromised individuals in whom BCG is contraindicated. However, subunit TB vaccines will almost certainly require formulation with a potent adjuvant. As the correlates of vaccine protection against TB are currently unclear, there are a variety of adjuvants currently being used in TB vaccines in preclinical and clinical development. This review describes the various adjuvants in use in TB vaccines, their effectiveness, and their proposed mechanisms of action. Notably, adjuvants with less inflammatory and reactogenic profiles that can be administered safely via mucosal routes, may have the biggest impact on future directions in TB vaccine design. Full article
(This article belongs to the Special Issue Virulence Identification and Analysis from Pathogenic Mycobacteria of Humans and Animals)
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19 pages, 726 KiB  
Review
Comparing the Metabolic Capabilities of Bacteria in the Mycobacterium tuberculosis Complex
by Rachael A. Fieweger, Kaley M. Wilburn and Brian C. VanderVen
Microorganisms 2019, 7(6), 177; https://doi.org/10.3390/microorganisms7060177 - 18 Jun 2019
Cited by 18 | Viewed by 4914
Abstract
Pathogenic mycobacteria are known for their ability to maintain persistent infections in various mammals. The canonical pathogen in this genus is Mycobacterium tuberculosis and this bacterium is particularly successful at surviving and replicating within macrophages. Here, we will highlight the metabolic processes that [...] Read more.
Pathogenic mycobacteria are known for their ability to maintain persistent infections in various mammals. The canonical pathogen in this genus is Mycobacterium tuberculosis and this bacterium is particularly successful at surviving and replicating within macrophages. Here, we will highlight the metabolic processes that M. tuberculosis employs during infection in macrophages and compare these findings with what is understood for other pathogens in the M. tuberculosis complex. Full article
(This article belongs to the Special Issue Virulence Identification and Analysis from Pathogenic Mycobacteria of Humans and Animals)
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10 pages, 2102 KiB  
Review
Metabolite Profiling: A Tool for the Biochemical Characterisation of Mycobacterium sp.
by Margit Drapal and Paul D. Fraser
Microorganisms 2019, 7(5), 148; https://doi.org/10.3390/microorganisms7050148 - 25 May 2019
Cited by 5 | Viewed by 3408
Abstract
Over the last decades, the prevalence of drug-resistance in Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis, has increased. These findings have rekindled interest in elucidating the unique adaptive molecular and biochemistry physiology of Mycobacterium. The use of metabolite profiling [...] Read more.
Over the last decades, the prevalence of drug-resistance in Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis, has increased. These findings have rekindled interest in elucidating the unique adaptive molecular and biochemistry physiology of Mycobacterium. The use of metabolite profiling independently or in combination with other levels of “-omic” analyses has proven an effective approach to elucidate key physiological/biochemical mechanisms associated with Mtb throughout infection. The following review discusses the use of metabolite profiling in the study of tuberculosis, future approaches, and the technical and logistical limitations of the methodology. Full article
(This article belongs to the Special Issue Virulence Identification and Analysis from Pathogenic Mycobacteria of Humans and Animals)
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17 pages, 1790 KiB  
Review
Mycobacterium abscessus: Environmental Bacterium Turned Clinical Nightmare
by Rose C. Lopeman, James Harrison, Maya Desai and Jonathan A. G. Cox
Microorganisms 2019, 7(3), 90; https://doi.org/10.3390/microorganisms7030090 - 22 Mar 2019
Cited by 104 | Viewed by 12147
Abstract
Mycobacteria are a large family of over 100 species, most of which do not cause diseases in humans. The majority of the mycobacterial species are referred to as nontuberculous mycobacteria (NTM), meaning they are not the causative agent of tuberculous (TB) or leprosy, [...] Read more.
Mycobacteria are a large family of over 100 species, most of which do not cause diseases in humans. The majority of the mycobacterial species are referred to as nontuberculous mycobacteria (NTM), meaning they are not the causative agent of tuberculous (TB) or leprosy, i.e., Mycobacterium tuberculous complex and Mycobacterium leprae, respectively. The latter group is undoubtedly the most infamous, with TB infecting an estimated 10 million people and causing over 1.2 million deaths in 2017 alone TB and leprosy also differ from NTM in that they are only transmitted from person to person and have no environmental reservoir, whereas NTM infections are commonly acquired from the environment. It took until the 1950′s for NTM to be recognised as a potential lung pathogen in people with underlying pulmonary disease and another three decades for NTM to be widely regarded by the medical community when Mycobacterium avium complex was identified as the most common group of opportunistic pathogens in AIDS patients. This review focuses on an emerging NTM called Mycobacterium abscessus (M. abs). M. abs is a rapidly growing NTM that is responsible for opportunistic pulmonary infections in patients with structural lung disorders such as cystic fibrosis and bronchiectasis, as well as a wide range of skin and soft tissue infections in humans. In this review, we discuss how we came to understand the pathogen, how it is currently treated and examine drug resistance mechanisms and novel treatments currently in development. We highlight the urgent need for new and effective treatments for M. abs infection as well as improved in vivo methods of efficacy testing. Full article
(This article belongs to the Special Issue Virulence Identification and Analysis from Pathogenic Mycobacteria of Humans and Animals)
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16 pages, 1282 KiB  
Review
MmpL Proteins in Physiology and Pathogenesis of M. tuberculosis
by Geoff Melly and Georgiana E. Purdy
Microorganisms 2019, 7(3), 70; https://doi.org/10.3390/microorganisms7030070 - 05 Mar 2019
Cited by 60 | Viewed by 9185
Abstract
Mycobacterium tuberculosis (Mtb) remains an important human pathogen. The Mtb cell envelope is a critical bacterial structure that contributes to virulence and pathogenicity. Mycobacterial membrane protein large (MmpL) proteins export bulky, hydrophobic substrates that are essential for the unique structure of [...] Read more.
Mycobacterium tuberculosis (Mtb) remains an important human pathogen. The Mtb cell envelope is a critical bacterial structure that contributes to virulence and pathogenicity. Mycobacterial membrane protein large (MmpL) proteins export bulky, hydrophobic substrates that are essential for the unique structure of the cell envelope and directly support the ability of Mtb to infect and persist in the host. This review summarizes recent investigations that have enabled insight into the molecular mechanisms underlying MmpL substrate export and the role that these substrates play during Mtb infection. Full article
(This article belongs to the Special Issue Virulence Identification and Analysis from Pathogenic Mycobacteria of Humans and Animals)
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1 pages, 154 KiB  
Correction
Correction: Stewart et al. Adjuvant Strategies for More Effective Tuberculosis Vaccine Immunity. Microorganisms 2019, 7, 255
by Erica Stewart, James A Triccas and Nikolai Petrovsky
Microorganisms 2022, 10(4), 757; https://doi.org/10.3390/microorganisms10040757 - 31 Mar 2022
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Abstract
The authors wish to make the following corrections to this paper [...] Full article
(This article belongs to the Special Issue Virulence Identification and Analysis from Pathogenic Mycobacteria of Humans and Animals)
5 pages, 805 KiB  
Opinion
Tuberculosis Progression Does Not Necessarily Equate with a Failure of Immune Control
by David G. Russell
Microorganisms 2019, 7(7), 185; https://doi.org/10.3390/microorganisms7070185 - 27 Jun 2019
Viewed by 2892
Abstract
Despite the obvious impact of tuberculosis on global health, there is currently no effective vaccine and there is increasing resistance against established front-line drug regiments. Our current understanding of disease progression in tuberculosis is shaped by data collected from the failure of immune [...] Read more.
Despite the obvious impact of tuberculosis on global health, there is currently no effective vaccine and there is increasing resistance against established front-line drug regiments. Our current understanding of disease progression in tuberculosis is shaped by data collected from the failure of immune control. We feel that this represents a biased approach, which constrains our capacity to understand both disease control and progression. In this opinion piece, we re-examine these questions in the context of recently published data from fluorescent bacterial reporter strains and the analysis of the different macrophage lineages present at sites of infection. We believe that this analysis provides alternative models for disease progression, which are not addressed through current vaccine or immune-therapeutic strategies. Full article
(This article belongs to the Special Issue Virulence Identification and Analysis from Pathogenic Mycobacteria of Humans and Animals)
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