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Pathogens
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Pathogenesis of Tuberculosis: Challenges and Opportunities
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Pathogenesis of Tuberculosis: Challenges and Opportunities

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

Deadline for manuscript submissions: closed (31 July 2021) | Viewed by 23532

Special Issue Editor

Prof. Dr. Robert L. Hunter

E-Mail Website
Guest Editor
Department of Pathology and Laboratory Medicine, University of Texas Health Sciences Center, Houston, TX, United States
Interests: Immunopathology; Pathogenesis of tuberculosis

Special Issue Information

Dear Colleagues,

Introductory statement

An enduring mystery of tuberculosis (TB) is how the immune response can simultaneously protect and cause tissue damage. We can understand why people with weak immune responses develop disease, but not why people with the strongest immune responses also have greater risk of clinical disease and death?

Mycobacterium tuberculosis (MTB) is not a typical bacterial pathogen, but is a highly successful human parasite that has evolved with us for a very long time. It has no natural host or reservoir other than humans. While we have made impressive progress in identifying cells, molecules, and pathways of the host response, we remain unable to understand host susceptibility/resistance beyond saying there must be a balance. There is need to question the paradigm that granulomas are the hallmark of TB since investigators in the preantibiotic era who had studied hundreds of cases wrote that granulomas are not involved in the development of post-primary (adult-type pulmonary) TB. Lack of informative human lung tissue for research is a major problem. Such tissues were widely studied in the preantibiotic era, but today most research relies on animal models that do not replicate all stages of human TB.

This issue of Pathogens seeks to describe the challenges and opportunities for putting the pieces together to develop an improved understanding of this disease. New research must be interpreted in a more inclusive context than ‘granulomas’. The attached review article is intended to provide a prospective for further critical discussion and action.

Suggested TOPICS

  • Role of immune responses in the pathogenesis of TB
    • Differences in the immune responses between primary and post-primary TB.
    • Role of the immune response in developing and maintaining post-primary TB
  • Animal models of particular stages of human TB, especially post-primary TB.
    • Validation of animal models: what is most relevant for which stage of the human disease.
  • Radiologic / pathologic correlations
    • Primary vs post-primary TB
  • Issues and availability of human tissues for research
    • Peripheral blood, BAL, surgical resections and autopsies.
    • Advantages and disadvantages of formalin fixed paraffin embedded tissues.
  • Emerging technologies for study of host-parasite interactions
    • Multiplexed immunohistochemistry, mass spec imaging and image analysis
  • Vaccines and host-directed therapies for post-primary TB
    • Methods to access the effectiveness of vaccines and / or host directed therapies.

Prof. Dr. Robert L. Hunter
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. Pathogens 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.

Published Papers (6 papers)

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Research

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7 pages, 9826 KiB  
Article
Early Lesion of Post-Primary Tuberculosis: Subclinical Driver of Disease and Target for Vaccines and Host-Directed Therapies
by Robert E. Brown and Robert L. Hunter
Pathogens 2021, 10(12), 1572; https://doi.org/10.3390/pathogens10121572 - 2 Dec 2021
Cited by 4 | Viewed by 2652
Abstract
The characteristic lesion of primary tuberculosis is the granuloma as is widely studied in human tissues and animal models. Post-primary tuberculosis is different. It develops only in human lungs and begins as a prolonged subclinical obstructive lobular pneumonia that slowly accumulates mycobacterial antigens [...] Read more.
The characteristic lesion of primary tuberculosis is the granuloma as is widely studied in human tissues and animal models. Post-primary tuberculosis is different. It develops only in human lungs and begins as a prolonged subclinical obstructive lobular pneumonia that slowly accumulates mycobacterial antigens and host lipids in alveolar macrophages with nearby highly sensitized T cells. After several months, the lesions undergo necrosis to produce a mass of caseous pneumonia large enough to fragment and be coughed out to produce a cavity or be retained as the focus of a post-primary granuloma. Bacteria grow massively on the cavity wall where they can be coughed out to infect new people. Here we extend these findings with the demonstration of secreted mycobacterial antigens, but not acid fast bacilli (AFB) of M. tuberculosis in the cytoplasm of ciliated bronchiolar epithelium and alveolar pneumocytes in association with elements of the programmed death ligand 1 (PD-L1), cyclo-oxygenase (COX)-2, and fatty acid synthase (FAS) pathways in the early lesion. This suggests that M. tuberculosis uses its secreted antigens to coordinate prolonged subclinical development of the early lesions in preparation for a necrotizing reaction sufficient to produce a cavity, post-primary granulomas, and fibrocaseous disease. Full article
(This article belongs to the Special Issue Pathogenesis of Tuberculosis: Challenges and Opportunities)
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17 pages, 2442 KiB  
Article
New Insights into the Methylation of Mycobacterium tuberculosis Heparin Binding Hemagglutinin Adhesin Expressed in Rhodococcus erythropolis
by Cristina Parada, Isabel Cecilia Neri-Badillo, Antonio J. Vallecillo, Erika Segura, Mayra Silva-Miranda, Silvia Laura Guzmán-Gutiérrez, Paola A. Ortega, Enrique Wenceslao Coronado-Aceves, Laura Cancino-Villeda, Alfredo Torres-Larios, Michel de Jesús Aceves Sánchez, Mario Alberto Flores Valdez and Clara Espitia
Pathogens 2021, 10(9), 1139; https://doi.org/10.3390/pathogens10091139 - 4 Sep 2021
Cited by 2 | Viewed by 2722
Abstract
In recent years, knowledge of the role that protein methylation is playing on the physiopathogenesis of bacteria has grown. In Mycobacterium tuberculosis, methylation of the heparin binding hemagglutinin adhesin modulates the immune response, making this protein a subunit vaccine candidate. Through its [...] Read more.
In recent years, knowledge of the role that protein methylation is playing on the physiopathogenesis of bacteria has grown. In Mycobacterium tuberculosis, methylation of the heparin binding hemagglutinin adhesin modulates the immune response, making this protein a subunit vaccine candidate. Through its C-terminal lysine-rich domain, this surface antigen interacts with heparan sulfate proteoglycans present in non-phagocytic cells, leading to extrapulmonary dissemination of the pathogen. In this study, the adhesin was expressed as a recombinant methylated protein in Rhodococcus erythropolis L88 and it was found associated to lipid droplets when bacteria were grown under nitrogen limitation. In order to delve into the role methylation could have in host–pathogen interactions, a comparative analysis was carried out between methylated and unmethylated protein produced in Escherichia coli. We found that methylation had an impact on lowering protein isoelectric point, but no differences between the proteins were found in their capacity to interact with heparin and A549 epithelial cells. An important finding was that HbhA is a Fatty Acid Binding Protein and differences in the conformational stability of the protein in complex with the fatty acid were observed between methylated and unmethylated protein. Together, these results suggest that the described role for this mycobacteria protein in lipid bodies formation could be related to its capacity to transport fatty acids. Obtained results also provide new clues about the role HbhA methylation could have in tuberculosis and point out the importance of having heterologous expression systems to obtain modified proteins. Full article
(This article belongs to the Special Issue Pathogenesis of Tuberculosis: Challenges and Opportunities)
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17 pages, 2529 KiB  
Article
Culture of Mycobacterium smegmatis in Different Carbon Sources to Induce In Vitro Cholesterol Consumption Leads to Alterations in the Host Cells after Infection: A Macrophage Proteomics Analysis
by Jaqueline Batista de Lima, Lana Patricia da Silva Fonseca, Luciana Pereira Xavier, Barbarella de Matos Macchi, Juliana Silva Cassoli, Edilene Oliveira da Silva, Rafael Borges da Silva Valadares, José Luiz Martins do Nascimento, Agenor Valadares Santos and Chubert Bernardo Castro de Sena
Pathogens 2021, 10(6), 662; https://doi.org/10.3390/pathogens10060662 - 28 May 2021
Cited by 2 | Viewed by 3632
Abstract
During tuberculosis, Mycobacterium uses host macrophage cholesterol as a carbon and energy source. To mimic these conditions, Mycobacterium smegmatis can be cultured in minimal medium (MM) to induce cholesterol consumption in vitro. During cultivation, M. smegmatis consumes MM cholesterol and changes the accumulation [...] Read more.
During tuberculosis, Mycobacterium uses host macrophage cholesterol as a carbon and energy source. To mimic these conditions, Mycobacterium smegmatis can be cultured in minimal medium (MM) to induce cholesterol consumption in vitro. During cultivation, M. smegmatis consumes MM cholesterol and changes the accumulation of cell wall compounds, such as PIMs, LM, and LAM, which plays an important role in its pathogenicity. These changes lead to cell surface hydrophobicity modifications and H2O2 susceptibility. Furthermore, when M. smegmatis infects J774A.1 macrophages, it induces granuloma-like structure formation. The present study aims to assess macrophage molecular disturbances caused by M. smegmatis after cholesterol consumption, using proteomics analyses. Proteins that showed changes in expression levels were analyzed in silico using OmicsBox and String analysis to investigate the canonical pathways and functional networks involved in infection. Our results demonstrate that, after cholesterol consumption, M. smegmatis can induce deregulation of protein expression in macrophages. Many of these proteins are related to cytoskeleton remodeling, immune response, the ubiquitination pathway, mRNA processing, and immunometabolism. The identification of these proteins sheds light on the biochemical pathways involved in the mechanisms of action of mycobacteria infection, and may suggest novel protein targets for the development of new and improved treatments. Full article
(This article belongs to the Special Issue Pathogenesis of Tuberculosis: Challenges and Opportunities)
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11 pages, 1575 KiB  
Article
The MTB/MDR ELITe MGB® Kit: Performance Assessment for Pulmonary, Extra-Pulmonary, and Resistant Tuberculosis Diagnosis, and Integration in the Laboratory Workflow of a French Center
by Elisabeth Hodille, Charlotte Genestet, Thomas Delque, Luna Ruffel, Yvonne Benito, Isabelle Fredenucci, Jean-Philippe Rasigade, Gérard Lina and Oana Dumitrescu
Pathogens 2021, 10(2), 176; https://doi.org/10.3390/pathogens10020176 - 6 Feb 2021
Cited by 3 | Viewed by 2078
Abstract
A rapid and reliable diagnostic for tuberculosis, including the detection of both rifampicin (RIF) and isoniazid (INH) resistance, is essential for appropriate patient care. Nucleic acid amplification tests are a fast alternative to methods based on Mycobacterium tuberculosis complex (MTB) cultures. Thus, the [...] Read more.
A rapid and reliable diagnostic for tuberculosis, including the detection of both rifampicin (RIF) and isoniazid (INH) resistance, is essential for appropriate patient care. Nucleic acid amplification tests are a fast alternative to methods based on Mycobacterium tuberculosis complex (MTB) cultures. Thus, the performance of the MDR/MTB ELITe MGB® Kit on the ELITe InGenius® platform was retrospectively evaluated for MTB detection on pulmonary and extra-pulmonary samples and for RIF/INH resistance detection on MTB strains. The sensitivity and specificity of the kit for MTB detection compared to the MTB culture were 80.0% and 100.0%, respectively. For the antimicrobial susceptibility prediction, the agreement with phenotypic antimicrobial susceptibility testing (AST) was 92.0%. For RIF, the sensitivity was 100.0% and the specificity was 95.5%. For INH, the sensitivity and specificity were 75.0% and 100.0%, respectively. A single RIF false-positive result was obtained for a strain with a low level of RIF resistance that was not detected by phenotypic AST, but carrying a rpoB L452P mutation. INH false-negative results (3) were due to mutations on the katG gene that were not probed by the test. Overall, the MTB/MDR ELITe MGB® Kit presents a strong performance for MTB detection and for the detection of both RIF and INH resistance, with an easy integration in laboratory workflow thanks to its fully automatized system. Full article
(This article belongs to the Special Issue Pathogenesis of Tuberculosis: Challenges and Opportunities)
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18 pages, 3972 KiB  
Article
Mycobacterium tuberculosis Rv0580c Impedes the Intracellular Survival of Recombinant Mycobacteria, Manipulates the Cytokines, and Induces ER Stress and Apoptosis in Host Macrophages via NF-κB and p38/JNK Signaling
by Md Kaisar Ali, Lambert Nzungize, Khushnood Abbas, Nzaou Stech Anomene Eckzechel, M. A. Abo-kadoum, Ulrich Aymard Ekomi Moure, Mohammed Asaad, Aftab Alam, Junqi Xu and Jianping Xie
Pathogens 2021, 10(2), 143; https://doi.org/10.3390/pathogens10020143 - 1 Feb 2021
Cited by 3 | Viewed by 2905
Abstract
The Mycobacterium tuberculosis (M. tb) genome encodes a large number of hypothetical proteins, which need to investigate their role in physiology, virulence, pathogenesis, and host interaction. To explore the role of hypothetical protein Rv0580c, we constructed the recombinant Mycobacterium smegmatis ( [...] Read more.
The Mycobacterium tuberculosis (M. tb) genome encodes a large number of hypothetical proteins, which need to investigate their role in physiology, virulence, pathogenesis, and host interaction. To explore the role of hypothetical protein Rv0580c, we constructed the recombinant Mycobacterium smegmatis (M. smegmatis) strain, which expressed the Rv0580c protein heterologously. We observed that Rv0580c expressing M. smegmatis strain (Ms_Rv0580c) altered the colony morphology and increased the cell wall permeability, leading to this recombinant strain becoming susceptible to acidic stress, oxidative stress, cell wall-perturbing stress, and multiple antibiotics. The intracellular survival of Ms_Rv0580c was reduced in THP-1 macrophages. Ms_Rv0580c up-regulated the IFN-γ expression via NF-κB and JNK signaling, and down-regulated IL-10 expression via NF-κB signaling in THP-1 macrophages as compared to control. Moreover, Ms_Rv0580c up-regulated the expression of HIF-1α and ER stress marker genes via the NF-κB/JNK axis and JNK/p38 axis, respectively, and boosted the mitochondria-independent apoptosis in macrophages, which might be lead to eliminate the intracellular bacilli. This study explores the crucial role of Rv0580c protein in the physiology and novel host-pathogen interactions of mycobacteria. Full article
(This article belongs to the Special Issue Pathogenesis of Tuberculosis: Challenges and Opportunities)
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Review

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25 pages, 4015 KiB  
Review
The Pathogenesis of Tuberculosis–The Koch Phenomenon Reinstated
by Robert L. Hunter
Pathogens 2020, 9(10), 813; https://doi.org/10.3390/pathogens9100813 - 4 Oct 2020
Cited by 37 | Viewed by 8602
Abstract
Research on the pathogenesis of tuberculosis (TB) has been hamstrung for half a century by the paradigm that granulomas are the hallmark of active disease. Human TB, in fact, produces two types of granulomas, neither of which is involved in the development of [...] Read more.
Research on the pathogenesis of tuberculosis (TB) has been hamstrung for half a century by the paradigm that granulomas are the hallmark of active disease. Human TB, in fact, produces two types of granulomas, neither of which is involved in the development of adult type or post-primary TB. This disease begins as the early lesion; a prolonged subclinical stockpiling of secreted mycobacterial antigens in foamy alveolar macrophages and nearby highly sensitized T cells in preparation for a massive necrotizing hypersensitivity reaction, the Koch Phenomenon, that produces caseous pneumonia that is either coughed out to form cavities or retained to become the focus of post-primary granulomas and fibrocaseous disease. Post-primary TB progresses if the antigens are continuously released and regresses when they are depleted. This revised paradigm is supported by nearly 200 years of research and suggests new approaches and animal models to investigate long standing mysteries of human TB and vaccines that inhibit the early lesion to finally end its transmission. Full article
(This article belongs to the Special Issue Pathogenesis of Tuberculosis: Challenges and Opportunities)
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