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Pathogens
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Pathogenicity of Mycobacterium tuberculosis
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Pathogenicity of Mycobacterium tuberculosis

A special issue of Pathogens (ISSN 2076-0817). This special issue belongs to the section "Bacterial Pathogens".

Deadline for manuscript submissions: closed (31 July 2023) | Viewed by 26051

Special Issue Editors

Prof. Dr. Delphi Chatterjee

E-Mail Website
Guest Editor
MIP, Mycobacteria Research Laboratories, Colorado State University, Fort Collins, CO, USA
Interests: mycobacterial glycobiology; host pathogen interaction; diagnostics in TB
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Jordi B. Torrelles

E-Mail Website
Guest Editor
Texas Biomedical Research Institute, San Antonio, TX, USA
Interests: Host-Pathogen interaction; Population Health; TB Diagnostics

Special Issue Information

Dear Colleagues,

Tuberculosis (TB) is a leading infectious cause of death worldwide (2nd to the coronavirus disease 2019, COVID-19). Indeed, TB kills 4,000 people each day and is also the leading infectious disease killer of people living with HIV/AIDS. The last World Health Organization (WHO) report estimated that 10 million people developed TB in 2019, and nearly half a million people developed drug-resistant TB (DR-TB). WHO has developed an End TB Strategy aimed at reducing the incidence of TB by 80% and TB related mortality by 90% by 2030.

TB is a chronic inflammatory disease caused by the pathogenic organism Mycobacterium tuberculosis (Mtb). Distinctive feature of Mtb infection is the formation of granulomas, a host cellular structure that contains the infection in a latent stage for years. TB pathogenesis is characterized by the ability of Mtb to escape the granuloma into the lung extracellular milieu, causing tissue necrosis originating in pulmonary lesions or cavitation that vary in the spectrum of the active TB disease.

At the bacterial level, the cell envelope of Mtb is a critical and complex structure that contributes to virulence and pathogenicity. Research into the detailed composition of the cell envelope constituents in Mtb over the last 30 years has formed a key part of the efforts to understand host–pathogen interactions and to control the ongoing TB pandemic. This is due, partly, to the better understanding of the great importance of the Mtb cell envelope components during the initial (host cell infection and granuloma formation) and later (granuloma maintenance and reactivation) stages of the infection. Importantly, the Mtb cell envelope also plays a critical role in virulence and during the development of drug resistance. Currently, there is an active search to define the Mtb metabolic status and its cell envelope surface-exposed entities at different stages of the infection to identify new therapeutics and vaccines.

To protect the progress made through global efforts and investments in TB, it is important that national TB programs ensure continuity of TB diagnosis, treatment and prevention services. In this regard, in 2020, the COVID-19 pandemic brought further challenges to TB control, especially in resource limited settings. Worldwide, the lockdown of TB diagnostic services due to the COVID-19 pandemic is expected to set back TB control efforts by more than 8 years, including in higher adverse TB treatment outcomes like death.

Prof. Dr. Delphi Chatterjee
Prof. Dr. Jordi B. Torrelles
Guest Editors

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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.

Keywords

  • tuberculosis
  • transmission
  • pathogenesis
  • animal models
  • anti-TB therapy
  • vaccines
  • diagnosis

Published Papers (9 papers)

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Research

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15 pages, 2762 KiB  
Article
Differential Role of Type 2 Diabetes as a Risk Factor for Tuberculosis in the Elderly versus Younger Adults
by Blanca I. Restrepo, Julia M. Scordo, Génesis P. Aguillón-Durán, Doris Ayala, Ana Paulina Quirino-Cerrillo, Raúl Loera-Salazar, America Cruz-González, Jose A. Caso, Mateo Joya-Ayala, Esperanza M. García-Oropesa, Alejandra B. Salinas, Leonardo Martinez, Larry S. Schlesinger, Jordi B. Torrelles and Joanne Turner
Pathogens 2022, 11(12), 1551; https://0-doi-org.brum.beds.ac.uk/10.3390/pathogens11121551 - 16 Dec 2022
Cited by 1 | Viewed by 1464
Abstract
The elderly are understudied despite their high risk of tuberculosis (TB). We sought to identify factors underlying the lack of an association between TB and type 2 diabetes (T2D) in the elderly, but not adults. We conducted a case–control study in elderly (≥65 [...] Read more.
The elderly are understudied despite their high risk of tuberculosis (TB). We sought to identify factors underlying the lack of an association between TB and type 2 diabetes (T2D) in the elderly, but not adults. We conducted a case–control study in elderly (≥65 years old; ELD) vs. younger adults (young/middle-aged adults (18–44/45–64 years old; YA|MAA) stratified by TB and T2D, using a research study population (n = 1160) and TB surveillance data (n = 8783). In the research study population the adjusted odds ratio (AOR) of TB in T2D was highest in young adults (AOR 6.48) but waned with age becoming non-significant in the elderly. Findings were validated using TB surveillance data. T2D in the elderly (vs. T2D in younger individuals) was characterized by better glucose control (e.g., lower hyperglycemia or HbA1c), lower insulin resistance, more sulphonylureas use, and features of less inflammation (e.g., lower obesity, neutrophils, platelets, anti-inflammatory use). We posit that differences underlying glucose dysregulation and inflammation in elderly vs. younger adults with T2D, contribute to their differential association with TB. Studies in the elderly provide valuable insights into TB-T2D pathogenesis, e.g., here we identified insulin resistance as a novel candidate mechanism by which T2D may increase active TB risk. Full article
(This article belongs to the Special Issue Pathogenicity of Mycobacterium tuberculosis)
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16 pages, 3201 KiB  
Article
Mycobacterium tuberculosis Rv2387 Facilitates Mycobacterial Survival by Silencing TLR2/p38/JNK Signaling
by Wu Li, Wanyan Deng, Nan Zhang, Huijuan Peng and Yi Xu
Pathogens 2022, 11(9), 981; https://0-doi-org.brum.beds.ac.uk/10.3390/pathogens11090981 - 27 Aug 2022
Cited by 4 | Viewed by 1512
Abstract
Mycobacterium tuberculosis (Mtb) can evade antimicrobial immunity and persist within macrophages by interfering with multiple host cellular functions through its virulence factors, causing latent tuberculosis. The Rv2387 protein has been identified as a putative effector that potentially participates in Mtb pathogenicity. To explore [...] Read more.
Mycobacterium tuberculosis (Mtb) can evade antimicrobial immunity and persist within macrophages by interfering with multiple host cellular functions through its virulence factors, causing latent tuberculosis. The Rv2387 protein has been identified as a putative effector that potentially participates in Mtb pathogenicity. To explore the role of the Rv2387 protein in host–mycobacteria interactions, we established recombinant M. smegmatis strains and RAW264.7 cell lines that stably express the Rv2387 protein. We found that this protein suppresses mycobacteria infection-induced macrophage apoptosis by inactivating caspase-3/-8, thus facilitating the intracellular survival of mycobacteria. In addition, Rv2387 inhibits the production of inflammatory cytokines in macrophages by specifically suppressing TLR2-dependent stimulation of p38 and JNK MAPK pathways. Moreover, we further determined that the Rv2387 protein conferred a growth advantage over recombinant M. smegmatis and suppressed the inflammatory response in a mouse infection model. Overall, these data suggested that Rv2387 facilitates mycobacteria to escape host immunity and might be an essential virulence factor in Mtb. Full article
(This article belongs to the Special Issue Pathogenicity of Mycobacterium tuberculosis)
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21 pages, 2966 KiB  
Article
Peripheral Blood Markers Correlate with the Progression of Active Tuberculosis Relative to Latent Control of Mycobacterium tuberculosis Infection in Macaques
by Maya Gough, Dhiraj K. Singh, Chivonne Moodley, Tianhua Niu, Nadia A. Golden, Deepak Kaushal and Smriti Mehra
Pathogens 2022, 11(5), 544; https://0-doi-org.brum.beds.ac.uk/10.3390/pathogens11050544 - 05 May 2022
Cited by 3 | Viewed by 1842
Abstract
Despite a century of research into tuberculosis (TB), there is a dearth of reproducible, easily quantifiable, biomarkers that can predict disease onset and differentiate between host disease states. Due to the challenges associated with human sampling, nonhuman primates (NHPs) are utilized for recapitulating [...] Read more.
Despite a century of research into tuberculosis (TB), there is a dearth of reproducible, easily quantifiable, biomarkers that can predict disease onset and differentiate between host disease states. Due to the challenges associated with human sampling, nonhuman primates (NHPs) are utilized for recapitulating the closest possible modelling of human TB. To establish a predictive peripheral biomarker profile based on a larger cohort of rhesus macaques (RM), we analyzed results pertaining to peripheral blood serum chemistry and cell counts from RMs that were experimentally exposed to Mtb in our prior studies and characterized as having either developed active TB (ATB) disease or latent TB infection (LTBI). We compared lung CFU burdens and quantitative pathologies with a number of measurables in the peripheral blood. Based on our results, the investigations were then extended to the study of specific molecules and cells in the lung compartments of a subset of these animals and their immune responses. In addition to the elevated serum C-reactive protein (CRP) levels, frequently used to discern the level of Mtb infection in model systems, reduced serum albumin-to-globulin (A/G) ratios were also predictive of active TB disease. Furthermore, higher peripheral myeloid cell levels, particularly those of neutrophils, kynurenine-to-tryptophan ratio, an indicator of induced expression of the immunosuppressive molecule indoleamine dioxygenase, and an influx of myeloid cell populations could also efficiently discriminate between ATB and LTBI in experimentally infected macaques. These quantifiable correlates of disease were then used in conjunction with a regression-based analysis to predict bacterial load. Our results suggest a potential biomarker profile of TB disease in rhesus macaques, that could inform future NHP–TB research. Our results thus suggest that specific biomarkers may be developed from the myeloid subset of peripheral blood or plasma with the ability to discriminate between active and latent Mtb infection. Full article
(This article belongs to the Special Issue Pathogenicity of Mycobacterium tuberculosis)
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16 pages, 2953 KiB  
Article
The Origin and Maintenance of Tuberculosis Is Explained by the Induction of Smear-Negative Disease in the Paleolithic
by Pere-Joan Cardona, Martí Català and Clara Prats
Pathogens 2022, 11(3), 366; https://0-doi-org.brum.beds.ac.uk/10.3390/pathogens11030366 - 17 Mar 2022
Cited by 4 | Viewed by 3892
Abstract
Is it possible that the origin of Mycobacterium tuberculosis (Mtb) infection was around 70,000 years before the common era? At that time Homo sapiens was just another primate species with discrete growth and a very low-density geographic occupation. Therefore, it is difficult to [...] Read more.
Is it possible that the origin of Mycobacterium tuberculosis (Mtb) infection was around 70,000 years before the common era? At that time Homo sapiens was just another primate species with discrete growth and a very low-density geographic occupation. Therefore, it is difficult to understand the origin of a highly virulent obligate human pathogen. We have designed a new SEIR model (TBSpectr) that allows the differentiation of smear-positive and -negative tuberculosis. The model reconciles currently accepted growth rates for the Middle Paleolithic (0.003%/year) and Neolithic (0.1%/year). The obtained data link the origin of Mtb infection in the Middle Paleolithic to the induction of smear-negative TB, and reveal that its persistence required interrelations among hunter–gatherer groups, while the risk of human extinction was negligible. It also highlights the number of people infected per case and the fast progression to disease for Mtb infection maintenance, as well as the link between poor health in the Neolithic with the increased incidence of more severe forms of TB (smear-positive). In conclusion, our data support the origin of TB as a well-tolerated, highly persistent disease, even in low-density populations, showing the difficulty of its eradication and highlighting the necessity for providing better health conditions to humans to reduce its severity. Full article
(This article belongs to the Special Issue Pathogenicity of Mycobacterium tuberculosis)
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Review

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15 pages, 2165 KiB  
Review
Collected Thoughts on Mycobacterial Lipoarabinomannan, a Cell Envelope Lipoglycan
by Jordi B. Torrelles and Delphi Chatterjee
Pathogens 2023, 12(11), 1281; https://0-doi-org.brum.beds.ac.uk/10.3390/pathogens12111281 - 26 Oct 2023
Cited by 1 | Viewed by 1917
Abstract
The presence of lipoarabinomannan (LAM) in the Mycobacterium tuberculosis (Mtb) cell envelope was first reported close to 100 years ago. Since then, numerous studies have been dedicated to the isolation, purification, structural definition, and elucidation of the biological properties of Mtb [...] Read more.
The presence of lipoarabinomannan (LAM) in the Mycobacterium tuberculosis (Mtb) cell envelope was first reported close to 100 years ago. Since then, numerous studies have been dedicated to the isolation, purification, structural definition, and elucidation of the biological properties of Mtb LAM. In this review, we present a brief historical perspective on the discovery of Mtb LAM and the herculean efforts devoted to structurally characterizing the molecule because of its unique structural and biological features. The significance of LAM remains high to this date, mainly due to its distinct immunological properties in conjunction with its role as a biomarker for diagnostic tests due to its identification in urine, and thus can serve as a point-of-care diagnostic test for tuberculosis (TB). In recent decades, LAM has been thoroughly studied and massive amounts of information on this intriguing molecule are now available. In this review, we give the readers a historical perspective and an update on the current knowledge of LAM with information on the inherent carbohydrate composition, which is unique due to the often puzzling sugar residues that are specifically found on LAM. We then guide the readers through the complex and myriad immunological outcomes, which are strictly dependent on LAM’s chemical structure. Furthermore, we present issues that remain unresolved and represent the immediate future of LAM research. Addressing the chemistry, functions, and roles of LAM will lead to innovative ways to manipulate the processes that involve this controversial and fascinating biomolecule. Full article
(This article belongs to the Special Issue Pathogenicity of Mycobacterium tuberculosis)
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16 pages, 11957 KiB  
Review
Brain Tuberculosis: An Odyssey through Time to Understand This Pathology
by Raluca Elena Patrascu, Andrei Ionut Cucu, Claudia Florida Costea, Mihaela Cosman, Laurentiu Andrei Blaj and Adriana Hristea
Pathogens 2023, 12(8), 1026; https://0-doi-org.brum.beds.ac.uk/10.3390/pathogens12081026 - 09 Aug 2023
Cited by 1 | Viewed by 1465
Abstract
Tuberculosis is a contagious disease that has been a concern for humanity throughout history, being recognized and referred to as the white plague. Since ancient times, starting with Hippocrates and Galen of Pergamon, doctors and scientists have attempted to understand the pathogenesis of [...] Read more.
Tuberculosis is a contagious disease that has been a concern for humanity throughout history, being recognized and referred to as the white plague. Since ancient times, starting with Hippocrates and Galen of Pergamon, doctors and scientists have attempted to understand the pathogenesis of tuberculosis and its manifestations in the brain. If, in the medieval period, it was believed that only the touch of a king could cure the disease, it was only in the early 17th and 18th centuries that the first descriptions of tuberculous meningitis and the first clinico-pathological correlations began to emerge. While the understanding of neurotuberculosis progressed slowly, it was only after the discovery of the pathogenic agent in the late 19th century that there was an upward curve in the occurrence of treatment methods. This review aims to embark on an odyssey through the centuries, from ancient Egypt to the modern era, and explore the key moments that have contributed to the emergence of a new era of hope in the history of neurotuberculosis. Understanding the history of treatment methods against this disease, from empirical and primitive ones to the emergence of new drugs used in multi-drug-resistant tuberculosis, leads us, once again, to realize the significant contribution of science and medicine in treating a disease that was considered incurable not long ago. Full article
(This article belongs to the Special Issue Pathogenicity of Mycobacterium tuberculosis)
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33 pages, 1659 KiB  
Review
Mouse Models for Mycobacterium tuberculosis Pathogenesis: Show and Do Not Tell
by Pablo Soldevilla, Cristina Vilaplana and Pere-Joan Cardona
Pathogens 2023, 12(1), 49; https://0-doi-org.brum.beds.ac.uk/10.3390/pathogens12010049 - 28 Dec 2022
Cited by 3 | Viewed by 3786
Abstract
Science has been taking profit from animal models since the first translational experiments back in ancient Greece. From there, and across all history, several remarkable findings have been obtained using animal models. One of the most popular models, especially for research in infectious [...] Read more.
Science has been taking profit from animal models since the first translational experiments back in ancient Greece. From there, and across all history, several remarkable findings have been obtained using animal models. One of the most popular models, especially for research in infectious diseases, is the mouse. Regarding research in tuberculosis, the mouse has provided useful information about host and bacterial traits related to susceptibility to the infection. The effect of aging, sexual dimorphisms, the route of infection, genetic differences between mice lineages and unbalanced immunity scenarios upon Mycobacterium tuberculosis infection and tuberculosis development has helped, helps and will help biomedical researchers in the design of new tools for diagnosis, treatment and prevention of tuberculosis, despite various discrepancies and the lack of deep study in some areas of these traits. Full article
(This article belongs to the Special Issue Pathogenicity of Mycobacterium tuberculosis)
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24 pages, 460 KiB  
Review
Resistance and Susceptibility Immune Factors at Play during Mycobacterium tuberculosis Infection of Macrophages
by Jan D. Simper, Esteban Perez, Larry S. Schlesinger and Abul K. Azad
Pathogens 2022, 11(10), 1153; https://0-doi-org.brum.beds.ac.uk/10.3390/pathogens11101153 - 06 Oct 2022
Cited by 1 | Viewed by 2367
Abstract
Tuberculosis (TB), caused by infection with Mycobacterium tuberculosis (M.tb), is responsible for >1.5 million deaths worldwide annually. Innate immune cells, especially macrophages, are the first to encounter M.tb, and their response dictates the course of infection. During infection, macrophages exert [...] Read more.
Tuberculosis (TB), caused by infection with Mycobacterium tuberculosis (M.tb), is responsible for >1.5 million deaths worldwide annually. Innate immune cells, especially macrophages, are the first to encounter M.tb, and their response dictates the course of infection. During infection, macrophages exert a variety of immune factors involved in either controlling or promoting the growth of M.tb. Research on this topic has been performed in both in vitro and in vivo animal models with discrepant results in some cases based on the model of study. Herein, we review macrophage resistance and susceptibility immune factors, focusing primarily on recent advances in the field. We include macrophage cellular pathways, bioeffector proteins and molecules, cytokines and chemokines, associated microbiological factors and bacterial strains, and host genetic factors in innate immune genes. Recent advances in mechanisms underlying macrophage resistance and susceptibility factors will aid in the successful development of host-directed therapeutics, a topic emphasized throughout this review. Full article
(This article belongs to the Special Issue Pathogenicity of Mycobacterium tuberculosis)
13 pages, 1194 KiB  
Review
Tuberculosis in an Aging World
by Angélica M. Olmo-Fontánez and Joanne Turner
Pathogens 2022, 11(10), 1101; https://0-doi-org.brum.beds.ac.uk/10.3390/pathogens11101101 - 26 Sep 2022
Cited by 11 | Viewed by 4531
Abstract
Tuberculosis (TB) is one of the leading causes of death due to its being an infectious disease, caused by the airborne pathogen Mycobacterium tuberculosis (M.tb). Approximately one-fourth of the world’s population is infected with latent M.tb, and TB is considered [...] Read more.
Tuberculosis (TB) is one of the leading causes of death due to its being an infectious disease, caused by the airborne pathogen Mycobacterium tuberculosis (M.tb). Approximately one-fourth of the world’s population is infected with latent M.tb, and TB is considered a global threat killing over 4000 people every day. The risk of TB susceptibility and mortality is significantly increased in individuals aged 65 and older, confirming that the elderly represent one of the largest reservoirs for M.tb infection. The elderly population faces many challenges that increase their risk of developing respiratory diseases, including TB. The challenges the elderly face in this regard include the following: decreased lung function, immuno-senescence, inflammaging, adverse drug effects, low tolerance to anti-TB drugs, lack of suitable diagnoses/interventions, and age-associated comorbidities. In order to find new therapeutic strategies to maintain lung homeostasis and resistance to respiratory infections as we age, it is necessary to understand the molecular and cellular mechanisms behind natural lung aging. This review focuses primarily on why the elderly are more susceptible to TB disease and death, with a focus on pulmonary function and comorbidities. Full article
(This article belongs to the Special Issue Pathogenicity of Mycobacterium tuberculosis)
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