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

Deadline for manuscript submissions: closed (15 November 2023) | Viewed by 22511

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Dr. Rogelio Hernández Pando

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Guest Editor

Sección de Patología Experimental, Departamento de Patología, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City 14080, Mexico
Interests: tuberculosis; anti-tuberculosis
Special Issues, Collections and Topics in MDPI journals

Dr. José Alberto Choreño-Parra

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Laboratorio de Inmunobiología y Genética, Instituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas, Mexico City 14080, Mexico
Interests: tuberculosis; anti-tuberculosis

Special Issue Information

Dear Colleagues,

Tuberculosis (TB) has been a prevalent infectious disease since ancient times and remains a major worldwide health problem. With 10 million active cases and 1.4 million deaths annually, TB morbidity represents the most significant number of incidences and human deaths attributable to a single bacterial agent. Its causal agent, Mycobacterium tuberculosis (Mtb), can survive in a latent state in infected individuals, thereby serving as a reservoir, awaiting reactivation that usually occurs in immune-suppressed individuals. According to the World Health Organization estimation, 2 billion people, almost one-quarter of the world’s population, are latent infected. From this vast population, it is estimated that 10% will reactivate progressive suffering disease. TB control has been severely limited by imperfect diagnostic testing. The gold-standard method of diagnosing TB is acid-fast bacilli (AFB) smear microscopy and sputum cultures for Mtb, followed by growth-based drug-susceptibility testing. The sensitivity of AFB is low and variable (ranges from 45% to 80%), is affected by specimen concentration and laboratory experience, and usually, these diagnostic testing takes months to complete. Molecular diagnostic testing for the detection of Mtb is rapid but complex and requires expensive equipment. Regarding TB prevention, the vaccine BCG (Bacillus Calmette-Guérin) is the most widely used vaccine in history but has proven insufficient for reversing this epidemic. The BCG vaccine has been outstandingly successful in preventing severe forms of TB (meningeal and miliary). Nonetheless, the vaccine presents considerable shortcomings in terms of preventing pulmonary TB, with considerable variability in efficacy, ranging from 0 to 75% in different regions of the world. Another significant problem is the continued emergence of multidrug-resistant (MDR) strains, which is currently considered a serious global health problem. The emergence of MDR strain is often associated with poor compliance due to the long, complex, toxic and expensive treatment. New therapeutic candidates should short the standard regimens and ideally be effective against MDR strains. Thus, new diagnostic methods, new vaccines and better anti-TB drugs and therapeutic strategies are urgently needed. In this Research Topic, we aim to provide a comprehensive overview of recent progress in the prevention, diagnosis and treatment of TB. We welcome the submission of Original Research, Reviews, and Perspective articles covering, but not limited to, the following sub-topics:

Novel methodologies for TB diagnosis.
Novel anti-TB drugs and therapeutic strategies, including immunotherapy.
Novel approaches in the design of new vaccines against TB.

Dr. Rogelio Hernández Pando
Dr. José Alberto Choreño-Parra
Guest Editors

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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

tuberculosis
anti-TB drugs
therapy
TB vaccines

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Published Papers (10 papers)

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Research

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12 pages, 1395 KiB

Open AccessArticle

Critical Review of Tuberculosis Diagnosis in Children from Papua New Guinea Presenting to Health Facilities in the Torres Strait Islands, Australia

by J’Belle Foster, Ben J. Marais, Diana Mendez and Emma S. McBryde

Microorganisms 2023, 11(12), 2947; https://doi.org/10.3390/microorganisms11122947 - 8 Dec 2023

Viewed by 1626

Abstract

Paediatric tuberculosis can be challenging to diagnose, and various approaches are used in different settings. A retrospective review was conducted on Papua New Guinea (PNG) children with presumptive TB who presented for health care in the Torres Strait Islands, Australia, between 2016 and 2019. We compared diagnostic algorithms including the modified Keith Edwards TB Score, The Union Desk Guide, and the new World Health Organization (WHO) algorithm, with diagnostic practices used in the remote Torres Strait Islands. Of the 66 children with presumptive TB, 7 had bacteriologically confirmed TB. The majority (52%) were under 5 years (median age 61 months), and 45% were malnourished. There was moderate agreement across the diagnostic methods (K = 0.34; 95% CI 0.23–0.46), with the highest concordance observed between The Union Desk Guide and the WHO’s algorithm (K = 0.61). Local TB physicians might have over-diagnosed presumed lymph node TB while under-diagnosing TB overall. Enhancing the precision and promptness of paediatric TB diagnosis using practical tools is pivotal to decrease TB-related child mortality, notably in isolated regions like the Torres Strait and the Western Province of PNG. Full article

(This article belongs to the Special Issue Prevention, Treatment and Diagnosis of Tuberculosis)

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13 pages, 3782 KiB

Open AccessArticle

Modulation of Cystatin F in Human Macrophages Impacts Cathepsin-Driven Killing of Multidrug-Resistant Mycobacterium tuberculosis

by Manoj Mandal, David Pires, Maria João Catalão, José Miguel Azevedo-Pereira and Elsa Anes

Microorganisms 2023, 11(7), 1861; https://doi.org/10.3390/microorganisms11071861 - 24 Jul 2023

Cited by 3 | Viewed by 1649

Abstract

Tuberculosis (TB) treatment relies primarily on 70-year-old drugs, and prophylaxis suffers from the lack of an effective vaccine. Among the 10 million people exhibiting disease symptoms yearly, 450,000 have multidrug or extensively drug-resistant (MDR or XDR) TB. A greater understanding of host and pathogen interactions will lead to new therapeutic interventions for TB eradication. One of the strategies will be to target the host for better immune bactericidal responses against the TB causative agent Mycobacterium tuberculosis (Mtb). Cathepsins are promising targets due to their manipulation of Mtb with consequences such as decreased proteolytic activity and improved pathogen survival in macrophages. We recently demonstrated that we could overcome this enzymatic blockade by manipulating protease inhibitors such as cystatins. Here, we investigate the role of cystatin F, an inhibitor that we showed previously to be strongly upregulated during Mtb infection. Our results indicate that the silencing of cystatin F using siRNA increase the proteolytic activity of cathepsins S, L, and B, significantly impacting pathogen intracellular killing in macrophages. Taken together, these indicate the targeting of cystatin F as a potential adjuvant therapy for TB, including MDR and XDR-TB. Full article

(This article belongs to the Special Issue Prevention, Treatment and Diagnosis of Tuberculosis)

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11 pages, 671 KiB

Open AccessArticle

Detection of Mycobacterial DNA in Human Bone Marrow

by Alba González-Escalada, María José Rebollo, Jorge Barrios Payan, Rogelio Hernández-Pando and María Jesús García

Microorganisms 2023, 11(7), 1788; https://doi.org/10.3390/microorganisms11071788 - 11 Jul 2023

Viewed by 1806

Abstract

Bone marrow is a cell-rich tissue of the reticuloendothelial system essential in the homeostasis and accurate functioning of hematopoiesis and of the immune system; moreover, it is also rich in lipids because it contains marrow adipocytes. This work aimed to evaluate the detection of mycobacterial DNA in human bone marrow as a tool to understand the complex pathology caused by the main pathogen Mycobacterium tuberculosis (Mtb). Formalin-fixed paraffin-embedded human bone marrow samples were studied using both conventional PCR + hybridization and in situ PCR to figure out the cell distribution of the targeted DNA. Samples were retrospectively collected from HIV+ patients with microbiologically proved mycobacterial infection and from subjects without evidence of infection. Mycobacterium avium (Mav) as well as Mtb DNA was detected in both settings, including tissues with and without granulomas. We detected DNA from both mycobacterial species, using in situ PCR, inside bone marrow macrophages. Other cell types, including adipocytes, showed positive signals only for Mtb DNA. This result suggested, for the first time, that marrow adipocytes could constitute an ideal reservoir for the persistence of Mtb, allowing the bacilli to establish long-lasting latent infection within a suitable lipid environment. This fact might differentiate pathogenic behavior of non-specialized pathogens such as Mav from that of specialized pathogens such as Mtb. Full article

(This article belongs to the Special Issue Prevention, Treatment and Diagnosis of Tuberculosis)

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14 pages, 4316 KiB

Open AccessArticle

Design of a Multi-Epitope Vaccine against Tuberculosis from Mycobacterium tuberculosis PE_PGRS49 and PE_PGRS56 Proteins by Reverse Vaccinology

by Maritriny Ruaro-Moreno, Gloria Paulina Monterrubio-López, Abraham Reyes-Gastellou, Juan Arturo Castelán-Vega, Alicia Jiménez-Alberto, Gerardo Aparicio-Ozores, Karen Delgadillo-Gutiérrez, Jorge Alberto González-Y-Merchand and Rosa María Ribas-Aparicio

Microorganisms 2023, 11(7), 1647; https://doi.org/10.3390/microorganisms11071647 - 24 Jun 2023

Cited by 1 | Viewed by 2145

Abstract

Tuberculosis is a disease caused by Mycobacterium tuberculosis, representing the second leading cause of death by an infectious agent worldwide. The available vaccine against this disease has insufficient coverage and variable efficacy, accounting for a high number of cases worldwide. In fact, an estimated third of the world’s population has a latent infection. Therefore, developing new vaccines is crucial to preventing it. In this study, the highly antigenic PE_PGRS49 and PE_PGRS56 proteins were analyzed. These proteins were used for predicting T- and B-cell epitopes and for human leukocyte antigen (HLA) protein binding efficiency. Epitopes GGAGGNGSLSS, FAGAGGQGGLGG, GIGGGTQSATGLG (PE_PGRS49), and GTGWNGGKGDTG (PE_PGRS56) were selected based on their best physicochemical, antigenic, non-allergenic, and non-toxic properties and coupled to HLA I and HLA II structures for in silico assays. A construct with an adjuvant (RS09) plus each epitope joined by GPGPG linkers was designed, and the stability of the HLA-coupled construct was further evaluated by molecular dynamics simulations. Although experimental and in vivo studies are still necessary to ensure its protective effect against the disease, this study shows that the vaccine construct is dynamically stable and potentially effective against tuberculosis. Full article

(This article belongs to the Special Issue Prevention, Treatment and Diagnosis of Tuberculosis)

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23 pages, 8925 KiB

Open AccessArticle

Effect of Low Doses of Dexamethasone on Experimental Pulmonary Tuberculosis

by Jacqueline V. Lara-Espinosa, María Fernanda Arce-Aceves, Jorge Barrios-Payán, Dulce Mata-Espinosa, Vasti Lozano-Ordaz, Enrique Becerril-Villanueva, María Dolores Ponce-Regalado and Rogelio Hernández-Pando

Microorganisms 2023, 11(6), 1554; https://doi.org/10.3390/microorganisms11061554 - 10 Jun 2023

Viewed by 3256

Abstract

Tuberculosis (TB) is the deadliest disease caused by a bacterial agent. Glucocorticoids (GCs) have a typical anti-inflammatory effect, but recently it has been shown that they can present proinflammatory activity, mainly by increasing molecules from innate immunity. In the current study, we evaluated the effect of low doses of dexamethasone on Mycobacterium tuberculosis in vivo and in vitro. We used an established mice model of progressing tuberculosis (TB) in the in vivo studies. Intratracheal or intranasal dexamethasone therapy administered with conventional antibiotics in the late stage of the disease decreased the lung bacilli load and lung pneumonia, and increased the survival of the animals. Finally, the treatment decreased the inflammatory response in the SNC and, therefore, sickness behavior and neurological abnormalities in the infected animals. In the in vitro experiments, we used a cell line of murine alveolar macrophages infected with Mtb. Low-dose dexamethasone treatment increased the clearance capacity of Mtb by MHS macrophages, MIP-1α, and TLR2 expression, decreased proinflammatory and anti-inflammatory cytokines, and induced apoptosis, a molecular process that contributes to the control of the mycobacteria. In conclusion, the administration of low doses of dexamethasone represents a promising adjuvant treatment for pulmonary TB. Full article

(This article belongs to the Special Issue Prevention, Treatment and Diagnosis of Tuberculosis)

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13 pages, 1952 KiB

Open AccessArticle

Antigen-Induced IL-1RA Production Discriminates Active and Latent Tuberculosis Infection

by Cesar Sanchez, Luis Jaramillo-Valverde, Silvia Capristano, Gilmer Solis, Alonso Soto, Julio Valdivia-Silva, Julio A. Poterico and Heinner Guio

Microorganisms 2023, 11(6), 1385; https://doi.org/10.3390/microorganisms11061385 - 25 May 2023

Cited by 2 | Viewed by 2623

Abstract

The IGRA (Interferon Gamma Release Assays) test is currently the standard specific test for Mycobacterium tuberculosis infection status. However, a positive test cannot distinguish between active tuberculosis disease (ATBD) and latent tuberculosis infection (LTBI). Developing a test with this characteristic is needed. We conducted longitudinal studies to identify a combination of antigen peptides and cytokines to discriminate between ATBD and LTBI. We studied 54 patients with ATBD disease and 51 with LTBI infection. Cell culture supernatant from cells stimulated with overlapping Mycobacterium tuberculosis novel peptides and 40 cytokines/chemokines were analyzed using the Luminex technology. To summarize longitudinal measurements of analyte levels, we calculated the area under the curve (AUC). Our results indicate that in vitro cell stimulation with a novel combination of peptides (Rv0849-12, Rv2031c-14, Rv2031c-5, and Rv2693-06) and IL-1RA detection in culture supernatants can discriminate between LTBI and ATBD. Full article

(This article belongs to the Special Issue Prevention, Treatment and Diagnosis of Tuberculosis)

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11 pages, 1414 KiB

Open AccessArticle

Diagnostic Performance of Different Laboratory Methods for the Detection of Extrapulmonary Tuberculosis

by Mohammad Khaja Mafij Uddin, Md. Fahim Ather, Senjuti Kabir, Arfatur Rahman, Sabrina Choudhury, Rumana Nasrin, Tanjina Rahman, S. M. Mazidur Rahman, Shahriar Ahmed and Sayera Banu

Microorganisms 2023, 11(4), 1066; https://doi.org/10.3390/microorganisms11041066 - 19 Apr 2023

Cited by 4 | Viewed by 2244

Abstract

Accurate and appropriate extrapulmonary tuberculosis (EPTB) diagnosis remains challenging due to its paucibacillary nature, requirement of invasive collection procedures, and lack of sensitive tests. This study investigated the diagnostic performance of different methods for the diagnosis of EPTB. A total of 1340 EPTB specimens were collected from presumptive EPTB patients from four different hospitals between November 2015 and March 2017. The collected specimens were tested with AFB microscopy, culture, Xpert MTB/RIF assay (Xpert), and MTBDRplus assay. Among the 1340 EPTB specimens, 49 (3.66%), 141 (10.52%), 166 (12.39%), and 154 (11.49%) were positive in AFB microscopy, culture, Xpert MTB/RIF, and MTBDRplus assay, respectively. A total of 194 (14.9%) cases were found positive in at least one of these methods. Using culture as a reference standard, the sensitivity and specificity of AFB microscopy, Xpert MTB/RIF, and MTBDRplus assay were: 27.0%/99.1%, 83.7%/96.0%, and 79.4%/96.5%, respectively. Compared to the composite reference standard, the sensitivity of culture, AFB microscopy, Xpert MTB/RIF, and MTBDRplus assay was 72.7%, 25.3%, 85.6%, and 79.4%, respectively, with a specificity of 100% for all the methods. The Xpert MTB/RIF assay showed the highest sensitivity compared to other methods. Considering the short turnaround time and promising findings, Xpert MTB/RIF assay should be integrated into national TB guidelines as a routine diagnostic test. Full article

(This article belongs to the Special Issue Prevention, Treatment and Diagnosis of Tuberculosis)

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Review

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19 pages, 2754 KiB

Open AccessReview

The Use of Particulate Systems for Tuberculosis Prophylaxis and Treatment: Opportunities and Challenges

by Alejandra Barrera-Rosales, Romina Rodríguez-Sanoja, Rogelio Hernández-Pando and Silvia Moreno-Mendieta

Microorganisms 2023, 11(8), 1988; https://doi.org/10.3390/microorganisms11081988 - 2 Aug 2023

Cited by 1 | Viewed by 2018

Abstract

The use of particles to develop vaccines and treatments for a wide variety of diseases has increased, and their success has been demonstrated in preclinical investigations. Accurately targeting cells and minimizing doses and adverse side effects, while inducing an adequate biological response, are important advantages that particulate systems offer. The most used particulate systems are liposomes and their derivatives, immunostimulatory complexes, virus-like particles, and organic or inorganic nano- and microparticles. Most of these systems have been proven using therapeutic or prophylactic approaches to control tuberculosis, one of the most important infectious diseases worldwide. This article reviews the progress and current state of the use of particles for the administration of TB vaccines and treatments in vitro and in vivo, with a special emphasis on polymeric particles. In addition, we discuss the challenges and benefits of using these particulate systems to provide researchers with an overview of the most promising strategies in current preclinical trials, offering a perspective on their progress to clinical trials. Full article

(This article belongs to the Special Issue Prevention, Treatment and Diagnosis of Tuberculosis)

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10 pages, 809 KiB

Open AccessReview

Machine Learning of the Whole Genome Sequence of Mycobacterium tuberculosis: A Scoping PRISMA-Based Review

by Ricardo Perea-Jacobo, Guillermo René Paredes-Gutiérrez, Miguel Ángel Guerrero-Chevannier, Dora-Luz Flores and Raquel Muñiz-Salazar

Microorganisms 2023, 11(8), 1872; https://doi.org/10.3390/microorganisms11081872 - 25 Jul 2023

Cited by 1 | Viewed by 2005

Abstract

Tuberculosis (TB) remains one of the most significant global health problems, posing a significant challenge to public health systems worldwide. However, diagnosing drug-resistant tuberculosis (DR-TB) has become increasingly challenging due to the rising number of multidrug-resistant (MDR-TB) cases, despite the development of new TB diagnostic tools. Even the World Health Organization-recommended methods such as Xpert MTB/XDR or Truenat are unable to detect all the Mycobacterium tuberculosis genome mutations associated with drug resistance. While Whole Genome Sequencing offers a more precise DR profile, the lack of user-friendly bioinformatics analysis applications hinders its widespread use. This review focuses on exploring various artificial intelligence models for predicting DR-TB profiles, analyzing relevant English-language articles using the PRISMA methodology through the Covidence platform. Our findings indicate that an Artificial Neural Network is the most commonly employed method, with non-statistical dimensionality reduction techniques preferred over traditional statistical approaches such as Principal Component Analysis or t-distributed Stochastic Neighbor Embedding. Full article

(This article belongs to the Special Issue Prevention, Treatment and Diagnosis of Tuberculosis)

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11 pages, 274 KiB

Open AccessReview

The Relative Positioning of Genotyping and Phenotyping for Tuberculosis Resistance Screening in Two EU National Reference Laboratories in 2023

by Richard Anthony, Ramona Groenheit, Mikael Mansjö, Rina de Zwaan and Jim Werngren

Microorganisms 2023, 11(7), 1809; https://doi.org/10.3390/microorganisms11071809 - 14 Jul 2023

Cited by 3 | Viewed by 1789

Abstract

The routine use of whole genome sequencing (WGS) as a reference typing technique for Mycobacterium tuberculosis epidemiology combined with the catalogued and extensive knowledge base of resistance-associated mutations means an initial susceptibility prediction can be derived from all cultured isolates in our laboratories based on WGS data alone. Preliminary work has confirmed, in our low-burden settings, these predictions are for first-line drugs, reproducible, robust with an accuracy similar to phenotypic drug susceptibility testing (pDST) and in many cases able to also predict the level of resistance (MIC). Routine screening for drug resistance by WGS results in approximately 80% of the isolates received being predicted as fully susceptible to the first-line drugs. Parallel testing with both WGS and pDST has demonstrated that routine pDST of genotypically fully susceptible isolates yields minimal additional information. Thus, rather than re-confirming all fully sensitive WGS-based predictions, we suggest that a more efficient use of available mycobacterial culture capacity in our setting is the development of a more extensive and detailed pDST targeted at any mono or multi-drug-resistant isolates identified by WGS screening. Phenotypic susceptibility retains a key role in the determination of an extended susceptibility profile for mono/multi-drugresistant isolates identified by WGS screening. The pDST information collected is also needed to support the development of future catalogues of resistance-associated mutations. Full article

(This article belongs to the Special Issue Prevention, Treatment and Diagnosis of Tuberculosis)

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