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13 pages, 665 KiB

Open AccessArticle

Universal Lineage-Independent Markers of Multidrug Resistance in Mycobacterium tuberculosis

by Hleliwe Hlanze, Awelani Mutshembele and Oleg N. Reva

Microorganisms 2024, 12(7), 1340; https://doi.org/10.3390/microorganisms12071340 - 30 Jun 2024

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Abstract

(1) Background: This study was aimed to identify universal genetic markers of multidrug resistance (MDR) in Mycobacterium tuberculosis (Mtb) and establish statistical associations among identified mutations to enhance understanding of MDR in Mtb and inform diagnostic and treatment development. (2) Methods: GWAS analysis [...] Read more.

(1) Background: This study was aimed to identify universal genetic markers of multidrug resistance (MDR) in Mycobacterium tuberculosis (Mtb) and establish statistical associations among identified mutations to enhance understanding of MDR in Mtb and inform diagnostic and treatment development. (2) Methods: GWAS analysis and the statistical evaluation of identified polymorphic sites within protein-coding genes of Mtb were performed. Statistical associations between specific mutations and antibiotic resistance were established using attributable risk statistics. (3) Results: Sixty-four polymorphic sites were identified as universal markers of drug resistance, with forty-seven in PE/PPE regions and seventeen in functional genes. Mutations in genes such as cyp123, fadE36, gidB, and ethA showed significant associations with resistance to various antibiotics. Notably, mutations in cyp123 at codon position 279 were linked to resistance to ten antibiotics. The study highlighted the role of PE/PPE and PE_PGRS genes in Mtb’s evolution towards a ‘mutator phenotype’. The pathways of acquisition of mutations forming the epistatic landscape of MDR were discussed. (4) Conclusions: This research identifies marker mutations across the Mtb genome associated with MDR. The findings provide new insights into the molecular basis of MDR acquisition in Mtb, aiding in the development of more effective diagnostics and treatments targeting these mutations to combat MDR tuberculosis. Full article

(This article belongs to the Special Issue Mycobacterial Tuberculosis Pathogenesis and Vaccine Development)

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12 pages, 1016 KiB

Open AccessArticle

Transcriptional Profiling of Homologous Recombination Pathway Genes in Mycobacterium bovis BCG Moreau

by Marcos Gustavo Araujo Schwarz, Paloma Rezende Corrêa and Leila Mendonça-Lima

Microorganisms 2023, 11(10), 2534; https://doi.org/10.3390/microorganisms11102534 - 11 Oct 2023

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Abstract

Mycobacterium bovis BCG Moreau is the main Brazilian strain for vaccination against tuberculosis. It is considered an early strain, more like the original BCG, whereas BCG Pasteur, largely used as a reference, belongs to the late strain clade. BCG Moreau, contrary to Pasteur, [...] Read more.

Mycobacterium bovis BCG Moreau is the main Brazilian strain for vaccination against tuberculosis. It is considered an early strain, more like the original BCG, whereas BCG Pasteur, largely used as a reference, belongs to the late strain clade. BCG Moreau, contrary to Pasteur, is naturally deficient in homologous recombination (HR). In this work, using a UV exposure test, we aimed to detect differences in the survival of various BCG strains after DNA damage. Transcription of core and regulatory HR genes was further analyzed using RT-qPCR, aiming to identify the molecular agent responsible for this phenotype. We show that early strains share the Moreau low survival rate after UV exposure, whereas late strains mimic the Pasteur phenotype, indicating that this increase in HR efficiency is linked to the evolutionary clade history. Additionally, RT-qPCR shows that BCG Moreau has an overall lower level of these transcripts than Pasteur, indicating a correlation between this gene expression profile and HR efficiency. Further assays should be performed to fully identify the molecular mechanism that may explain this differential phenotype between early and late BCG strains. Full article

(This article belongs to the Special Issue Mycobacterial Tuberculosis Pathogenesis and Vaccine Development)

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12 pages, 802 KiB

Open AccessArticle

Vaccination of White-Tailed Deer with Mycobacterium bovis Bacillus Calmette–Guérin (BCG): Effect of Mycobacterium avium ssp. paratuberculosis Infection

by Mitchell V. Palmer, Carly Kanipe, Kimberly A. Lehman, Tyler C. Thacker, Ellie J. Putz and Paola M. Boggiatto

Microorganisms 2023, 11(10), 2488; https://doi.org/10.3390/microorganisms11102488 - 4 Oct 2023

Cited by 1 | Viewed by 1661

Abstract

In many parts of the world, bovine tuberculosis eradication efforts are hampered by wildlife reservoirs of Mycobacterium bovis, which serve as a constant source of M. bovis for nearby cattle. The human tuberculosis vaccine, M. bovis BCG has been investigated for use [...] Read more.

In many parts of the world, bovine tuberculosis eradication efforts are hampered by wildlife reservoirs of Mycobacterium bovis, which serve as a constant source of M. bovis for nearby cattle. The human tuberculosis vaccine, M. bovis BCG has been investigated for use in several wildlife species, including deer. In the US, white-tailed deer in Michigan have been the source of infection for over 82 cattle herds since M. bovis was discovered in free-ranging deer in 1995. The efficacy of BCG may be influenced by many factors, including prior exposure or infection with non-tuberculous mycobacteria, that is, species other than members of the M. tuberculosis complex. M. avium subspecies paratuberculosis (Map) infection is not uncommon in ruminants such as deer. Using natural exposure to Map and experimental infection with M. bovis, we demonstrate that Map infection increased BCG vaccine efficacy as measured by lesion severity scores. Full article

(This article belongs to the Special Issue Mycobacterial Tuberculosis Pathogenesis and Vaccine Development)

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15 pages, 1344 KiB

Open AccessArticle

Functional Whole Genome Screen of Nutrient-Starved Mycobacterium tuberculosis Identifies Genes Involved in Rifampin Tolerance

by William M. Matern, Harley T. Harris, Carina Danchik, Marissa McDonald, Gopi Patel, Aashish Srivastava, Thomas R. Ioerger, Joel S. Bader and Petros C. Karakousis

Microorganisms 2023, 11(9), 2269; https://doi.org/10.3390/microorganisms11092269 - 9 Sep 2023

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Abstract

Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), poses a global health challenge and is responsible for over a million deaths each year. Current treatment is lengthy and complex, and new, abbreviated regimens are urgently needed. Mtb adapts to nutrient [...] Read more.

Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), poses a global health challenge and is responsible for over a million deaths each year. Current treatment is lengthy and complex, and new, abbreviated regimens are urgently needed. Mtb adapts to nutrient starvation, a condition experienced during host infection, by shifting its metabolism and becoming tolerant to the killing activity of bactericidal antibiotics. An improved understanding of the mechanisms mediating antibiotic tolerance in Mtb can serve as the basis for developing more effective therapies. We performed a forward genetic screen to identify candidate Mtb genes involved in tolerance to the two key first-line antibiotics, rifampin and isoniazid, under nutrient-rich and nutrient-starved conditions. In nutrient-rich conditions, we found 220 mutants with differential antibiotic susceptibility (218 in the rifampin screen and 2 in the isoniazid screen). Following Mtb adaptation to nutrient starvation, 82 mutants showed differential antibiotic susceptibility (80 in the rifampin screen and 2 in the isoniazid screen). Using targeted mutagenesis, we validated the rifampin-hypersusceptible phenotype under nutrient starvation in Mtb mutants lacking the following genes: ercc3, moeA1, rv0049, and rv2179c. These findings shed light on potential therapeutic targets, which could help shorten the duration and complexity of antitubercular regimens. Full article

(This article belongs to the Special Issue Mycobacterial Tuberculosis Pathogenesis and Vaccine Development)

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15 pages, 5430 KiB

Open AccessArticle

The Immunogenicity and Safety of Mycobacterium tuberculosis-mosR-Based Double Deletion Strain in Mice

by Rachel E. Hildebrand, Chungyi Hansen, Brock Kingstad-Bakke, Chia-Wei Wu, Marulasiddappa Suresh and Adel Talaat

Microorganisms 2023, 11(8), 2105; https://doi.org/10.3390/microorganisms11082105 - 18 Aug 2023

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Abstract

Mycobacterium tuberculosis (M. tuberculosis) remains a significant global health threat, accounting for ~1.7 million deaths annually. The efficacy of the current vaccine, M. bovis BCG, ranges from 0 to 80% in children and does not prevent adulthood tuberculosis. We explored the [...] Read more.

Mycobacterium tuberculosis (M. tuberculosis) remains a significant global health threat, accounting for ~1.7 million deaths annually. The efficacy of the current vaccine, M. bovis BCG, ranges from 0 to 80% in children and does not prevent adulthood tuberculosis. We explored the immune profile and safety of a live-attenuated M. tuberculosis construct with double deletions of the mosR and echA7 genes, where previously, single mutations were protective against an M. tuberculosis aerosol challenge. Over 32 weeks post-vaccination (WPV), immunized mice with M. tuberculosisΔmosRΔechA7 (double mutant) were sacrificed to evaluate the vaccine persistence, histopathology, and immune responses. Interestingly, despite similar tissue colonization between the vaccine double mutant and wild-type M. tuberculosis, the vaccine construct showed a greater reaction to the ESAT-6, TB.10, and Ag85B antigens with peptide stimulation. Additionally, there was a greater number of antigen-specific CD4 T cells in the vaccine group, accompanied by significant polyfunctional T-cell responses not observed in the other groups. Histologically, mild but widely distributed inflammatory responses were recorded in the livers and lungs of the immunized animals at early timepoints, which turned into organized inflammatory foci via 32WPV, a pathology not observed in BCG-immunized mice. A lower double-mutant dose resulted in significantly less tissue colonization and less tissue inflammation. Overall, the double-mutant vaccine elicited robust immune responses dominated by antigen-specific CD4 T cells, but also triggered tissue damage and vaccine persistence. The findings highlight key features associated with the immunogenicity and safety of the examined vaccine construct that can benefit the future evaluation of other live vaccines. Full article

(This article belongs to the Special Issue Mycobacterial Tuberculosis Pathogenesis and Vaccine Development)

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18 pages, 2356 KiB

Open AccessArticle

Association between High Interferon-Gamma Production in Avian Tuberculin-Stimulated Blood from Mycobacterium avium subsp. paratuberculosis-Infected Cattle and Candidate Genes Implicated in Necroptosis

by Gerard Badia-Bringué, María Canive, Patricia Vázquez, Joseba M. Garrido, Almudena Fernández, Ramón A. Juste, José Antonio Jiménez, Oscar González-Recio and Marta Alonso-Hearn

Microorganisms 2023, 11(7), 1817; https://doi.org/10.3390/microorganisms11071817 - 15 Jul 2023

Cited by 3 | Viewed by 1669

Abstract

The mechanisms underlying host resistance to Mycobacterium avium subsp. paratuberculosis (MAP) infection are largely unknown. In the current study, we hypothesize that cows with an ability to produce higher levels of interferon-gamma (IFNɣ) might control MAP infection more successfully. To test this hypothesis, [...] Read more.

The mechanisms underlying host resistance to Mycobacterium avium subsp. paratuberculosis (MAP) infection are largely unknown. In the current study, we hypothesize that cows with an ability to produce higher levels of interferon-gamma (IFNɣ) might control MAP infection more successfully. To test this hypothesis, IFNɣ production was measured using a specific IFNɣ ELISA kit in avian purified protein derivative (aPPD)-stimulated blood samples collected from 152 Holstein cattle. DNA isolated from peripheral blood samples of the animals included in the study was genotyped with the EuroG Medium-Density Bead Chip, and the genotypes were imputed to whole-genome sequencing. A genome-wide association analysis (GWAS) revealed that high levels of IFNɣ in response to the aPPD were associated with a specific genetic profile (heritability = 0.64) and allowed the identification of 71 SNPs, 40 quantitative trait loci (QTL), and 104 candidate genes. A functional analysis using the 104 candidate genes revealed a significant enrichment of genes involved in the innate immune response and, more specifically, in necroptosis. Taken together, our results define a heritable and distinct immunogenetic profile associated with the production of high IFNɣ levels and with the capacity of the host to lyse MAP-infected macrophages by necroptosis. Full article

(This article belongs to the Special Issue Mycobacterial Tuberculosis Pathogenesis and Vaccine Development)

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8 pages, 3666 KiB

Open AccessCase Report

Empyema Necessitatis Caused by Prevotella melaninogenica and Dialister pneumosintes Resolved with Vacuum-Assisted Closure System: A Case Report

by Esteban Bladimir Martínez Castrejón, Erika Reina-Bautista, Sandra Tania Ventura-Gómez, Araceli Maldonado Cisneros, Jessica Alejandra Juárez Ramos, Miguel Alejandro Sánchez Durán, Jesús Aguilar Ventura, Omar Esteban Valencia-Ledezma, María Guadalupe Frías-De-León, Eduardo García Salazar and Carlos Alberto Castro-Fuentes

Microorganisms 2024, 12(9), 1881; https://doi.org/10.3390/microorganisms12091881 - 12 Sep 2024

Viewed by 805

Abstract

Empyema necessitatis is a rare complication of an untreated or inadequately controlled empyema. We present the case of an 11-year-old female adolescent living in precarious conditions, overcrowding, incomplete vaccinations, irregular dental hygiene, and no significant family or personal medical history. The patient started [...] Read more.

Empyema necessitatis is a rare complication of an untreated or inadequately controlled empyema. We present the case of an 11-year-old female adolescent living in precarious conditions, overcrowding, incomplete vaccinations, irregular dental hygiene, and no significant family or personal medical history. The patient started with symptoms one week prior to her hospitalization, presenting a persistent sporadic dry cough, and was later diagnosed with complicated pneumonia, resulting in the placement of an endopleural tube. Vancomycin (40 mg/kg/day) and ceftriaxone (75 mg/kg/day) were administered. However, the clinical evolution was unfavorable, with fever and respiratory distress, so a right jugular catheter was placed. The CT scan showed a loculated collection that occupied the entire right lung parenchyma and pneumothorax at the right upper lobe level. After four days of treatment, the patient still presented purulent drainage with persistent right pleural effusion syndrome. P. melaninogenica and D. pneumosintes were identified from the purulent collection on the upper right lobe, so the antimicrobial treatment was adapted to a glycopeptide, Teicoplanin, at a weight-based dosing of 6 mg/kg/day and Metronidazole at a weight-based dosing of 30 mg/kg/day. In addition, VAC therapy was used for 26 days with favorable resolution. Full article

(This article belongs to the Special Issue Mycobacterial Tuberculosis Pathogenesis and Vaccine Development)

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8 pages, 377 KiB

Open AccessBrief Report

Specific Mycobacterium tuberculosis Strain Circulating in Prison Revealed by Cost-Effective Amplicon Sequencing

by Joaquín Hurtado, María Noel Bentancor, Paula Laserra, Cecilia Coitinho and Gonzalo Greif

Microorganisms 2024, 12(5), 999; https://doi.org/10.3390/microorganisms12050999 - 15 May 2024

Viewed by 1122

Abstract

This scientific study focuses on tuberculosis (TB) within prison settings, where persons deprived of liberty (PDL) face significantly higher rates of the disease compared to the general population. The research employs the low-cost amplicon sequencing of Mycobacterium tuberculosis strains, aiming first to identify [...] Read more.

This scientific study focuses on tuberculosis (TB) within prison settings, where persons deprived of liberty (PDL) face significantly higher rates of the disease compared to the general population. The research employs the low-cost amplicon sequencing of Mycobacterium tuberculosis strains, aiming first to identify specific lineages and also to detect mutations associated with drug resistance. The method involves multiplex amplification, DNA extraction, and sequencing, providing valuable insights into TB dynamics and resistance-mutation profiles within the prison system at an affordable cost. The study identifies a characteristic lineage (X) circulating among PDLs in the penitentiary system in Uruguay, absent in the general population, and notes its prevalence at prison entry. No high-confidence mutations associated with drug resistance were found. The findings underscore the importance of molecular epidemiology in TB control, emphasizing the potential for intra-prison transmissions and the need for broader studies to understand strain dynamics. Full article

(This article belongs to the Special Issue Mycobacterial Tuberculosis Pathogenesis and Vaccine Development)

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