Pub Date : 2025-03-01Epub Date: 2025-01-21DOI: 10.1016/j.tube.2025.102611
Lauma Freimane , Agnija Kivrāne , Viktorija Ulanova , Anda Vīksna , Eduards Sevostjanovs , Solveiga Grīnberga , Andra Cīrule , Alvils Krams , Renāte Ranka
Biomarker research characterising the effect of anti-tuberculosis (TB) chemotherapy on systemic body response is still limited. In this study, we aimed to investigate fluctuations in circulating cell-free mitochondrial DNA (ccf-mtDNA) and circulating cell-free nuclear DNA (ccf-nDNA) copy number (CN) in blood plasma of patients with drug-susceptible TB (DS-TB) and to decipher factors related to these fluctuations.
The results showed considerable changes in ccf-mtDNA CN in plasma samples before drug intake and 2 and 6 h afterwards, with high inter patient variability at each time point. Multivariate linear regression revealed that the dynamics of ccf-mtDNA CN was influenced by patients’ age, ethambutol pharmacokinetics, and body-mass index (BMI); ethambutol exposure emerged as the most significant factor. Very low ccf-nDNA CN in all three time points with little variation was observed; none factors were strongly associated with ccf-nDNA.
In conclusion, our study revealed the effect of anti-TB chemotherapy, age and BMI on acute changes in circulating ccf-mtDNA CN in blood plasma and highlighted the systemic, mitochondria-related effects of ethambutol in patients with TB. Further studies with larger cohorts are needed to understand the biological relevance of ccf-DNA in patients with TB and to validate its application in TB treatment monitoring.
{"title":"Fluctuations in circulating cell-free mitochondrial and nuclear DNA copy numbers in blood plasma after anti-tuberculosis drug intake in patients with drug-susceptible tuberculosis","authors":"Lauma Freimane , Agnija Kivrāne , Viktorija Ulanova , Anda Vīksna , Eduards Sevostjanovs , Solveiga Grīnberga , Andra Cīrule , Alvils Krams , Renāte Ranka","doi":"10.1016/j.tube.2025.102611","DOIUrl":"10.1016/j.tube.2025.102611","url":null,"abstract":"<div><div>Biomarker research characterising the effect of anti-tuberculosis (TB) chemotherapy on systemic body response is still limited. In this study, we aimed to investigate fluctuations in circulating cell-free mitochondrial DNA (ccf-mtDNA) and circulating cell-free nuclear DNA (ccf-nDNA) copy number (CN) in blood plasma of patients with drug-susceptible TB (DS-TB) and to decipher factors related to these fluctuations.</div><div>The results showed considerable changes in ccf-mtDNA CN in plasma samples before drug intake and 2 and 6 h afterwards, with high inter patient variability at each time point. Multivariate linear regression revealed that the dynamics of ccf-mtDNA CN was influenced by patients’ age, ethambutol pharmacokinetics, and body-mass index (BMI); ethambutol exposure emerged as the most significant factor. Very low ccf-nDNA CN in all three time points with little variation was observed; none factors were strongly associated with ccf-nDNA.</div><div>In conclusion, our study revealed the effect of anti-TB chemotherapy, age and BMI on acute changes in circulating ccf-mtDNA CN in blood plasma and highlighted the systemic, mitochondria-related effects of ethambutol in patients with TB. Further studies with larger cohorts are needed to understand the biological relevance of ccf-DNA in patients with TB and to validate its application in TB treatment monitoring.</div></div>","PeriodicalId":23383,"journal":{"name":"Tuberculosis","volume":"151 ","pages":"Article 102611"},"PeriodicalIF":2.8,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143042376","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-03-01Epub Date: 2025-01-22DOI: 10.1016/j.tube.2025.102609
C Kanipe , EJ Putz , MV Palmer
Bovine tuberculosis is mainly caused by Mycobacterium bovis. Bacillus Calmette-Guérin (BCG) is an attenuated strain of M. bovis which provides variable disease protection. Lesions have been characterized in infected cattle, but little comparison has been done with lesions which form in BCG-vaccinates. Here, in situ hybridization examined differences in expression of M. bovis RNA, inducible nitric oxide synthase 2, and vascular endothelial growth factor A in relation to vaccination status and granuloma grade, using two different groups of cattle. Data found no differences between vaccination groups or granuloma grade in average copies of M. bovis mRNA per μm2 of total granuloma area or per μm2 of necrotic areas. Within a vaccination group high-grade granulomas had more NOS2 per cell, per μm2 and a higher percentage of cells expressing NOS2 than low-grade granulomas. Non-vaccinates had a higher percentage of cells producing NOS2 than vaccinates. Differences in NOS2 expression varied by group. Vaccination status and granuloma grade did not affect the average copies of VEGFA per cell or the percent of cells expressing RNA, however VEGFA copies per μm2 varied between groups. These findings suggest NOS2 and VEGFA are likely not mechanisms of BCG vaccination protection but may impact disease severity.
{"title":"Differential expression of vascular endothelial growth factor A (VEGFA) and M1 macrophage marker nitric oxide synthase 2 (NOS2) in lymph node granulomas of BCG-vaccinated and non-vaccinated cattle infected with Mycobacterium bovis","authors":"C Kanipe , EJ Putz , MV Palmer","doi":"10.1016/j.tube.2025.102609","DOIUrl":"10.1016/j.tube.2025.102609","url":null,"abstract":"<div><div>Bovine tuberculosis is mainly caused by <em>Mycobacterium bovis</em>. Bacillus Calmette-Guérin (BCG) is an attenuated strain of <em>M. bovis</em> which provides variable disease protection. Lesions have been characterized in infected cattle, but little comparison has been done with lesions which form in BCG-vaccinates. Here, <em>in situ</em> hybridization examined differences in expression of <em>M. bovis</em> RNA, inducible nitric oxide synthase 2, and vascular endothelial growth factor A in relation to vaccination status and granuloma grade, using two different groups of cattle. Data found no differences between vaccination groups or granuloma grade in average copies of <em>M. bovis</em> mRNA per μm<sup>2</sup> of total granuloma area or per μm<sup>2</sup> of necrotic areas. Within a vaccination group high-grade granulomas had more NOS2 per cell, per μm<sup>2</sup> and a higher percentage of cells expressing NOS2 than low-grade granulomas. Non-vaccinates had a higher percentage of cells producing NOS2 than vaccinates. Differences in NOS2 expression varied by group. Vaccination status and granuloma grade did not affect the average copies of VEGFA per cell or the percent of cells expressing RNA, however VEGFA copies per μm<sup>2</sup> varied between groups. These findings suggest NOS2 and VEGFA are likely not mechanisms of BCG vaccination protection but may impact disease severity.</div></div>","PeriodicalId":23383,"journal":{"name":"Tuberculosis","volume":"151 ","pages":"Article 102609"},"PeriodicalIF":2.8,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143042374","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-03-01Epub Date: 2024-12-20DOI: 10.1016/j.tube.2024.102595
Petter Holmberg , Martina Janoušková , Tobias Schmidt , Ariane Neumann , Oskar Olsson , Per-Erik Isberg , Maja Reimann , Kristian Riesbeck , Sten Skogmar , Per Björkman
Background
Interferon-γ release assays (IGRAs) for tuberculosis infection (TBI) cannot distinguish different stages of the TBI spectrum (including spontaneously cleared infection). We investigated patterns of Mtb-specific blood mediators in people with and without TBI during tuberculosis preventive therapy (TPT).
Methods
Individuals with likelihood of recent Mtb exposure, aged 15–25 years, with valid IGRA results, in whom tuberculosis (TB) had been excluded, were included. Persons with TBI were sampled prior to TPT (IGRA + pre-treatment, n = 15) or after completion of TPT (IGRA + post-treatment, n = 15). Five persons without TBI were included as controls (IGRA-). Levels of 40 mediators related to TB immune control in blood incubated with Mtb antigens in the QuantiFERON-TB Plus® kit were assessed with electrochemiluminescence assay and compared between participant categories.
Results
The concentration of 10 mediators (GM-CSF, interferon-γ, IL-2, I-TAC, IL-12, IP-10, I-309, MCP-2, MIG, and VEGF) significantly differed between IGRA + pre-treatment and IGRA-. A non-significant trend in levels of these markers was observed between IGRA + pre-treatment, IGRA + post-treatment and IGRA-. Based on these mediators two clusters were identified: A (n = 16), including 5 IGRA-, 4 IGRA + pre-treatment, 7 IGRA + post-treatment and B (n = 19), including 11 IGRA + pre-treatment and 8 IGRA + post-treatment.
Conclusion
Plasma levels of several Mtb-triggered mediators differed with regard to TBI status among persons recently exposed to TB, suggesting the potential for alternative markers to assess TBI status. Longitudinal analysis of these mediators during TPT is warranted to explore whether these markers can be used to assess likelihood of persistence of viable bacilli in Mtb-exposed individuals.
{"title":"Blood levels of Mycobacterium tuberculosis (Mtb)antigen-triggered immune markers in people exposed to tuberculosis with regard to Mtb infection status and receipt of tuberculosis preventive therapy","authors":"Petter Holmberg , Martina Janoušková , Tobias Schmidt , Ariane Neumann , Oskar Olsson , Per-Erik Isberg , Maja Reimann , Kristian Riesbeck , Sten Skogmar , Per Björkman","doi":"10.1016/j.tube.2024.102595","DOIUrl":"10.1016/j.tube.2024.102595","url":null,"abstract":"<div><h3>Background</h3><div>Interferon-γ release assays (IGRAs) for tuberculosis infection (TBI) cannot distinguish different stages of the TBI spectrum (including spontaneously cleared infection). We investigated patterns of Mtb-specific blood mediators in people with and without TBI during tuberculosis preventive therapy (TPT).</div></div><div><h3>Methods</h3><div>Individuals with likelihood of recent Mtb exposure, aged 15–25 years, with valid IGRA results, in whom tuberculosis (TB) had been excluded, were included. Persons with TBI were sampled prior to TPT (IGRA + pre-treatment, <em>n</em> = 15) or after completion of TPT (IGRA + post-treatment, <em>n</em> = 15). Five persons without TBI were included as controls (IGRA-). Levels of 40 mediators related to TB immune control in blood incubated with Mtb antigens in the QuantiFERON-TB Plus® kit were assessed with electrochemiluminescence assay and compared between participant categories.</div></div><div><h3>Results</h3><div>The concentration of 10 mediators (GM-CSF, interferon-γ, IL-2, I-TAC, IL-12, IP-10, I-309, MCP-2, MIG, and VEGF) significantly differed between IGRA + pre-treatment and IGRA-. A non-significant trend in levels of these markers was observed between IGRA + pre-treatment, IGRA + post-treatment and IGRA-. Based on these mediators two clusters were identified: A (<em>n</em> = 16), including 5 IGRA-, 4 IGRA + pre-treatment, 7 IGRA + post-treatment and B (<em>n</em> = 19), including 11 IGRA + pre-treatment and 8 IGRA + post-treatment.</div></div><div><h3>Conclusion</h3><div>Plasma levels of several Mtb-triggered mediators differed with regard to TBI status among persons recently exposed to TB, suggesting the potential for alternative markers to assess TBI status. Longitudinal analysis of these mediators during TPT is warranted to explore whether these markers can be used to assess likelihood of persistence of viable bacilli in Mtb-exposed individuals.</div><div>ClinicalTrials.govID:NCT05621343.</div></div>","PeriodicalId":23383,"journal":{"name":"Tuberculosis","volume":"151 ","pages":"Article 102595"},"PeriodicalIF":2.8,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142915599","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-03-01Epub Date: 2024-12-19DOI: 10.1016/j.tube.2024.102596
Sabir Awad Mustafa
Purpose
Tuberculosis (TB) remains a significant public health concern globally. Bacille Calmette-Guérin (BCG) vaccination is widely used, but scar formation post-vaccination is not universal, which raises concerns about its efficacy. The Mantoux test is used to assess the immune response following BCG vaccination. This study aims to evaluate the prevalence of BCG scar formation among vaccinated children and its correlation with Mantoux test reactions.
Methods
This quantitative, cross-sectional descriptive study was conducted among children aged 3 months to 9 years at the vaccination office in Omdawanban, Sudan, from September to October 2021. Data were collected using structured surveys and the Mantoux skin test.
Results
Out of 350 vaccinated children, 285 (81.4 %) exhibited a visible BCG scar, while 65 (18.6 %) did not. Mantoux test positivity was observed in 132 children (37.7 %). A significant association was found between the presence of a BCG scar and a positive Mantoux test result (p < 0.05), with 39.3 % of children with a visible scar showing positive Mantoux results compared to 30.8 % of children without a scar. The likelihood of a positive Mantoux test was 3.2 times higher in children with a visible BCG scar (OR = 3.2, 95 % CI [1.8–5.8]). Mantoux positivity also varied by age, with the highest rate (41.2 %) observed among children aged 5–9 years (p = 0.03).
Conclusions
There is a significant association between BCG scar formation and Mantoux test positivity. Improved training for healthcare workers and better education for mothers about vaccination are recommended.
{"title":"Prevalence of BCG scar among vaccinated children and its correlation with Mantoux skin test at Omdawanban area, Sudan","authors":"Sabir Awad Mustafa","doi":"10.1016/j.tube.2024.102596","DOIUrl":"10.1016/j.tube.2024.102596","url":null,"abstract":"<div><h3>Purpose</h3><div>Tuberculosis (TB) remains a significant public health concern globally. Bacille Calmette-Guérin (BCG) vaccination is widely used, but scar formation post-vaccination is not universal, which raises concerns about its efficacy. The Mantoux test is used to assess the immune response following BCG vaccination. This study aims to evaluate the prevalence of BCG scar formation among vaccinated children and its correlation with Mantoux test reactions.</div></div><div><h3>Methods</h3><div>This quantitative, cross-sectional descriptive study was conducted among children aged 3 months to 9 years at the vaccination office in Omdawanban, Sudan, from September to October 2021. Data were collected using structured surveys and the Mantoux skin test.</div></div><div><h3>Results</h3><div>Out of 350 vaccinated children, 285 (81.4 %) exhibited a visible BCG scar, while 65 (18.6 %) did not. Mantoux test positivity was observed in 132 children (37.7 %). A significant association was found between the presence of a BCG scar and a positive Mantoux test result (p < 0.05), with 39.3 % of children with a visible scar showing positive Mantoux results compared to 30.8 % of children without a scar. The likelihood of a positive Mantoux test was 3.2 times higher in children with a visible BCG scar (OR = 3.2, 95 % CI [1.8–5.8]). Mantoux positivity also varied by age, with the highest rate (41.2 %) observed among children aged 5–9 years (p = 0.03).</div></div><div><h3>Conclusions</h3><div>There is a significant association between BCG scar formation and Mantoux test positivity. Improved training for healthcare workers and better education for mothers about vaccination are recommended.</div></div>","PeriodicalId":23383,"journal":{"name":"Tuberculosis","volume":"151 ","pages":"Article 102596"},"PeriodicalIF":2.8,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142915617","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-03-01Epub Date: 2024-12-24DOI: 10.1016/j.tube.2024.102594
Maxwell T. Stevens , Paige M.E. Hawkins , Trixie Wang , Richard J. Payne , Warwick J. Britton
Multi-drug-resistant Mycobacterium tuberculosis is an escalating global health problem, and a strong pipeline of novel compounds is needed to combat rising antimicrobial resistance. Ecumicin is a novel analogue of the natural antimycobacterial cyclic peptide ecumicin, with selective activity against Mycobacterium species. The activity of ecumicin∗ was compared to that of frontline tuberculosis therapies under in vitro conditions representative of niches where M. tuberculosis resides in the human lung. M. tuberculosis expressing luciferase was cultured in defined 7H9-based media containing glucose, butyrate, valerate, acidified glucose, low or high cholesterol concentrations, or intracellularly in human THP-1 and mouse RAW264.7 macrophages. Ecumicin∗ effectively killed M. tuberculosis under all assay conditions. The IC90 of ecumicin∗ was increased in acidified 7H9 media, and both IC90 and AUC90 values were increased in valerate, cholesterol, high cholesterol culture media. In time-kill assays, anti-M. tuberculosis activity of ecumicin∗ was sustained for 28 days. By comparison, IC50 and IC90 of isoniazid were decreased in butyrate and cholesterols medias, and mycobacterial regrowth occurred in glucose and cholesterol culture medias within 14 days at high isoniazid concentrations. Ecumicin∗ inhibited M. tuberculosis growth in THP-1 macrophages, and at higher IC90 in mouse RAW264.7 macrophages. Drug testing under disease-relevant conditions is important prior to in vivo examination, and ecumicin∗ has proven effective in multiple in vitro conditions typical of the lung environment of tuberculosis patients.
{"title":"Analogue of the natural product ecumicin causes sustained growth inhibition of Mycobacterium tuberculosis under multiple growth conditions","authors":"Maxwell T. Stevens , Paige M.E. Hawkins , Trixie Wang , Richard J. Payne , Warwick J. Britton","doi":"10.1016/j.tube.2024.102594","DOIUrl":"10.1016/j.tube.2024.102594","url":null,"abstract":"<div><div>Multi-drug-resistant <em>Mycobacterium tuberculosis</em> is an escalating global health problem, and a strong pipeline of novel compounds is needed to combat rising antimicrobial resistance. Ecumicin is a novel analogue of the natural antimycobacterial cyclic peptide ecumicin, with selective activity against <em>Mycobacterium</em> species. The activity of ecumicin∗ was compared to that of frontline tuberculosis therapies under <em>in vitro</em> conditions representative of niches where <em>M. tuberculosis</em> resides in the human lung. <em>M. tuberculosis</em> expressing luciferase was cultured in defined 7H9-based media containing glucose, butyrate, valerate, acidified glucose, low or high cholesterol concentrations, or intracellularly in human THP-1 and mouse RAW264.7 macrophages. Ecumicin∗ effectively killed <em>M. tuberculosis</em> under all assay conditions. The IC<sub>90</sub> of ecumicin∗ was increased in acidified 7H9 media, and both IC<sub>90</sub> and AUC<sub>90</sub> values were increased in valerate, cholesterol, high cholesterol culture media. In time-kill assays, <em>anti</em>-<em>M. tuberculosis</em> activity of ecumicin∗ was sustained for 28 days. By comparison, IC<sub>50</sub> and IC<sub>90</sub> of isoniazid were decreased in butyrate and cholesterols medias, and mycobacterial regrowth occurred in glucose and cholesterol culture medias within 14 days at high isoniazid concentrations. Ecumicin∗ inhibited <em>M. tuberculosis</em> growth in THP-1 macrophages, and at higher IC<sub>90</sub> in mouse RAW264.7 macrophages. Drug testing under disease-relevant conditions is important prior to <em>in vivo</em> examination, and ecumicin∗ has proven effective in multiple <em>in vitro</em> conditions typical of the lung environment of tuberculosis patients.</div></div>","PeriodicalId":23383,"journal":{"name":"Tuberculosis","volume":"151 ","pages":"Article 102594"},"PeriodicalIF":2.8,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142932802","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-03-01Epub Date: 2025-01-31DOI: 10.1016/j.tube.2025.102612
Sara C. Auld , Artur T.L. Queiroz , Mariana Araujo-Pereira , Pholo Maenetje , Nomsa Mofokeng , Lerato Mngomezulu , Duduzile Masilela , Brian Dobosh , Rabindra Tirouvanziam , Hardy Kornfeld , Bruno B. Andrade , Gregory P. Bisson
{"title":"Inflammatory profiles in sputum and blood of people with TB with and without HIV coinfection","authors":"Sara C. Auld , Artur T.L. Queiroz , Mariana Araujo-Pereira , Pholo Maenetje , Nomsa Mofokeng , Lerato Mngomezulu , Duduzile Masilela , Brian Dobosh , Rabindra Tirouvanziam , Hardy Kornfeld , Bruno B. Andrade , Gregory P. Bisson","doi":"10.1016/j.tube.2025.102612","DOIUrl":"10.1016/j.tube.2025.102612","url":null,"abstract":"","PeriodicalId":23383,"journal":{"name":"Tuberculosis","volume":"151 ","pages":"Article 102612"},"PeriodicalIF":2.8,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143177297","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-03-01Epub Date: 2025-01-20DOI: 10.1016/j.tube.2025.102607
Jeremiah Khayumbi , Loren E. Sasser , Taryn A. McLaughlin , Joshua Ongalo , Joan Tonui , Samuel Gurrion Ouma , Angie Campbell , Felix Hayara Odhiambo , Neel R. Gandhi , Chelimo Kiprotich , Cheryl L. Day
Infection with HIV is associated with dysregulated CD4 T cell responses to Mycobacterium tuberculosis (Mtb) and increased risk of developing tuberculosis. Mtb-specific CD4 T cells in people with HIV have diminished Th1 cytokine production capacity, thus we utilized a flow cytometry-based assay to measure CD40L expression by Mtb-specific CD4 T cells in a cytokine-independent manner. We evaluated the frequency and phenotype of Mtb-specific CD4 responses in Kenyan adults with latent Mtb infection and found that the majority of Mtb-specific CD4 T cells expressed CD40L in the absence of IFN-γ, regardless of HIV infection status. Expression of HLA-DR was increased on Mtb-specific CD4 T cells in people with HIV, compared to people without HIV. These data suggest expression of HLA-DR by Mtb-specific CD4 T cells may represent an early biomarker of increased mycobacterial antigen stimulation in people with HIV prior to the development of symptomatic tuberculosis disease.
{"title":"HIV co-infection is associated with increased HLA-DR expression by Mycobacterium tuberculosis-specific CD4 T cells in people with latent tuberculosis infection","authors":"Jeremiah Khayumbi , Loren E. Sasser , Taryn A. McLaughlin , Joshua Ongalo , Joan Tonui , Samuel Gurrion Ouma , Angie Campbell , Felix Hayara Odhiambo , Neel R. Gandhi , Chelimo Kiprotich , Cheryl L. Day","doi":"10.1016/j.tube.2025.102607","DOIUrl":"10.1016/j.tube.2025.102607","url":null,"abstract":"<div><div>Infection with HIV is associated with dysregulated CD4 T cell responses to <em>Mycobacterium tuberculosis</em> (Mtb) and increased risk of developing tuberculosis. Mtb-specific CD4 T cells in people with HIV have diminished Th1 cytokine production capacity, thus we utilized a flow cytometry-based assay to measure CD40L expression by Mtb-specific CD4 T cells in a cytokine-independent manner. We evaluated the frequency and phenotype of Mtb-specific CD4 responses in Kenyan adults with latent Mtb infection and found that the majority of Mtb-specific CD4 T cells expressed CD40L in the absence of IFN-γ, regardless of HIV infection status. Expression of HLA-DR was increased on Mtb-specific CD4 T cells in people with HIV, compared to people without HIV. These data suggest expression of HLA-DR by Mtb-specific CD4 T cells may represent an early biomarker of increased mycobacterial antigen stimulation in people with HIV prior to the development of symptomatic tuberculosis disease.</div></div>","PeriodicalId":23383,"journal":{"name":"Tuberculosis","volume":"151 ","pages":"Article 102607"},"PeriodicalIF":2.8,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143048035","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-03-01Epub Date: 2025-01-16DOI: 10.1016/j.tube.2025.102608
Sanha Lee , Taeyoon Kim , Keum-Yong Seong , Sang-Gu Yim , Won-Kyu Lee , Semin Kim , Kang-Oh Lee , Seung Yun Yang , Sungweon Ryoo
Tuberculosis (TB) remains a highly lethal infectious disease. The primary preventive measure is Bacille Calmette-Guérin (BCG), a live attenuated vaccine. However, the current intradermal vaccination method with 10-dose vials faces challenges such as inadequate infant injection, inaccurate dispensing, and unstable storage. Researchers have explored microneedle (MN) technology to address these concerns as a intradermal vaccine delivery approach. MN array patches offer painless administration, convenience, improved immunogenicity, and vaccine stability. This study aimed to develop a coated MN system using a micro-dispensing technique at a low temperature (4 °C) and specific excipients for precise dosing and vaccine viability enhancement. Long-term storage stability revealed enhanced storage stability of the BCG-coated MN (BCG-MN) vaccine, maintaining a survival rate of over 60 % for 8 weeks at −20 °C. In vivo vaccination tests using BCG-MN vaccines on guinea pigs exhibited no adverse reactions. Moreover, the BCG-MN vaccine demonstrated superior immune response compared to injections, suggesting that this BCG vaccine-coated MN platform has the potential as a single-dose TB vaccination technology, offering precise dosing control and enhanced immune effectiveness with high storage stability.
{"title":"Microneedle-mediated intradermal delivery of Bacille Calmette-Guérin (BCG) vaccines for single-dose tuberculosis vaccination","authors":"Sanha Lee , Taeyoon Kim , Keum-Yong Seong , Sang-Gu Yim , Won-Kyu Lee , Semin Kim , Kang-Oh Lee , Seung Yun Yang , Sungweon Ryoo","doi":"10.1016/j.tube.2025.102608","DOIUrl":"10.1016/j.tube.2025.102608","url":null,"abstract":"<div><div>Tuberculosis (TB) remains a highly lethal infectious disease. The primary preventive measure is Bacille Calmette-Guérin (BCG), a live attenuated vaccine. However, the current intradermal vaccination method with 10-dose vials faces challenges such as inadequate infant injection, inaccurate dispensing, and unstable storage. Researchers have explored microneedle (MN) technology to address these concerns as a intradermal vaccine delivery approach. MN array patches offer painless administration, convenience, improved immunogenicity, and vaccine stability. This study aimed to develop a coated MN system using a micro-dispensing technique at a low temperature (4 °C) and specific excipients for precise dosing and vaccine viability enhancement. Long-term storage stability revealed enhanced storage stability of the BCG-coated MN (BCG-MN) vaccine, maintaining a survival rate of over 60 % for 8 weeks at −20 °C. <em>In vivo</em> vaccination tests using BCG-MN vaccines on guinea pigs exhibited no adverse reactions. Moreover, the BCG-MN vaccine demonstrated superior immune response compared to injections, suggesting that this BCG vaccine-coated MN platform has the potential as a single-dose TB vaccination technology, offering precise dosing control and enhanced immune effectiveness with high storage stability.</div></div>","PeriodicalId":23383,"journal":{"name":"Tuberculosis","volume":"151 ","pages":"Article 102608"},"PeriodicalIF":2.8,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143012387","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The limitations of existing mouse models of lung infection with Mycobacteroides abscessus impede drug discovery and development. In contrast to current animal models that introduce NTM intravenously or by intranasal/intra-tracheal instillation or via bronchoscopy-guided insufflation, we developed a dry powder inhalation (DPI) of M. abscessus ATCC 19977 that generated paucibacillary lung infection and histopathology in immunocompetent mice. Swiss outbred mice receiving ∼1000 (3-log) colony forming units (CFU) of M. abscessus/gram lung tissue via the DPI administered by nose-only inhalation for 90 s showed peak bacterial burden of ∼3.35-log CFU/g in the lungs after 28 days. This was maintained at ∼2-log/g from Day 35 through 56 in the lungs, but not in the spleen. Histopathology indicated increasing severity of inflammation, fibrosis and lung consolidation. Bacteria were rarely recovered from spleen, and histopathological examination indicated partial resolution in the spleen between Days 49–56. The DPI, prepared by freeze-drying log-phase liquid culture with cryoprotectants was formulated to possess aerosol characteristics suitable for alveolar deposition. Aerosol exposure to inoculum mimics natural airborne infection. Non-invasive aerosol infection is convenient, inexpensive, does not require special equipment or extensive training and mitigates stress to animals, but biosafety level 3 containment is recommended to mitigate risk to experimenters.
{"title":"Preclinical model of Mycobacteroides abscessus lung disease by nose-only exposure of mice to bacterial powder aerosol","authors":"Khushboo Verma , Tanu Garg , Shriya Singh , Venkata Siva Reddy Deivreddy , Sunil K. Raman , Reena Bharti , Hasham Shafi Sofi , Kavita Singh , Mehazabeen Shaik , Arunava Dasgupta , Madhav N. Mugale , Amit Misra","doi":"10.1016/j.tube.2025.102606","DOIUrl":"10.1016/j.tube.2025.102606","url":null,"abstract":"<div><div>The limitations of existing mouse models of lung infection with <em>Mycobacteroides abscessus</em> impede drug discovery and development. In contrast to current animal models that introduce NTM intravenously or by intranasal/intra-tracheal instillation or via bronchoscopy-guided insufflation, we developed a dry powder inhalation (DPI) of <em>M. abscessus</em> ATCC 19977 that generated paucibacillary lung infection and histopathology in immunocompetent mice. Swiss outbred mice receiving ∼1000 (3-log) colony forming units (CFU) of <em>M. abscessus</em>/gram lung tissue via the DPI administered by nose-only inhalation for 90 s showed peak bacterial burden of ∼3.35-log CFU/g in the lungs after 28 days. This was maintained at ∼2-log/g from Day 35 through 56 in the lungs, but not in the spleen. Histopathology indicated increasing severity of inflammation, fibrosis and lung consolidation. Bacteria were rarely recovered from spleen, and histopathological examination indicated partial resolution in the spleen between Days 49–56. The DPI, prepared by freeze-drying log-phase liquid culture with cryoprotectants was formulated to possess aerosol characteristics suitable for alveolar deposition. Aerosol exposure to inoculum mimics natural airborne infection. Non-invasive aerosol infection is convenient, inexpensive, does not require special equipment or extensive training and mitigates stress to animals, but biosafety level 3 containment is recommended to mitigate risk to experimenters.</div></div>","PeriodicalId":23383,"journal":{"name":"Tuberculosis","volume":"151 ","pages":"Article 102606"},"PeriodicalIF":2.8,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143012388","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-03-01Epub Date: 2025-02-06DOI: 10.1016/j.tube.2025.102613
Raquel S.B. Câmara , Isabela A.G. Pereira , Geise C. Espíndola , Daniela P. Lage , Ana L. Silva , Camila S. Freitas , Bárbara P.N. Assis , Laís V.A. Corrêa , Ricardo L.F. Moreira , Sandra Lyon , Rozana C. Silva , Tiago S. Barros , Ana Laura G. de Oliveira , Fernanda Ludolf , Miguel A. Chávez-Fumagalli , Myron Christodoulides , Ricardo A. Machado-de-Ávila , Unaí Tupinambás , Denise U. Gonçalves , Manoel O. da Costa Rocha , Ana T. Chaves
Leprosy diagnosis is difficult to perform due to variable sensitivity and/or specificity of the tests. In addition, the collection of the blood samples requires laboratorial structure and trained professionals. In the present study, the diagnostic efficacy of M1 chimeric protein, which was recently showed to be antigenic for leprosy using a serum-based ELISA, was evaluated against patient urine. Paired serum and urine samples were collected from patients with paucibacillary (PB) and multibacillary (MB) leprosy, tegumentary and visceral leishmaniasis, tuberculosis, Chagas disease, malaria, and HIV-infected subjects. Samples from healthy individuals and household contacts were also used. The protein and peptides used to compose it were used as antigens, and results showed that the four peptides presented good sensitivity and specificity to detect MB leprosy, while M1 protein showed sensitivity and specificity of 98.5 % and 100 %, respectively, to detect both PB and MB leprosy, when an urine-based ELISA was performed. Positive (PPV) and negative (NPV) predictive values were 100 % and 98.3 %, respectively. In a serum-based ELISA, sensitivity and specificity were 96.9 % and 100 %, respectively, with PPV and NPV of 100 % and 96.5 %, respectively. In conclusion, preliminary data suggest that M1 protein could be considered for diagnosis of leprosy by using patient urine.
{"title":"Urine-based ELISA using a recombinant chimeric protein for the diagnosis of paucibacillary and multibacillary leprosy","authors":"Raquel S.B. Câmara , Isabela A.G. Pereira , Geise C. Espíndola , Daniela P. Lage , Ana L. Silva , Camila S. Freitas , Bárbara P.N. Assis , Laís V.A. Corrêa , Ricardo L.F. Moreira , Sandra Lyon , Rozana C. Silva , Tiago S. Barros , Ana Laura G. de Oliveira , Fernanda Ludolf , Miguel A. Chávez-Fumagalli , Myron Christodoulides , Ricardo A. Machado-de-Ávila , Unaí Tupinambás , Denise U. Gonçalves , Manoel O. da Costa Rocha , Ana T. Chaves","doi":"10.1016/j.tube.2025.102613","DOIUrl":"10.1016/j.tube.2025.102613","url":null,"abstract":"<div><div>Leprosy diagnosis is difficult to perform due to variable sensitivity and/or specificity of the tests. In addition, the collection of the blood samples requires laboratorial structure and trained professionals. In the present study, the diagnostic efficacy of M1 chimeric protein, which was recently showed to be antigenic for leprosy using a serum-based ELISA, was evaluated against patient urine. Paired serum and urine samples were collected from patients with paucibacillary (PB) and multibacillary (MB) leprosy, tegumentary and visceral leishmaniasis, tuberculosis, Chagas disease, malaria, and HIV-infected subjects. Samples from healthy individuals and household contacts were also used. The protein and peptides used to compose it were used as antigens, and results showed that the four peptides presented good sensitivity and specificity to detect MB leprosy, while M1 protein showed sensitivity and specificity of 98.5 % and 100 %, respectively, to detect both PB and MB leprosy, when an urine-based ELISA was performed. Positive (PPV) and negative (NPV) predictive values were 100 % and 98.3 %, respectively. In a serum-based ELISA, sensitivity and specificity were 96.9 % and 100 %, respectively, with PPV and NPV of 100 % and 96.5 %, respectively. In conclusion, preliminary data suggest that M1 protein could be considered for diagnosis of leprosy by using patient urine.</div></div>","PeriodicalId":23383,"journal":{"name":"Tuberculosis","volume":"151 ","pages":"Article 102613"},"PeriodicalIF":2.8,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143350107","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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