Mycobacterium tuberculosis (Mtb) is a crucial and destructive intracellular pathogen responsible for causing tuberculosis (TB), a disease of substantial morbidity and mortality. Mtb capsular polysaccharides can misdirect the host's immune response pathways, resulting in additional challenges in TB treatment. These capsule polysaccharides are biosynthesized by a series of stealth proteins including CpsY. Our prior investigations elucidated the structural and functional information of the central domain (aa 201–520) of CpsY within Mtb. However, within the host milieu, it is the full-length iteration of CpsY, rather than its truncated form CpsY201-520, that assumes pivotal roles in immune evasion. Consequently, investigating the functional mechanism of full-length CpsY is extremely important. Here, we found that the indispensable role of four conserved regions (CR1-CR4) in governing the phosphotransferase activity of full-length CpsY. Notably, the deletion of S2 (ΔS2) dramatically increased the activity compared to the wild-type (WT) full-length CpsY, thereby revealing S2 in the regulatory dynamics governing the inactivation and activation of full-length CpsY. The gene cpsY helps Mtb to survive in macrophages. Our findings were useful for the development of vaccines and immunotherapies targeting Mtb.
{"title":"Functional and mechanistic insights into the stealth protein full-length CpsY is conducive to understanding immune evasion mechanisms by Mycobacterium tuberculosis","authors":"Dafeng Liu , Ablikim Abdiriyim , Lvxia Zhang , Buayxam Ruzitohti","doi":"10.1016/j.tube.2025.102616","DOIUrl":"10.1016/j.tube.2025.102616","url":null,"abstract":"<div><div><em>Mycobacterium tuberculosis</em> (<em>Mtb</em>) is a crucial and destructive intracellular pathogen responsible for causing tuberculosis (TB), a disease of substantial morbidity and mortality. <em>Mtb</em> capsular polysaccharides can misdirect the host's immune response pathways, resulting in additional challenges in TB treatment. These capsule polysaccharides are biosynthesized by a series of stealth proteins including CpsY. Our prior investigations elucidated the structural and functional information of the central domain (aa 201–520) of CpsY within <em>Mtb</em>. However, within the host milieu, it is the full-length iteration of CpsY, rather than its truncated form CpsY<sup>201-520</sup>, that assumes pivotal roles in immune evasion. Consequently, investigating the functional mechanism of full-length CpsY is extremely important. Here, we found that the indispensable role of four conserved regions (CR1-CR4) in governing the phosphotransferase activity of full-length CpsY. Notably, the deletion of S2 (ΔS2) dramatically increased the activity compared to the wild-type (WT) full-length CpsY, thereby revealing S2 in the regulatory dynamics governing the inactivation and activation of full-length CpsY. The gene <em>cpsY</em> helps <em>Mtb</em> to survive in macrophages. Our findings were useful for the development of vaccines and immunotherapies targeting <em>Mtb</em>.</div></div>","PeriodicalId":23383,"journal":{"name":"Tuberculosis","volume":"152 ","pages":"Article 102616"},"PeriodicalIF":2.8,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143463837","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 : 2025-02-11DOI: 10.1016/j.tube.2025.102614
Qingqiu Zeng , Zhaowei Tong , Jianfeng Zhong , Xiaofeng Li , Bin Shen , Haiyan Chen , Dating Ge
Most of Mycobacterium tuberculosis(Mtb) infection result in the formation of granulomas, which are often rich in immune cells, with subsequent clinical symptoms. However, the role of the immune system in the formation of tuberculosis granuloma structures has not been fully revealed. Here we first analyzed single-cell transcriptome and microenvironment spatial characteristics to reveal the contribution of immune cells to granuloma expansion with validation by immunofluorescence. We then integrated published peripheral blood transcriptome data for Mtb-infected patients and healthy controls. Immune cell profiles were deconvoluted and results were validated on a local cohort using flow cytometry. At the same time, an in-depth evaluation of the changes in the population and function of multiple peripheral blood immune cells during tuberculosis infection were conducted to define correlation with granuloma area. Finally, we screened 6 cytokines (IL6, IL8, IL10, IFNγ, TNFα, TGFβ) through machine learning bioinformatics and analyzed their correlation with the size of tuberculosis granuloma. Based on these findings, we confirmed that the dynamic variation in proportion of immune cells in peripheral blood and the levels of cytokine profiles are closely related to the occurrence and development of tuberculosis granuloma. This study provides a theoretical basis for the molecular mechanism of tuberculosis granuloma.
{"title":"The correlation between immune profiles and pathological changes in pulmonary tuberculosis granulomas revealed by bioinformatic analysis and experimental validation","authors":"Qingqiu Zeng , Zhaowei Tong , Jianfeng Zhong , Xiaofeng Li , Bin Shen , Haiyan Chen , Dating Ge","doi":"10.1016/j.tube.2025.102614","DOIUrl":"10.1016/j.tube.2025.102614","url":null,"abstract":"<div><div>Most of Mycobacterium tuberculosis(Mtb) infection result in the formation of granulomas, which are often rich in immune cells, with subsequent clinical symptoms. However, the role of the immune system in the formation of tuberculosis granuloma structures has not been fully revealed. Here we first analyzed single-cell transcriptome and microenvironment spatial characteristics to reveal the contribution of immune cells to granuloma expansion with validation by immunofluorescence. We then integrated published peripheral blood transcriptome data for Mtb-infected patients and healthy controls. Immune cell profiles were deconvoluted and results were validated on a local cohort using flow cytometry. At the same time, an in-depth evaluation of the changes in the population and function of multiple peripheral blood immune cells during tuberculosis infection were conducted to define correlation with granuloma area. Finally, we screened 6 cytokines (IL6, IL8, IL10, IFNγ, TNFα, TGFβ) through machine learning bioinformatics and analyzed their correlation with the size of tuberculosis granuloma. Based on these findings, we confirmed that the dynamic variation in proportion of immune cells in peripheral blood and the levels of cytokine profiles are closely related to the occurrence and development of tuberculosis granuloma. This study provides a theoretical basis for the molecular mechanism of tuberculosis granuloma.</div></div>","PeriodicalId":23383,"journal":{"name":"Tuberculosis","volume":"152 ","pages":"Article 102614"},"PeriodicalIF":2.8,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143474762","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 : 2025-02-06DOI: 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":"2025-02-06","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}
Pub 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":"2025-01-31","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 : 2025-01-26DOI: 10.1016/j.tube.2025.102610
Elizna Maasdorp , Yonas Ghebrekristos , Amanda Khumalo , Lynthia Paul , Monique J. Williams
In recent years, a rise in non-tuberculosis mycobacteria pulmonary disease (NTM-PD) has been reported in several countries. However, data for high-burden tuberculosis settings, including South Africa, is currently limited. In this study, we conducted a retrospective analysis of routine diagnostic data obtained from one diagnostic laboratory in South Africa between 2015 and 2019. During this period, samples from 275 individuals with suspected mycobacterial infection were tested using the GenoType Mycobacterium CM (Common mycobacteria) or AS (Additional species) line probe assay (LPA) (Brucker-Hain Life science, Nehren, Germany), yielding an NTM-positive result for 163 of these individuals. Interestingly, the positivity rate in respiratory samples declined from 93 % in 2015 to 79 % in 2019. Just over half of the positive samples were of respiratory origin, and the most common species identified in respiratory samples was Mycobacterium intracellulare/Mycobacteium avium complex (28.9 %), followed by M. avium (17.4 %). Where the mycobacterial species was not identified by the LPA, a higher proportion of the subsequent cultures were negative, suggestive of colonisation rather than infection. More than half of patients with a positive NTM-LPA were HIV positive (55.9 %), and this association declined slightly during the study period (62.5 %–50 %).
{"title":"Non-tuberculosis mycobacteria identified by line probe assays in respiratory and non-respiratory samples in South Africa between 2015 and 2019","authors":"Elizna Maasdorp , Yonas Ghebrekristos , Amanda Khumalo , Lynthia Paul , Monique J. Williams","doi":"10.1016/j.tube.2025.102610","DOIUrl":"10.1016/j.tube.2025.102610","url":null,"abstract":"<div><div>In recent years, a rise in non-tuberculosis mycobacteria pulmonary disease (NTM-PD) has been reported in several countries. However, data for high-burden tuberculosis settings, including South Africa, is currently limited. In this study, we conducted a retrospective analysis of routine diagnostic data obtained from one diagnostic laboratory in South Africa between 2015 and 2019. During this period, samples from 275 individuals with suspected mycobacterial infection were tested using the GenoType Mycobacterium CM (Common mycobacteria) or AS (Additional species) line probe assay (LPA) (Brucker-Hain Life science, Nehren, Germany), yielding an NTM-positive result for 163 of these individuals. Interestingly, the positivity rate in respiratory samples declined from 93 % in 2015 to 79 % in 2019. Just over half of the positive samples were of respiratory origin, and the most common species identified in respiratory samples was <em>Mycobacterium intracellulare</em>/<em>Mycobacteium avium</em> complex (28.9 %), followed by <em>M</em>. <em>avium</em> (17.4 %). Where the mycobacterial species was not identified by the LPA, a higher proportion of the subsequent cultures were negative, suggestive of colonisation rather than infection. More than half of patients with a positive NTM-LPA were HIV positive (55.9 %), and this association declined slightly during the study period (62.5 %–50 %).</div></div>","PeriodicalId":23383,"journal":{"name":"Tuberculosis","volume":"151 ","pages":"Article 102610"},"PeriodicalIF":2.8,"publicationDate":"2025-01-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143068177","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 : 2025-01-22DOI: 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":"2025-01-22","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 : 2025-01-21DOI: 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":"2025-01-21","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 : 2025-01-20DOI: 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":"2025-01-20","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 : 2025-01-16DOI: 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":"2025-01-16","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":"2025-01-10","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}
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