Tuberculosis最新文献

英文中文

Customized MHC Class I & II restricted peptides from clinical isolates of Mycobacterium tuberculosis tweak strong cellular immune response in Healthy individuals and Pulmonary Tuberculosis patients: A potential candidate in vaccine design

IF 2.8 3区医学 Q3 IMMUNOLOGY

Tuberculosis

Pub Date : 2025-04-15 DOI: 10.1016/j.tube.2025.102640

Niharika Sharma , Beenu Joshi , Bhawna Sharma , Santosh Kumar , Keshar Kunja Mohanty , Hridayesh Prakash

Tuberculosis (TB) remains a global health challenge as annual mortality rate due to drug resistant TB is increasing exponentially. This is mostly associated with the delayed diagnosis of Multidrug-resistant (MDR) or latent TB. Effective management of TB demands development of novel immunological strategies, such as peptide-based/subunit vaccines that can stimulate specific immune responses. In this context, we evaluated the immunogenic potential of two Major Histocompatibility Complex (MHC) Class I/II-restricted peptides from Mycobacterium tuberculosis (M. tuberculosis): Rv2588c and Rv0148. The peptides were tested on T and monocyte populations from healthy donors and pulmonary TB (PTB) patients. Flow cytometry analysis revealed significant T cell activation in peripheral blood mononuclear cells (PBMC) from both groups. Enzyme-linked immunosorbent assay (ELISA) demonstrated a strong IFN-γ response, confirming effective T cell activation. Additionally, these peptides induced increased nitric oxide (NO) production in macrophages, indicating their role in activating the innate immune system. Overall, Rv2588c and Rv0148 peptides exhibited robust immunogenicity, stimulating both adaptive and innate immune responses in PBMCs from healthy and PTB individuals. These findings highlight their potential as promising TB vaccine candidates, paving the way for improved TB treatment and prevention strategies.

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引用次数: 0

Response to “Prevalence of non-tuberculous mycobacteria by Line-Probe Assay”

IF 2.8 3区医学 Q3 IMMUNOLOGY

Tuberculosis

Pub Date : 2025-04-02 DOI: 10.1016/j.tube.2025.102637

Elizna Maasdorp , Monique J. Williams

引用次数: 0

The anti-mycobacterial potential of ibuprofen

IF 2.8 3区医学 Q3 IMMUNOLOGY

Tuberculosis

Pub Date : 2025-04-01 DOI: 10.1016/j.tube.2025.102638

Pir Tariq Shah , Li Xing

Background

Ibuprofen (IBU) is a non-prescription analgesic drug from the non-steroidal anti-inflammatory drug class. It is widely used for treating pain, fever, and inflammation. Both the in silico and in vitro experiments were performed to determine the antibacterial potentials of the IBU against Mycobacterium tuberculosis (Mtb).

Methods

The STITCH v.5 pipeline was used to analyze the interaction of IBU with the proteome of the Mtb H37Ra and H37Rv strains. The GFP-tagged Bacillus Calmette Guerin (BCG) and td-tomato-tagged Mtb H37Ra were used to determine the bacteriostatic and bactericidal activities of IBU. The IBU-treated THP-1-derived macrophages were infected by td-tomato-tagged Mtb H37Ra and wild-type BCG to analyze the effects of IBU on bacterial phagocytosis and apoptosis, respectively.

Results

The in-silico study revealed that the IBU interacts with Mtb proteins primarily involved in cellular process, metabolism, and virulence, and targets four virulent proteins of Mtb, e.g., Cyp-123, Cyp-126, Cyp-130, and Cyp-139 in the cytochrome p450 system. The increasing concentrations of IBU showed significant bacteriostatic activity against Mtb H37Ra in vitro, where the 100 μg/ml and 200 μg/ml concentrations especially led to almost complete bacterial growth arrest. The IBU treatment does not affect BCG-induced apoptosis of THP-1-derived macrophages, but significantly enhances bacterial uptake, especially at 100 μg/ml and 200 μg/ml concentrations.

Conclusions

The IBU enhances Mtb uptake by macrophages and exhibits direct bacteriostatic activity in vitro.

背景布洛芬（IBU）是一种非处方镇痛药，属于非甾体抗炎药类。它被广泛用于治疗疼痛、发烧和炎症。为了确定 IBU 对结核分枝杆菌（Mtb）的抗菌潜力，我们进行了硅学和体外实验。方法使用 STITCH v.5 管道分析 IBU 与 Mtb H37Ra 和 H37Rv 菌株蛋白质组的相互作用。用GFP标记的卡介苗（Bacillus Calmette Guerin，BCG）和td-tomato标记的Mtb H37Ra来测定IBU的抑菌和杀菌活性。IBU处理的THP-1衍生巨噬细胞分别被td-番茄标记的Mtb H37Ra和野生型卡介苗感染，以分析IBU对细菌吞噬和细胞凋亡的影响、细胞色素 p450 系统中的 Cyp-123、Cyp-126、Cyp-130 和 Cyp-139 。在体外，浓度不断增加的 IBU 对 Mtb H37Ra 有明显的抑菌作用，尤其是 100 μg/ml 和 200 μg/ml 浓度的 IBU 几乎完全抑制了细菌的生长。IBU 处理不会影响卡介苗诱导的 THP-1 巨噬细胞的凋亡，但会显著增强细菌的吸收，尤其是在 100 μg/ml 和 200 μg/ml 的浓度下。

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引用次数: 0

Construction and expression of multi-stage antigen fusion protein RPC4 vaccine for Mycobacterium tuberculosis and its immunogenicity analysis in combination with adjuvant DIMQ

IF 2.8 3区医学 Q3 IMMUNOLOGY

Tuberculosis

Pub Date : 2025-03-26 DOI: 10.1016/j.tube.2025.102635

Xiaochun Wang , Yun Xu , Qiangsen Zhong , Zian Zhang , LingYun Kong , Mingming Zhou , Runlin Wang , Xinxin Pi , Suwen Qiao

Mycobacterium tuberculosis (M. tb) serves as the main pathogen responsible for Tuberculosis (TB). It predominantly targets the lungs and leads to a persistent infectious disease. The spread of drug-resistant tuberculosis and the exacerbation of economic burdens due to co-infections with Human Immunodeficiency Virus (HIV)/M. tb pose significant challenges in prevention and treatment. The BCG vaccine is currently the only approved (TB) vaccine, but its protective effect is limited for adults. In this research, we engineered the fusion protein gene RPC4, incorporating four crucial antigens from M. tb. The study revealed that the IFN-γ levels in the peripheral blood of infected patients significantly surpassed those in healthy individuals. To assess the immune response of RPC4 as a BCG-enhanced vaccine following initial immunity, researchers administered it alongside the novel adjuvant DIMQ to immunize mice. Experiments revealed that the BCG + RPC4/DIMQ vaccine induces a substantial immunogenic response in the mice.

{"title":"Construction and expression of multi-stage antigen fusion protein RPC4 vaccine for Mycobacterium tuberculosis and its immunogenicity analysis in combination with adjuvant DIMQ","authors":"Xiaochun Wang , Yun Xu , Qiangsen Zhong , Zian Zhang , LingYun Kong , Mingming Zhou , Runlin Wang , Xinxin Pi , Suwen Qiao","doi":"10.1016/j.tube.2025.102635","DOIUrl":"10.1016/j.tube.2025.102635","url":null,"abstract":"<div><div><em>Mycobacterium tuberculosis</em> (<em>M. tb</em>) serves as the main pathogen responsible for Tuberculosis (TB). It predominantly targets the lungs and leads to a persistent infectious disease. The spread of drug-resistant tuberculosis and the exacerbation of economic burdens due to co-infections with Human Immunodeficiency Virus (HIV)/<em>M. tb</em> pose significant challenges in prevention and treatment. The BCG vaccine is currently the only approved (TB) vaccine, but its protective effect is limited for adults. In this research, we engineered the fusion protein gene RPC4, incorporating four crucial antigens from <em>M. tb</em>. The study revealed that the IFN-γ levels in the peripheral blood of infected patients significantly surpassed those in healthy individuals. To assess the immune response of RPC4 as a BCG-enhanced vaccine following initial immunity, researchers administered it alongside the novel adjuvant DIMQ to immunize mice. Experiments revealed that the BCG + RPC4/DIMQ vaccine induces a substantial immunogenic response in the mice.</div></div>","PeriodicalId":23383,"journal":{"name":"Tuberculosis","volume":"152 ","pages":"Article 102635"},"PeriodicalIF":2.8,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143738964","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}

引用次数: 0

Prevalence of non-tuberculous mycobacteria estimated by line-probe assay

IF 2.8 3区医学 Q3 IMMUNOLOGY

Tuberculosis

Pub Date : 2025-03-26 DOI: 10.1016/j.tube.2025.102636

Sarman Singh

引用次数: 0

IgG antibody response to Mycobacterium tuberculosis curli pili (MTP) in people from different geographical regions in Sub-Saharan Africa

IF 2.8 3区医学 Q3 IMMUNOLOGY

Tuberculosis

Pub Date : 2025-03-20 DOI: 10.1016/j.tube.2025.102634

Koobashnee Pillay , Theresa Coetzer , Catherine Connolly , Balakrishna Pillay , Thamsanqa Chiliza , Kogieleum Naidoo , Jayne Sutherland , Thumbi Ndung'u , Harriet Mayanja-Kizza , Manormoney Pillay

Previously, a slot blot or an indirect enzyme-linked immunosorbent assay (ELISA) using a synthetic or purified MTP antigen, conceptually demonstrated IgG antibody induction in pulmonary TB patients, albeit with small sample sizes and differing sensitivity. Therefore, we evaluated an IgG MTP ELISA in larger populations from The Gambia (n = 549), Uganda (n = 161), and South Africa (n = 193), comprising human immunodeficiency virus (HIV) positive and negative, with microbiologically confirmed active TB. The association between the IgG level and demographic characteristics was determined by multivariate logistic regression. The sensitivity (44.8–61.2 %) and specificity (33.4–78.5 %) varied in the three cohorts. Anti-MTP antibody titres differed between the TB positive and negative groups within the South African and The Gambian cohorts (p < 0.001), but not in Uganda (p = 0.35). Antibodies were detected in HIV positive and negative patients and were reduced at 6-month follow-up after treatment (p > 0.067). The study verified previous findings that anti-MTP antibodies, and therefore MTP antigen, are produced during active TB. However, the accuracy of the MTP-IgG ELISA was low, and is therefore not suitable as a target product profile in the high burden TB areas investigated. Further studies are needed to clarify the variable reactivities in different geographical areas.

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引用次数: 0

High centrifugation speed improves recovery of M. tuberculosis and yield of culture

IF 2.8 3区医学 Q3 IMMUNOLOGY

Tuberculosis

Pub Date : 2025-03-15 DOI: 10.1016/j.tube.2025.102633

Godlove T. Chaula , Lucy Namkinga , Ally Mahadhy , Wilber Sabiiti , Nyanda Elias Ntinginya , Bariki Mtafya

Background

We assessed the impact of centrifugation on recovery of Mycobacterium tuberculosis (M.tb).

Methods

We used 0.5 McFarland from the 2 weeks M. tb, H37Rv culture and homogenized sputum for our experiments. Samples were decontaminated by 2 % NaOH for 20 min and with PBS for controls. Decontaminated aliquots were centrifuged at 2000×g, 3000×g and 6000×g for 40 min and inoculated on MGIT and LJ media. MGITs were incubated into the BACTEC MGIT 960 Systems following BD manuals and data analyzed on GraphPad Software.

Results

The positivity (days) for M. tb, H37Rv in MGIT and LJ decreased from 20.4 to 17.7 and from 47.6 to 26.6 at 2000×g and 6000×g, respectively; P > 0.05. For controls, MGIT and LJ positivity (days) decreased from 19 to 10 and from 39.2 to 11.2 at 2000×g and 6000×g, respectively; P > 0.05. MGIT positivity was 6(60 %) at 2000×g and 8(80 %) at 6000×g, corresponding to mean (±SD) of 13.7 ± 6.7 and 9.06 ± 4.6 days, respectively for sputum. LJ positivity was 1(10 %) at 2000×g and 7(70 %) at 6000×g. MGIT contamination for controls (sputum) was over 50 % and 80 % for LJ.

Conclusion

Higher centrifugation speed improves yield and sensitivity of TB culture.

{"title":"High centrifugation speed improves recovery of M. tuberculosis and yield of culture","authors":"Godlove T. Chaula , Lucy Namkinga , Ally Mahadhy , Wilber Sabiiti , Nyanda Elias Ntinginya , Bariki Mtafya","doi":"10.1016/j.tube.2025.102633","DOIUrl":"10.1016/j.tube.2025.102633","url":null,"abstract":"<div><h3>Background</h3><div>We assessed the impact of centrifugation on recovery of <em>Mycobacterium tuberculosis</em> (<em>M.tb</em>).</div></div><div><h3>Methods</h3><div>We used 0.5 McFarland from the 2 weeks <em>M. tb,</em> H37Rv culture and homogenized sputum for our experiments. Samples were decontaminated by 2 % NaOH for 20 min and with PBS for controls. Decontaminated aliquots were centrifuged at 2000×<em>g</em>, 3000×<em>g</em> and 6000×<em>g</em> for 40 min and inoculated on MGIT and LJ media. MGITs were incubated into the BACTEC MGIT 960 Systems following BD manuals and data analyzed on GraphPad Software.</div></div><div><h3>Results</h3><div>The positivity (days) for <em>M. tb</em>, <em>H37Rv</em> in MGIT and LJ decreased from 20.4 to 17.7 and from 47.6 to 26.6 at 2000×<em>g</em> and 6000×<em>g</em>, respectively; P > 0.05. For controls, MGIT and LJ positivity (days) decreased from 19 to 10 and from 39.2 to 11.2 at 2000×<em>g</em> and 6000×<em>g</em>, respectively; P > 0.05. MGIT positivity was 6(60 %) at 2000×<em>g</em> and 8(80 %) at 6000×<em>g</em>, corresponding to mean (±SD) of 13.7 ± 6.7 and 9.06 ± 4.6 days, respectively for sputum. LJ positivity was 1(10 %) at 2000×<em>g</em> and 7(70 %) at 6000×<em>g</em>. MGIT contamination for controls (sputum) was over 50 % and 80 % for LJ.</div></div><div><h3>Conclusion</h3><div>Higher centrifugation speed improves yield and sensitivity of TB culture.</div></div>","PeriodicalId":23383,"journal":{"name":"Tuberculosis","volume":"152 ","pages":"Article 102633"},"PeriodicalIF":2.8,"publicationDate":"2025-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143706412","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}

引用次数: 0

Functional analysis of genetic mutations in ddn and fbiA linked to delamanid resistance in rifampicin-resistant Mycobacterium tuberculosis

IF 2.8 3区医学 Q3 IMMUNOLOGY

Tuberculosis

Pub Date : 2025-03-14 DOI: 10.1016/j.tube.2025.102630

Seungmo Kim , Seung Heon Lee , Gisu Kang , Gyeong In Lee , Hyeon-Su Kim , Jeong Seong Yang , Youngsuk Park , Byoung Oh Hwang , Hyejin Kim

The connection between genetic mutations linked to delamanid resistance and phenotypic resistance remains unclear. We assessed the phenotypic effects of delamanid-resistant mutations in the Mycobacterium tuberculosis H37Rv strain through gene disruption using homologous recombination and complementation tests. Delamanid resistance was assessed by determining the minimum inhibitory concentration (MIC) via the 7H9 microdilution method. Sanger sequencing identified mutations, and conservation of the mutated residues was predicted through multiple sequence alignments of orthologs. A total of 116 isolates with MIC ≥0.025 μg/mL were analyzed, among which mutations were identified in the ddn and fbiA genes. Isogenic strains were generated based on these mutations. The ddn or fbiA isogenic strains with Ala77Val, Gly81Ser, Asn25fs, and Leu104Phe in fbiA had MICs ≥0.8 μg/mL, indicating resistance. In contrast, the ddn isogenic strain with Pro12Ala had an MIC of 0.012 μg/mL, showing susceptibility, while Gly96Asp in fbiA had an MIC of 0.1 μg/mL, indicating resistance. All mutations, except for Pro12Ala, were conserved in the protein sequences of both FbiA and Ddn and their mycobacterial orthologs. The characterization of these mutations provides insights into the mechanisms of delamanid resistance, which may inform the development of optimized treatment strategies.

{"title":"Functional analysis of genetic mutations in ddn and fbiA linked to delamanid resistance in rifampicin-resistant Mycobacterium tuberculosis","authors":"Seungmo Kim , Seung Heon Lee , Gisu Kang , Gyeong In Lee , Hyeon-Su Kim , Jeong Seong Yang , Youngsuk Park , Byoung Oh Hwang , Hyejin Kim","doi":"10.1016/j.tube.2025.102630","DOIUrl":"10.1016/j.tube.2025.102630","url":null,"abstract":"<div><div>The connection between genetic mutations linked to delamanid resistance and phenotypic resistance remains unclear. We assessed the phenotypic effects of delamanid-resistant mutations in the <em>Mycobacterium tuberculosis</em> H37Rv strain through gene disruption using homologous recombination and complementation tests. Delamanid resistance was assessed by determining the minimum inhibitory concentration (MIC) via the 7H9 microdilution method. Sanger sequencing identified mutations, and conservation of the mutated residues was predicted through multiple sequence alignments of orthologs. A total of 116 isolates with MIC ≥0.025 μg/mL were analyzed, among which mutations were identified in the <em>ddn</em> and <em>fbiA</em> genes. Isogenic strains were generated based on these mutations. The <em>ddn</em> or <em>fbiA</em> isogenic strains with Ala77Val, Gly81Ser, Asn25fs, and Leu104Phe in <em>fbiA</em> had MICs ≥0.8 μg/mL, indicating resistance. In contrast, the <em>ddn</em> isogenic strain with Pro12Ala had an MIC of 0.012 μg/mL, showing susceptibility, while Gly96Asp in <em>fbiA</em> had an MIC of 0.1 μg/mL, indicating resistance. All mutations, except for Pro12Ala, were conserved in the protein sequences of both FbiA and Ddn and their mycobacterial orthologs. The characterization of these mutations provides insights into the mechanisms of delamanid resistance, which may inform the development of optimized treatment strategies.</div></div>","PeriodicalId":23383,"journal":{"name":"Tuberculosis","volume":"152 ","pages":"Article 102630"},"PeriodicalIF":2.8,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143680656","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}

引用次数: 0

Chasing the “White Plague” in the Barbaricum of the Carpathian Basin – A case with tuberculous meningitis discovered in a Sarmatian-period (2nd–3rd-century-CE) storage pit from the archaeological site of Kiskundorozsma–Daruhalom-dűlő II (Hungary)

IF 2.8 3区医学 Q3 IMMUNOLOGY

Tuberculosis

Pub Date : 2025-03-12 DOI: 10.1016/j.tube.2025.102632

Ágota Madai , Marcos De Andrés Montero , Luca Kis , Csaba Szalontai , Anna Szigeti , István Major , Attila Kiss P. , Olga Spekker

The aim of our paper is to demonstrate a case (KD429) with tuberculous meningitis (TBM) from the 2nd–3rd‒century‒CE Carpathian Basin. The skeleton of KD429 was subject to a detailed macromorphological evaluation, focusing on the detection of pathological lesions likely related to tuberculosis (TB). It was the presence of endocranial alterations, especially the TB-specific granular impressions, based on which the diagnosis of TBM was established in KD429. Besides KD429, only eight cases with TB have been published from the Sarmatian-period (1st–5th centuries CE) Carpathian Basin. Reports of archaeological cases with TB, like KD429, can provide invaluable information about the spatio-temporal distribution of the disease in the past. Nonetheless, to get a more accurate picture about the burden that TB may have put on the Sarmatians, the systematic macromorphological (re-)evaluation of their osteoarchaeological series would be advantageous. Interestingly, the skeleton of KD429 was unearthed from not a grave-pit but a storage pit from the archaeological site of Kiskundorozsma–Daruhalom-dűlő II (Hungary). At the current state of research, the motive behind the exclusion of KD429 from the “normal” burial custom cannot be determined; therefore, it remains an open question whether their disease (TBM) played a role in it or not.

{"title":"Chasing the “White Plague” in the Barbaricum of the Carpathian Basin – A case with tuberculous meningitis discovered in a Sarmatian-period (2nd–3rd-century-CE) storage pit from the archaeological site of Kiskundorozsma–Daruhalom-dűlő II (Hungary)","authors":"Ágota Madai , Marcos De Andrés Montero , Luca Kis , Csaba Szalontai , Anna Szigeti , István Major , Attila Kiss P. , Olga Spekker","doi":"10.1016/j.tube.2025.102632","DOIUrl":"10.1016/j.tube.2025.102632","url":null,"abstract":"<div><div>The aim of our paper is to demonstrate a case (<strong>KD429</strong>) with tuberculous meningitis (TBM) from the 2nd–3rd‒century‒CE Carpathian Basin. The skeleton of <strong>KD429</strong> was subject to a detailed macromorphological evaluation, focusing on the detection of pathological lesions likely related to tuberculosis (TB). It was the presence of endocranial alterations, especially the TB-specific granular impressions, based on which the diagnosis of TBM was established in <strong>KD429</strong>. Besides <strong>KD429</strong>, only eight cases with TB have been published from the Sarmatian-period (1st–5th centuries CE) Carpathian Basin. Reports of archaeological cases with TB, like <strong>KD429</strong>, can provide invaluable information about the spatio-temporal distribution of the disease in the past. Nonetheless, to get a more accurate picture about the burden that TB may have put on the Sarmatians, the systematic macromorphological (re-)evaluation of their osteoarchaeological series would be advantageous. Interestingly, the skeleton of <strong>KD429</strong> was unearthed from not a grave-pit but a storage pit from the archaeological site of Kiskundorozsma–Daruhalom-dűlő II (Hungary). At the current state of research, the motive behind the exclusion of <strong>KD429</strong> from the “normal” burial custom cannot be determined; therefore, it remains an open question whether their disease (TBM) played a role in it or not.</div></div>","PeriodicalId":23383,"journal":{"name":"Tuberculosis","volume":"152 ","pages":"Article 102632"},"PeriodicalIF":2.8,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143628521","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}

引用次数: 0

Dry powder Inhalation of lytic mycobacteriophages for adjunct therapy in a mouse model of infection with Mycobacterium tuberculosis

IF 2.8 3区医学 Q3 IMMUNOLOGY

Tuberculosis

Pub Date : 2025-03-11 DOI: 10.1016/j.tube.2025.102631

Sunil K. Raman , Trisha Roy , Khushboo Verma , Chunna Yadav , Sonia Verma , Venkata Siva Reddy Deivreddy , Hasham Shafi Sofi , Reena Bharti , Rahul Sharma , Himanshu Bansode , Akhilesh Kumar , Rakesh Kumar Sharma , Jyotsna Singh , Madhav N. Mugale , Urmi Bajpai , Vikas Jain , Amit Kumar Singh , Amit Misra

Inhaled therapy of tuberculosis (TB) by a Dry Powder Inhalation (DPI) comprising mycobacteriophage D29 and TM4 was non-inferior to oral anti-tuberculosis therapy (ATT) with isoniazid and rifampicin in a mouse model of infection with Mycobacterium tuberculosis (Mtb). No pharmaceutical phage product of mycobacteriophages is approved for large-scale production. We scaled up preparation and downstream processing of phages, developed DPI formulations, and established methods for determining identity, purity, assay, stability, and critical quality attributes (CQA). We carried out cell-based assays of intracellular bactericidal activity and pharmacokinetics and comparative efficacy in Mtb-infected mice. Daily doses of the DPI containing ∼10¹⁰ Plaque Forming Units/dose DPI reduced Mtb colony forming units (CFU) in the lungs from 6.4 ± 0.3-log to 4.8 ± 0.7-log in four weeks, while oral human equivalent doses (HED) of isoniazid and rifampicin reduced CFU to 3.8 ± 0.8-log. Combining inhaled phages with oral drugs sterilized the lungs of one of four mice and reduced group mean CFU to 2.3-log. Inhalations significantly upregulated tumor necrosis factor (TNF) in lung tissue to ∼1500 pg/ml of homogenate, improved organ morphology, and reduced histopathology. The HD DPI may be a useful adjunct to oral drugs. Dose-finding animal efficacy studies are required before assessing preclinical safety.

{"title":"Dry powder Inhalation of lytic mycobacteriophages for adjunct therapy in a mouse model of infection with Mycobacterium tuberculosis","authors":"Sunil K. Raman , Trisha Roy , Khushboo Verma , Chunna Yadav , Sonia Verma , Venkata Siva Reddy Deivreddy , Hasham Shafi Sofi , Reena Bharti , Rahul Sharma , Himanshu Bansode , Akhilesh Kumar , Rakesh Kumar Sharma , Jyotsna Singh , Madhav N. Mugale , Urmi Bajpai , Vikas Jain , Amit Kumar Singh , Amit Misra","doi":"10.1016/j.tube.2025.102631","DOIUrl":"10.1016/j.tube.2025.102631","url":null,"abstract":"<div><div>Inhaled therapy of tuberculosis (TB) by a Dry Powder Inhalation (DPI) comprising mycobacteriophage D29 and TM4 was non-inferior to oral anti-tuberculosis therapy (ATT) with isoniazid and rifampicin in a mouse model of infection with <em>Mycobacterium tuberculosis</em> (Mtb). No pharmaceutical phage product of mycobacteriophages is approved for large-scale production. We scaled up preparation and downstream processing of phages, developed DPI formulations, and established methods for determining identity, purity, assay, stability, and critical quality attributes (CQA). We carried out cell-based assays of intracellular bactericidal activity and pharmacokinetics and comparative efficacy in Mtb-infected mice. Daily doses of the DPI containing ∼10<sup>10</sup> Plaque Forming Units/dose DPI reduced Mtb colony forming units (CFU) in the lungs from 6.4 ± 0.3-log to 4.8 ± 0.7-log in four weeks, while oral human equivalent doses (HED) of isoniazid and rifampicin reduced CFU to 3.8 ± 0.8-log. Combining inhaled phages with oral drugs sterilized the lungs of one of four mice and reduced group mean CFU to 2.3-log. Inhalations significantly upregulated tumor necrosis factor (TNF) in lung tissue to ∼1500 pg/ml of homogenate, improved organ morphology, and reduced histopathology. The HD DPI may be a useful adjunct to oral drugs. Dose-finding animal efficacy studies are required before assessing preclinical safety.</div></div>","PeriodicalId":23383,"journal":{"name":"Tuberculosis","volume":"152 ","pages":"Article 102631"},"PeriodicalIF":2.8,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143628522","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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