Search Results (3,943)

Background: Novel vaccines targeting the world’s deadliest pathogen Mycobacterium tuberculosis (Mtb) are urgently needed as the efficacy of the Bacillus Calmette–Guérin (BCG) vaccine in its current use is limited. HLA-E is a virtually monomorphic unconventional antigen presentation molecule, and HLA-E-restricted Mtb-specific CD8⁺ T cells can control intracellular Mtb growth, making HLA-E a promising vaccine target for Mtb. Methods: In this study, we evaluated the frequency and phenotype of HLA-E-restricted Mtb-specific CD4⁺/CD8⁺ T cells in the circulation and bronchoalveolar lavage fluid of two independent non-human primate (NHP) studies and from humans receiving BCG either intradermally or mucosally. Results: BCG vaccination followed by Mtb challenge in NHPs did not affect the frequency of circulating and local HLA-E–Mtb CD4⁺ and CD8⁺ T cells, and we saw the same in humans receiving BCG. HLA-E–Mtb T cell frequencies were significantly increased after Mtb challenge in unvaccinated NHPs, which was correlated with higher TB pathology. Conclusions: Together, HLA-E–Mtb-restricted T cells are minimally induced by BCG in humans and rhesus macaques (RMs) but can be elicited after Mtb infection in unvaccinated RMs. These results give new insights into targeting HLA-E as a potential immune mechanism against TB. Full article

Background/Objectives: Mycobacterium tuberculosis (M. tb) is a pathogen that causes tuberculosis (TB), an extremely infectious disease which is responsible for millions of deaths worldwide. The severity of this pathogen is further amplified with the emergence of multidrug-resistant strains that are becoming more prevalent at an alarming rate, and novel treatments are needed. Methods: In this paper, we discuss the pathology M. tb infection. We review the literature on the role that mTOR plays in autophagy and the immune system as well as its impact on M. tb infection. Lastly, we discuss the current therapies targeting mTOR and potential routes to explore for future treatments. Results: The mTOR protein acts as a negative regulator of the autophagy pathway and presents as a potent target to establish new treatments for TB. M. tb survival is affected by mTOR, the PI3K/mTOR/AKT pathway, and autophagy. M. tb evades destruction by manipulating host cellular mechanisms, which increases resistance and complicates treatment. Conclusions: Targeting mTOR can enhance autophagy and increase M. tb clearance. Existing drugs such as everolimus, rapamycin + CC214-2, and bazedoxifene are all being currently studied for effectiveness and show positive results. Alternative therapies, including Chinese herbs, baicalin, BTLA, glutathione, and precision medicine can modulate the PI3K/mTOR/AKT pathway and the host’s immune response, resulting in increased M. tb clearance, and these may be the future treatments for M. tb infection. Full article

Despite the achievements of modern medicine, tuberculosis remains one of the leading causes of mortality globally. The difficulties in differential diagnosis have particular relevance in the case of suspicion of tuberculosis with other granulomatous diseases. The most similar clinical and radiologic changes are sarcoidosis. The aim of this study is to apply mathematical modeling to determine diagnostically significant immunological parameters and an algorithm for the differential diagnosis of tuberculosis and sarcoidosis. Materials and methods: The serum samples of patients with sarcoidosis (SD) (n = 29), patients with pulmonary tuberculosis (TB) (n = 32) and the control group (n = 31) (healthy subjects) collected from 2017 to 2022 (the average age 43.4 ± 5.3 years) were examined. Circulating ‘polarized’ T-helper cell subsets were analyzed by multicolor flow cytometry. A symbolic regression method was used to find general mathematical relations between cell concentrations and diagnosis. The parameters of the selected model were finally fitted through multi-objective optimization applied to two conflicting indices: sensitivity to sarcoidosis and sensitivity to tuberculosis. Results: The difference in Bm2 and CD5−CD27− concentrations was found to be more significant for the differential diagnosis of sarcoidosis and tuberculosis than any individual concentrations: the combined feature Bm2 − [CD5−CD27−] differentiates sarcoidosis and tuberculosis with p < 0.00001 and AUC = 0.823. An algorithm for differential diagnosis was developed. It is based on the linear model with two variables: the first variable is the difference Bm2 − [CD5−CD27−] mentioned above, and the second is the naïve-Tregs concentration. The algorithm uses the model twice and returns “dubious” in 26.7% of cases for patients with sarcoidosis and in 16.1% of cases for patients with tuberculosis. For the remaining patients with one of these two diagnoses, its sensitivity to sarcoidosis is 90.5%, and its sensitivity to tuberculosis is 88.5%. Conclusions: A simple algorithm was developed that can distinguish, by certain immunological features, the cases in which sarcoidosis is likely to be present instead of tuberculosis. Such cases may be further investigated to rule out tuberculosis conclusively. The mathematical model underlying the algorithm is based on the analysis of “naive” T-regulatory cells and “naive” B-cells. This may be a promising approach for differential diagnosis between pulmonary sarcoidosis and pulmonary tuberculosis. The findings may be useful in the absence of clear differential diagnostic criteria between pulmonary tuberculosis and sarcoidosis. Full article

Lung disease is one of the leading causes of death worldwide. This emphasizes the need for early diagnosis in order to provide appropriate treatment and save lives. Physicians typically require information about patients’ clinical symptoms, various laboratory and pathology tests, along with chest X-rays to confirm the diagnosis of lung disease. In this study, we present a transformer-based multimodal deep learning approach that incorporates imaging and clinical data for effective lung disease diagnosis on a new multimodal medical dataset. The proposed method employs a cross-attention transformer module to merge features from the heterogeneous modalities. Then unified fused features are used for disease classification. The experiments were performed and evaluated on several classification metrics to illustrate the performance of the proposed approach. The study’s results revealed that the proposed method achieved an accuracy of 95% in terms of accurate classification of tuberculosis and outperformed other traditional fusion methods on multimodal tuberculosis data used in this study. Full article

Appropriate animal models of human diseases are a cornerstone in the advancement of science and medicine. To create animal models of neuropsychiatric and neurobehavioral diseases such as autism spectrum disorder (ASD) necessitates the development of sufficient neurobehavioral measuring tools to translate human behavior to expected measurable behavioral features in animals. If possible, the severity of the symptoms should also be assessed. Indeed, at least in rodents, adequate neurobehavioral and neurological tests have been developed. Since ASD is characterized by a number of specific behavioral trends with significant severity, animal models of autistic-like behavior have to demonstrate the specific characteristic features, namely impaired social interactions, communication deficits, and restricted, repetitive behavioral patterns, with association to several additional impairments such as somatosensory, motor, and memory impairments. Thus, an appropriate model must show behavioral impairment of a minimal number of neurobehavioral characteristics using an adequate number of behavioral tests. The proper animal models enable the study of ASD-like-behavior from the etiologic, pathogenetic, and therapeutic aspects. From the etiologic aspects, models have been developed by the use of immunogenic substances like polyinosinic-polycytidylic acid (PolyIC), lipopolysaccharide (LPS), and propionic acid, or other well-documented immunogens or pathogens, like Mycobacterium tuberculosis. Another approach is the use of chemicals like valproic acid, polychlorinated biphenyls (PCBs), organophosphate pesticides like chlorpyrifos (CPF), and others. These substances were administered either prenatally, generally after the period of major organogenesis, or, especially in rodents, during early postnatal life. In addition, using modern genetic manipulation methods, genetic models have been created of almost all human genetic diseases that are manifested by autistic-like behavior (i.e., fragile X, Rett syndrome, SHANK gene mutation, neuroligin genes, and others). Ideally, we should not only evaluate the different behavioral modes affected by the ASD-like behavior, but also assess the severity of the behavioral deviations by an appropriate scoring system, as applied to humans. We therefore propose a scoring system for improved assessment of ASD-like behavior in animal models. Full article

Mycobacterial infections caused by tuberculous and non-tuberculous strains pose significant treatment challenges, especially among immunocompromised patients. Conventional antibiotic therapies often fail due to bacterial resistance, highlighting the need for alternative therapeutic strategies. Mycobacteriophages are emerging as promising candidates for the treatment of mycobacteria. This review comprehensively explores phage isolation, characterization, and clinical applications. Despite the need for more extensive in vitro and in vivo studies, existing evidence shows their efficacy against both sensitive and antibiotic-resistant mycobacterial strains, even under disease-mimicking conditions, particularly when used in cocktails to minimize resistance development. Mycobacteriophages can be engineered and evolved to overcome limitations associated with lysogeny and narrow host range. Furthermore, they exhibit activity in ex vivo and in vivo infection models, successfully targeting mycobacteria residing within macrophages. Delivery methods such as bacterial and liposomal vectors facilitate their entry into human cells. Considering the potential for phage-treatment-induced bacterial resistance, as described in this review, the combination of mycobacteriophages with antibiotics shows efficacy in countering mycobacterial growth, both in the laboratory setting and in animal models. Interestingly, phage-encoded products can potentiate the activity of relevant antibiotics. Finally, the application of phages in different compassionate cases is reported. The positive outcomes indicate that phage therapy represents a promising solution for the treatment of antibiotic-resistant mycobacteria. Full article

We investigated the rise of nontuberculous mycobacteria (NTM) infections in Bulgaria, focusing on species identification and distribution from 2018 to 2022. Utilizing advanced diagnostic tools, including the Hain Mycobacterium CM/AS method, Myco-biochip assay, and whole-genome sequencing, the study identifies and characterizes a diverse range of Mycobacterium species from clinical samples. While M. avium, M. gordonae, M. fortuitum, and M. chelonae were dominating, a number of rare species were also found. They include such species as M. marseillense and M. celatum. Moreover, the noticeable prevalence of M. terrae complex species missed by conventional testing was observed. We identified a rare species, highly homologous to previously described strains from Japan; based on genome–genome distance data, we propose its reannotation as a new species. Further, a novel species was identified, which is significantly distinct from its closest neighbor, M. iranicum, with ANI = 87.18%. Based on the SeqCode procedure, we propose to name this new species Mycobacterium bulgaricum sp. nov. Dynamic changes in NTM species prevalence in Bulgaria observed from 2011 to 2022 highlight the emergence of new species and variations tied to environmental and demographic factors. This underscores the importance of accurate species identification and genotyping for understanding NTM epidemiology, informing public health strategies, and enhancing diagnostic accuracy and treatment protocols. Full article

In Zimbabwe, artisanal and small-scale miners (ASMs) are a key vulnerable group with high risk for tuberculosis (TB), HIV, and silicosis. The main purpose of this study was to investigate treatment outcomes of TB among ASMs. We conducted a follow-up observational study using secondary data. We analyzed data from 208 ASMs treated for TB at two occupational health clinics. We found a high treatment success rate of 87%, comparable to the national average for drug-sensitive TB. Unsuccessful outcomes were due to death (5%) and loss to follow-up (7%). Over a quarter of ASMs had unknown HIV status. Our study is the first to document treatment outcomes of TB among ASMs in Zimbabwe. Encouragingly, this study demonstrates the possibility of achieving good TB treatment outcomes even among highly mobile populations like ASMs. Further research is needed to analyze leakages across the whole TB patient pathway among ASMs. Additionally, addressing the high rate of unknown HIV statuses among ASMs is crucial to further improve overall TB treatment outcomes in this population. Full article

The management of resistant tuberculosis (tb) can be extremely difficult, especially in case of novel unpredicted complications. In this report, we present a case of a 48-year-old patient with pre-extensively drug-resistant (XDR) tb who received a treatment regimen including pretomanid, bedaquiline, linezolid, cycloserine, and amikacin and died due to myocarditis. Acquired resistance to first- and second-line drugs developed due to previous poor adherence to medication. The clinical presentation of the patient, along with her initial ultrasonographical, electrocardiogram (ECG), and laboratory examinations, were typical for acute myocarditis; however, the patient was considered unstable, and further investigations, including magnetic resonance imaging (MRI), pericardiocentesis, and endomyocardial biopsy were not performed. To our knowledge, this is the first case of myocarditis in such a patient, the clinical features of which raised a high suspicion of drug induction that could be attributed to the treatment regimen that was administered. Clinicians who manage cases of drug-resistant tb should be aware of this newly reported, potentially lethal, adverse event. Full article

Despite the existing effective treatment methods, tuberculosis (TB) is the second most deadly infectious disease, its carriers in the latent and active phases accounting for more than 20% of the world population. An effective method for controlling TB and reducing TB mortality is regular population screening aimed at diagnosing the latent form of TB and taking preventive and curative measures. Numerous methods allow diagnosing TB by directly detecting Mycobacterium tuberculosis (M.tb) biomarkers, including M.tb DNA, proteins, and specific metabolites or antibodies produced by the host immune system in response to M.tb. PCR, ELISA, immunofluorescence and immunochemical analyses, flow cytometry, and other methods allow the detection of M.tb biomarkers or the host immune response to M.tb by recording the optical signal from fluorescent or colorimetric dyes that are components of the diagnostic systems. Current research in biosensors is aimed at increasing the sensitivity of detection, a promising approach being the use of fluorescent quantum dots as brighter and more photostable optical tags. Here, we review current methods for the detection of M.tb biomarkers using quantum dot-based nanosensors and summarize data on the M.tb biomarkers whose detection can be made considerably more sensitive by using these sensors. Full article

Interferon-gamma release assays (IGRAs) have gained attention for the diagnosis of latent tuberculosis infection (LTBI) due to their higher specificity compared to the tuberculin skin test (TST). However, the IGRA’s performance varies across different populations. This study evaluated the diagnostic performance of three IGRAs (TBF-FIA, TBF-ELISA, and QFT-Plus) in Ghana, comparing them among individuals exposed and unexposed to MTB infection. Conducted in TB clinics across three regions, this prospective and cross-sectional study included healthy individuals with no known TB exposure (unexposed group) and patients with confirmed active TB (exposed group). Blood samples were tested using all three assays as per the manufacturers’ guidelines. The TBF-ELISA showed 3.4% higher sensitivity but 4.6% lower specificity compared to QFT-Plus. The TBF-FIA had sensitivity of 78.5–87.3% and specificity of 82.9–90.0%. These findings indicate that while the three IGRAs offer similar diagnostic accuracy, the variations in specificity and limited data on assays like TBF-FIA require further investigation. Full article

A focussed library of pyridyl and 2-hydroxyphenyl chalcones were synthesized and tested for growth inhibitory activity against Mycobacterium tuberculosis H37Rv, and normal and cancer breast cell lines. Pyridyl chalcones bearing lipophilic A-ring, e.g., dichloro-phenyl-(14), pyrene-1-yl (20)- and biphenyl-4-yl (21) moieties were found to be the most potent of the series inhibiting the growth of M. tuberculosis H37Rv with IC₉₀ values ranging from 8.9–28 µM. Aryl chalcones containing a 3-methoxyphenyl A-ring and either p-Br-phenyl (25) or p-Cl-phenyl (26) B-rings showed an IC₉₀ value of 28 µM. Aryl-chalcones were generally less toxic to HepG2 cells compared to pyridyl-chalcones. Dose-dependent antiproliferative activity against MDA468 cells was observed for trimethoxy-phenyl (16) and anthracene-9-yl (19) pyridyl-chalcones with IC₅₀ values of 0.7 and 0.3 µM, respectively. Docking studies revealed that chalone 20 was predicted to bind to the M. tuberculosis protein tyrosine phosphatases B (PtpB) with higher affinity compared to a previously reported PtpB inhibitor. Full article

Influenza can lead to or coexist with severe bacterial pneumonia, with the potential to permanently damage lung tissue, refractory to conservative treatment in the post-COVID-19 period. It can lead to serious complications; therefore, annual vaccinations are recommended. This case series with a literature review pertains to two young female patients with an insignificant past medical history, who required emergency lobectomy due to bacterial complications after influenza infection. Urgent lobectomy proves to be a feasible therapeutic option for selected patients with pleural complications. Full article

A drug design strategy with reduced side effects and economic feasibility is desirable for fatal diseases. Increasing the bioavailability of a drug using a bioenhancer is a smart strategy. Herbal/natural bioenhancers with no probable side effects are an ideal choice to enhance the pharmacokinetics of a therapeutic drug synergistically. The mechanism of bioenhancers relies on the retention of the drug molecule in the cell without causing any changes in the metabolic activity. Most of the herbal bioenhancers achieve this feat by inhibiting metabolic enzymes such as cytochrome P450 and Uridine 5′-diphospho-glucuronosyltransferase. The efflux pump p-glycoprotein, responsible for removal of xenobiotics, is also inhibited by herbal/natural bioenhancers. The increased bioavailability because of the higher C_max and t_max of chemotherapeutics or anti-infectious agents such as rifampicin can result in a lower drug dosage regimen. The reduction in drug dosage is directly linked to fewer side effects and economic viability. Further, there is a significant effort in clinical trials to incorporate bioenhancers in drug regimens for cancer. The role of herbal/natural bioenhancers and their potential to augment the bioavailability of therapeutics used in cancer and infectious diseases, with a focus on the mechanisms of action, clinical studies and patents, have been summarized in this review article. Full article

Background: Tuberculosis (TB) poses a significant global health challenge; although low–middle income countries carry the heaviest burden, its diagnosis and treatment can be challenging in any country. The clinical picture can be complex and vary from person to person, with autoimmune complications that can hinder TB diagnosis and treatment. Case Presentation: We report the case of a 38-year-old man from Bangladesh who had recently arrived in Italy through the Balkan route. He presented with TB in the cervical lymph nodes and long-standing chronic myalgias. While a wide range of TB-triggered autoimmune entities can be found in the literature, this case is the first to describe immune-mediated necrotizing myopathy (IMNM) triggered by active TB. Conclusions: IMNM has been previously associated only with other infections like SARS-CoV-2 and Dengue. The successful diagnosis and management of TB-induced IMNM was achieved through a collaborative, multidisciplinary approach involving rheumatologists, immunologists, and infectious diseases specialists, showcasing an innovative treatment strategy and adding new insights into the complexities of TB and IMNM. Full article