Construction and evaluation of a novel multi-antigenic Mycobacterium tuberculosis subunit vaccine candidate BfrB-GrpE/DPC
Hongxia NiuQianqian CaoTingting ZhangYunjie DuPu HeLei JiaoBingxiang WangBingdong ZhuLina HuYing Zhang
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ABSTRACT Background Studies on human intraocular tuberculosis (IOTB) are extremely challenging. For understanding the pathogenesis of IOTB, it is important to investigate the mycobacterial transcriptional changes in ocular environment. Methods Mice were challenged intravenously with Mycobacterium tuberculosis H37Rv and at 45 days post-infection, experimental IOTB was confirmed based on bacteriological and molecular assays. M. tuberculosis transcriptome was analyzed in the infected eyes using microarray technology. The identified M. tuberculosis signature genes were further validated and investigated in human IOTB samples using real-time polymerase chain reaction. Results Following intravenous challenge with M. tuberculosis, 45% (5/12) mice showed bacilli in the eyes with positivity for M. tuberculosis ribonucleic acid in 100% (12/12), thus confirming the paucibacillary nature of IOTB similar to human IOTB. M. tuberculosis transcriptome in these infected eyes showed significant upregulation of 12 M. tuberculosis genes and five of these transcripts (Rv0962c, Rv0984, Rv2612c, Rv0974c and Rv0971c) were also identified in human clinically confirmed cases of IOTB. Conclusions Differentially expressed mycobacterial genes identified in an intravenously challenged paucibacillary mouse IOTB model and presence of these transcripts in human IOTB samples highlight the possible role of these genes for survival of M. tuberculosis in the ocular environment, thus contributing to pathogenesis of IOTB.
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Mycobacterium tuberculosis (M. tuberculosis) causes an enormous burden of disease worldwide. As a central aspect of its pathogenesis, M. tuberculosis grows in macrophages, and host and microbe influence each other's metabolism. To define the metabolic impact of M. tuberculosis infection, we performed global metabolic profiling of M. tuberculosis–infected macrophages. M. tuberculosis induced metabolic hallmarks of inflammatory macrophages and a prominent signature of cholesterol metabolism. We found that infected macrophages accumulate cholestenone, a mycobacterial-derived, oxidized derivative of cholesterol. We demonstrated that the accumulation of cholestenone in infected macrophages depended on the M. tuberculosis enzyme 3β-hydroxysteroid dehydrogenase (3β-Hsd) and correlated with pathogen burden. Because cholestenone is not a substantial human metabolite, we hypothesized it might be diagnostic of M. tuberculosis infection in clinical samples. Indeed, in 2 geographically distinct cohorts, sputum cholestenone levels distinguished subjects with tuberculosis (TB) from TB-negative controls who presented with TB-like symptoms. We also found country-specific detection of cholestenone in plasma samples from M. tuberculosis–infected subjects. While cholestenone was previously thought to be an intermediate required for cholesterol degradation by M. tuberculosis, we found that M. tuberculosis can utilize cholesterol for growth without making cholestenone. Thus, the accumulation of cholestenone in clinical samples suggests it has an alternative role in pathogenesis and could be a clinically useful biomarker of TB infection.
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Current theory in the molecular epidemiology of tuberculosis holds that tuberculosis cases harboring Mycobacterium tuberculosis strains with a common deoxyribonucleic acid (DNA) fingerprint are the result of recent M. tuberculosis transmission. Here we propose a mathematical approach independent of DNA fingerprinting to estimating the percentage of recent transmissions responsible for current tuberculosis incidence. The “short-term reproductive number” of tuberculosis is defined as the average number of tuberculosis cases developing within 1 year of infection. Multiplying the short-term reproductive number by the number of tuberculosis cases in each year and dividing by the subsequent year’s tuberculosis case burden equals the proportion of tuberculosis cases in the subsequent year that are due to recent transmission. We carried out separate calculations for human immunodeficiency virus (HIV)-negative and HIV-positive tuberculosis cases. We applied the model to pulmonary (infectious) tuberculosis cases diagnosed in New York City during 1989–1993, using tuberculosis and AIDS surveillance data. Model-based estimates of the proportion of tuberculosis due to recent transmission were lower than estimates based on DNA fingerprints. Reconciliation of these divergent estimates may require the re-estimation of model parameters from data collected de novo, additional model development, and further advances in DNA fingerprinting methods.
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Tuberculosis is one of the most dangerous infectious diseases and has among the highest mortality rates of all infectious diseases. There are 9 million cases of active tuberculosis reported annually; however, an estimated one-third of the world's population is infected with Mycobacterium tuberculosis and remains asymptomatic. Despite the great progress in its diagnosis and treatment, tuberculosis is still a serious health and social problem. The contact between the immune system and Mycobacterium tuberculosis initiates cell-specific (Th1) and humoral-specific (Th2) responses. Many studies about the presence of antituberculotic antibodies in the serum have produced inconsistent results because of a high proportion of false-positive or false-negative results. The purpose of this study was to confirm whether circulating immune complexes (CIC) isolated from the serum of patients with tuberculosis are accompanied by antigenic proteins typical of Mycobacterium tuberculosis.We assayed serum samples from 42 patients with tuberculosis. The control group consisted of the sera samples taken from 45 healthy subjects. The immunochemical analysis of dissociated immune complexes using the dot blot method demonstrated positive reaction on the presence of Mycobacterium tuberculosis antigens in all patients with tuberculosis.All patients with tuberculosis demonstrated a high serum concentration of CIC protein. The mean serum concentration of CIC protein was significantly higher in patients than in controls: 0.081 g/l in the control group and 0.211 g/l in the tuberculosis patients.The analysis of CIC suggests that it may be a helpful test for patients with tuberculosis because of its quickness, simplicity of the idea, and limited invasiveness.
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Transcriptional Biomarkers of Differentially Detectable Mycobacterium tuberculosis in Patient Sputum
Certain populations of Mycobacterium tuberculosis go undetected by standard diagnostics but can be enumerated using limiting dilution assays. These differentially detectable M. tuberculosis (DD M. tuberculosis) populations may have relevance for persistence due to their drug tolerance. It is unclear how well DD M. tuberculosis from patients is modeled by a recently developed
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Extensively drug-resistant tuberculosis
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Introduction. Relapses of tuberculosis are fairly rare nowdays and they represent the onset of tuberculosis two, or more than two years after completion of previous treatment. Material and Methods. In the previous period, relapses of tuberculosis occurred in 141 patients (87 male and 54 female). Their mean age was 46.2 years. Results. Relapses of tuberculosis occurred after 11.3 years, on average. All patients presented with pulmonary tuberculosis, and two patients also had pulmonary and extrapulmonary tuberculosis(bones). Resistance was one of the statistically significant factors for relapse of tuberculosis. Resistance to one antituberculotic agent was most common - 8 patients, resistance to two drugs - 4 patients, resistance to three drugs - 4 patients, resistance to four drugs in 5 patients. Due to these findings on resistant strains of mycobacterium tuberculosis, a huge number of patients with relapses of tuberculosis had full recovery and completed the treatment. Conclusion. The importance of resistant strains of mycobacterium tuberculosis is really huge in our conditions. The findings of these resistant strains of mycobacterium tuberculosis and adequate medical treatment are obligatory nowadays. .
Mycobacterium tuberculosis complex
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Objective To study the contribution of exogenous reinfeciton to tuberculosis recurrence. Methods Mycobacterium tuberculosis isolates from patients who had experienced 2 successive tuberculosis episodes during the years from January 1999 to March 2004 were genotyped by mycobacterial interspersed repetitive units (MIRU) method. The cause of tuberculosis recurrence was determined by comparing the MIRU pattern of Mycobacterium tuberculosis isolates responsible for different tuberculosis episodes from patients. Results Of 37 qualified patients with recurrent tuberculosis, the isolates from 25 patients in their two tuberculosis episodes showed different MIRU patterns, indicating that 68% recurrent patients were due to exogenous reinfection. The exogenous reinfection rate decreased with the age from 3/3 (under 30 years) to 73% (11/15, 30 to 60 years) and 58% (11/19, over 60 years). The frequency of exogenous reinfection increased with the tuberculosis recurrent interval. Within 6 months, the exogenous reinfection accounted for 58% (7/12) of all the recurrentce, while for the time more than one year, the percentage increased to 79% (11/14). Conclusions Exogenous reinfection was a major cause of tuberculosis recurrence in Shanghai. MIRU genotyping method is useful to study the cause of tuberculosis recurrence.
Mycobacterium tuberculosis complex
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There is considerable variability in the outcome of Mycobacterium tuberculosis infection. We hypothesized that Mycobacterium africanum was less likely than M. tuberculosis to transmit and progress to tuberculosis disease.In a cohort study of patients with tuberculosis and their household contacts in The Gambia, we categorized 1808 HIV-negative tuberculosis contacts according to exposure to M. tuberculosis or M. africanum. Positive skin test results indicated transmission, and development of tuberculosis during 2 years of follow-up indicated progression to disease.Transmission rates were similar, but rates of progression to disease were significantly lower in contacts exposed to M. africanum than in those exposed to M. tuberculosis (1.0% vs. 2.9%; hazard ratio [HR], 3.1 [95% confidence interval {CI}, 1.1-8.7]). Within M. tuberculosis sensu stricto, contacts exposed to a Beijing family strain were most likely to progress to disease (5.6%; HR relative to M. africanum, 6.7 [95% CI, 2.0-22]).M. africanum and M. tuberculosis transmit equally well to household contacts, but contacts exposed to M. africanum are less likely to progress to tuberculosis disease than those exposed to M. tuberculosis. The variable rate of progression by lineage suggests that tuberculosis variability matters in clinical settings and should be accounted for in studies evaluating tuberculosis vaccines and treatment regimens for latent tuberculosis infection.
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