Tuberculosis RSS feed: Articles in Press. Tuberculosis is a speciality journal focusing on basic experimental research on tuberculosis, notably on bacteriological, immunological and pathogenesis aspects of the disease. The journal publishes original research and reviews on the host response and immunology of tuberculosis and the molecular biology, genetics and physiology of the organism. Areas covered include: immunology immunogenetics pathogenetics microbiology microbial physiology pathogenesis pathology molecular epidemiology diagnostics vaccine development drug resistance The resurgence of interest in tuberculosis has accelerated the pace of relevant research and Tuberculosis has grown with it, as the only journal dedicated to experimental biomedical research in tuberculosis. To view the benefits of Online Submission please click here. http://www.tuberculosisjournal.com//inpress?rss=yesElsevier Inc.en © 2010 Elsevier Ltd. All rights reserved. Tuberculosis1472-97922010-03-08 © 2010 Elsevier Ltd. All rights reserved. healthpermissions@elsevier.comhttp://www.tuberculosisjournal.com/article/PIIS147297921000003X/abstract?rss=yesSummary: Ectocytosis, the cellular process by which ectosomes (Ects) are released, is an important phenomenon by which eukaryotic cells exchange molecular information. Ects released from N-formylmethionyl-leucyl-phenylalanine (fMLP)-activated human polymorphonuclear neutrophils (PMNs) have recently been characterized. Molecules such as CD35 and phosphatidylserine (PS), and enzymes such as myeloperoxidase and elastase were found in these vesicles, suggesting that Ects from PMNs could function as ecto-organelles with anti-microbial activity. Here we show for the first time that human PMNs release ectosomes in response to Mycobacterium tuberculosis H37Rv infection. We found that the release of ectosomes was not associated exclusively with mycobacterial infection since infection with other microorganisms (e.g., Leishmania mexicana, Staphylococcus aureus, and Escherichia coli or activation with phorbol myristate acetate (PMA)) also induced ectocytosis. Ects release started as early as 10min after infection or activation. Expression of CD35, PS, Rab5, Rab7 and gp91Phox, a subunit of Cyt b555 was demonstrated on the Ects membrane. Based on our observations we conclude that Ects are released from human neutrophils in response to cell activation and that this process is not related to apoptosis.Mycobacterium tuberculosis H37Rv induces ectosome release in human polymorphonuclear neutrophils - Corrected ProofPatricia González-Cano, Ricardo Mondragón-Flores, Luvia E. Sánchez-Torres, Sirenia González-Pozos, Mayra Silva-Miranda, Amalia Monroy-Ostria, Sergio Estrada-Parra, Iris Estrada-García10.1016/j.tube.2010.01.002Tuberculosis (2010)2010-03-08Tuberculosis2010-03-08IMMUNOLOGICAL ASPECTShttp://www.tuberculosisjournal.com/article/PIIS1472979210000193/abstract?rss=yesSummary: The evidence for a human genetic component in susceptibility to tuberculosis (TB) is incontrovertible. Quite apart from studies of rare disease events illustrating the importance of key genes in humans and animals, TB at the population level is also influenced by the genetics of the host. Heritability of disease concordance and immune responses to mycobacterial antigens has been clearly shown, and ranges up to 71%. Linkage studies, designed to identify major susceptibility genes in a disease, have produced a number of candidate loci but few, except for regions on chromosome 5p15, 20p and 20q, have been replicated. The region on 5p15 regulates the intensity of the response to the tuberculin skin test, and another locus on 11p14 appears to control resistance to the bacterium. In addition, numerous genes and pathways have been implicated in candidate gene association studies, with validation of polymorphisms in IFNG, NRAMP1, and NOS2A and equivocal results for IL10, CCL2, DC-SIGN, P2RX7, VDR, TLR2, TLR9 and SP110. Other more recently researched candidate genes such as TNFRSF1B remain to be validated, preferably in meta-analyses. New approaches have provided early evidence for the importance of gene–gene interactions in regulating resistance to disease, and also the prospect that applying host genetics in the field of vaccinomics could lead to a more targeted approach in designing interventions to aid the human immune system in combating mycobacteria. Genome-wide association studies and admixture mapping are approaches that remain to be applied to TB, and it is not clear, as is the case with other complex diseases, how much of the heritability of the TB susceptibility phenotype will be determined by multiple genes of small effect versus rare variants with disproportionately large effects.Current findings, challenges and novel approaches in human genetic susceptibility to tuberculosis - Corrected ProofMarlo Möller, Eileen G. Hoal10.1016/j.tube.2010.02.002Tuberculosis (2010)2010-03-08Tuberculosis2010-03-08REVIEWhttp://www.tuberculosisjournal.com/article/PIIS147297921000020X/abstract?rss=yesSummary: Mycobacterium tuberculosis (the causal agent of TB) has co-evolved with humans for centuries. It infects via the airborne route and is a prototypic highly adapted intracellular pathogen of macrophages. Extensive sequencing of the M. tuberculosis genome along with recent molecular phylogenetic studies is enabling us to gain insight into the biologic diversity that exists among bacterial strains that impact the pathogenesis of latent infection and disease. The majority of the M. tuberculosis cell envelope is comprised of carbohydrates and lipids, and there is increasing evidence that these microbial determinants that are readily exposed to the host immune system play critical roles in disease pathogenesis. Studies from our laboratory and others have raised the possibility that M. tuberculosis is adapting to the human host by cloaking its cell envelope molecules with terminal mannosylated (i.e. Man-α-(1→2)-Man) oligosaccharides that resemble the glycoforms of mammalian mannoproteins. These mannosylated biomolecules engage the mannose receptor (MR) on macrophages during phagocytosis and dictate the intracellular fate of M. tuberculosis by regulating formation of the unique vesicular compartment in which the bacterium survives. The MR is highly expressed on alveolar macrophages (predominant C-type lectin on human cells) and functions as a scavenger receptor to maintain the healthiness of the lung by clearing foreign particles and at the same time regulating dangerous inflammatory responses. Thus M. tuberculosis exploits MR functions to gain entry into the macrophage and survive. Key biochemical pathways and mycobacterial determinants involved in the development and maintenance of the M. tuberculosis phagosome are being identified. The phylogenetic diversity observed in M. tuberculosis strains that impact its cell wall structure together with the genetic diversity observed in human populations, including those elements that affect macrophage function, may help to explain the extraordinary evolutionary adaptation of this pathogen to the human host. Major developments in these areas are the focus of this review.Diversity in Mycobacterium tuberculosis mannosylated cell wall determinants impacts adaptation to the host - Corrected ProofJordi B. Torrelles, Larry S. Schlesinger10.1016/j.tube.2010.02.003Tuberculosis (2010)2010-03-04Tuberculosis2010-03-04REVIEWhttp://www.tuberculosisjournal.com/article/PIIS1472979210000156/abstract?rss=yesSummary: Background: Volatile organic compounds (VOCs) in breath may contain biomarkers of active pulmonary tuberculosis derived from the infectious organism (metabolites of Mycobacterium tuberculosis) and from the infected host (products of oxidative stress).Methods: We analyzed breath VOCs in 226 symptomatic high-risk patients in USA, Philippines, and UK, using gas chromatography/mass spectroscopy. Diagnosis of disease was based on sputum culture, smear microscopy, chest radiography and clinical suspicion of tuberculosis (CSTB). Chromatograms were converted to a series of 8s overlapping time slices. Biomarkers of active pulmonary tuberculosis were identified with a Monte Carlo analysis of time-slice alveolar gradients (abundance in breath minus abundance in room air).Results: Breath VOCs contained apparent biomarkers of active pulmonary tuberculosis comprising oxidative stress products (alkanes and alkane derivatives) and volatile metabolites of M. tuberculosis (cyclohexane and benzene derivatives). Breath biomarkers identified active pulmonary tuberculosis with C-statistic (area under curve of receiver operating characteristic)=0.85 (i.e. 85% overall accuracy, sensitivity=84.0%, specificity=64.7%) when sputum culture, microscopy, and chest radiography were either all positive or all negative. Employing a single criterion of disease, C-statistic=0.76 (smear microscopy), 0.68 (sputum culture), 0.66 (chest radiography) and 0.65 (CSTB).Conclusion: A breath test identified apparent biomarkers of active pulmonary tuberculosis with 85% accuracy in symptomatic high-risk subjects.Breath biomarkers of active pulmonary tuberculosis - Corrected ProofMichael Phillips, Victoria Basa-Dalay, Graham Bothamley, Renee N. Cataneo, Phung Kim Lam, Maria Piedad R. Natividad, Peter Schmitt, James Wai10.1016/j.tube.2010.01.003Tuberculosis (2010)2010-03-02Tuberculosis2010-03-02DIAGNOSTICShttp://www.tuberculosisjournal.com/article/PIIS147297921000017X/abstract?rss=yesSummary: Experimental models of infection are good tools for establishing immunological parameters that have an effect on the host–pathogen relationship and also for designing new vaccines and immune therapies. In this work, we evaluated the evolution of experimental tuberculosis in mice infected with increasing bacterial doses or via distinct routes. We showed that mice infected with low bacterial doses by the intratracheal route were able to develop a progressive infection that was proportional to the inoculum size. In the initial phase of disease, mice developed a specific Th1-driven immune response independent of inoculum concentration. However, in the late phase, mice infected with higher concentrations exhibited a mixed Th1/Th2 response, while mice infected with lower concentrations sustained the Th1 pattern. Significant IL-10 concentrations and a more preeminent T regulatory cell recruitment were also detected at 70 days post-infection with high bacterial doses. These results suggest that mice infected with higher concentrations of bacilli developed an immune response similar to the pattern described for human tuberculosis wherein patients with progressive tuberculosis exhibit a down modulation of IFN-γ production accompanied by increased levels of IL-4. Thus, these data indicate that the experimental model is important in evaluating the protective efficacy of new vaccines and therapies against tuberculosis.Experimental tuberculosis: Designing a better model to test vaccines against tuberculosis - Corrected ProofDenise Morais Fonseca, Rogério Silva Rosada, Marina Oliveira e Paula, Pryscilla Fanini Wowk, Luis Henrique Franco, Edson Garcia Soares, Célio Lopes Silva, Vânia Luiza Deperon Bonato10.1016/j.tube.2010.01.005Tuberculosis (2010)2010-02-26Tuberculosis2010-02-26MOLECULAR ASPECTShttp://www.tuberculosisjournal.com/article/PIIS1472979210000028/abstract?rss=yesSummary: Rifampin is a key component of standard short-course first-line therapy against Mycobacterium tuberculosis (MTB). Rifampin monoresistant MTB, previously a rare phenomenon, is now being reported at increasing rates worldwide. We report a mutation in the rpoB region leading to low level rifampin monoresistance in a cluster of HIV-positive patients. All rifampin monoresistant isolates identified from 2004 to 2006 underwent susceptibility confirmation, sequencing of rpoB and genotyping. Three patients were found to have a previously undocumented 3 base pair insertion at codon 525 in the rpoB region. The earliest initial case was infected with fully susceptible MTB. Disease relapse occurred 7 months later with a genotypically identical MTB isolate, showing acquired rifampin monoresistance. MTB isolates from 2 subsequent patients showed primary rifampin monoresistance with an identical genotype to the index case. Patients with rifampin monoresistant MTB tend to have poorer outcomes than those with fully susceptible strains. Risk factors for the development of rifampin monoresistance include co-morbid HIV infection and previously treated tuberculosis. HIV infection has been associated with malabsorption of anti-tuberculous medications leading to sub-therapeutic levels of administered drugs. These factors may have played a role in the development of this previously undocumented mutation.A mutation in Mycobacterium tuberculosis rpoB gene confers rifampin resistance in three HIV-TB cases - Corrected ProofSangita Malhotra, Victoria J. Cook, Joyce N. Wolfe, Patrick Tang, Kevin Elwood, Meenu K. Sharma10.1016/j.tube.2010.01.001Tuberculosis (2010)2010-01-25Tuberculosis2010-01-25DRUG DISCOVERY AND RESISTANCEhttp://www.tuberculosisjournal.com/article/PIIS1472979204000721/abstract?rss=yesSummary: In this brief review I will discuss some of the more interesting [and in some cases, confusing] aspects that have arisen from the current NIH-funded TB vaccine screening program at Colorado State University, how they affect our understanding of the vaccination process, and how this may influence the rational vaccine design in the near future.Mouse and guinea pig models for testing new tuberculosis vaccines - Corrected ProofIan M. Orme10.1016/j.tube.2004.09.004Tuberculosis (2005)2005-01-17Tuberculosis2005-01-17