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The Heat Shock Response of Mycobacterium tuberculosis: Linking Gene Expression, Immunology and Pathogenesis  [PDF]
Graham R. Stewart,Lorenz Wernisch,Richard Stabler,Joseph A. Mangan,Jason Hinds,Ken G. Laing,Philip D. Butcher,Douglas B. Young
Comparative and Functional Genomics , 2002, DOI: 10.1002/cfg.183
Abstract: The regulation of heat shock protein (HSP) expression is critically important to pathogens such as Mycobacterium tuberculosis and dysregulation of the heat shock response results in increased immune recognition of the bacterium and reduced survival during chronic infection. In this study we use a whole genome spotted microarray to characterize the heat shock response of M. tuberculosis. We also begin a dissection of this important stress response by generating deletion mutants that lack specific transcriptional regulators and examining their transcriptional profiles under different stresses. Understanding the stimuli and mechanisms that govern heat shock in mycobacteria will allow us to relate observed in vivo expression patterns of HSPs to particular stresses and physiological conditions. The mechanisms controlling HSP expression also make attractive drug targets as part of a strategy designed to enhance immune recognition of the bacterium.
Microbial pathogenesis: An insight into Mycobacterium tuberculosis  [cached]
Manjula S,Sritharan V
Indian Journal of Medical Microbiology , 2002,
Abstract: Tuberculosis, as yet, is far from being controlled. Several reasons can be attributed to this, a major contributing factor being the development of resistance to the currently available drugs due to the successful adaptation of the pathogen. Most of the inferences about the pathogen are based on the observation of mycobacteria grown in synthetic media in vitro and of the mycobacteria maintained in macrophages simulating the in vivo conditions. Molecular studies in mycobacteria had been slow to come due to the difficulty in the generation of mutants. However, new technologies that have now been developed for studying in vivo expressed molecules in other bacterial systems are being successfully applied to mycobacteria, especially the pathogenic M. tuberculosis. Additionally, an equally important factor in the study of the disease is the genetic predisposition of population to the infection. New findings link the Nramp1 and Toll receptor polymorphisms to susceptibility to infectious diseases.
Identification of T-Cell Antigens Specific for Latent Mycobacterium Tuberculosis Infection  [PDF]
Sebastian D. Schuck, Henrik Mueller, Frank Kunitz, Albert Neher, Harald Hoffmann, Kees L. C. M. Franken, Dirk Repsilber, Tom H. M. Ottenhoff, Stefan H. E. Kaufmann, Marc Jacobsen
PLOS ONE , 2009, DOI: 10.1371/journal.pone.0005590
Abstract: Background T-cell responses against dormancy-, resuscitation-, and reactivation-associated antigens of Mycobacterium tuberculosis are candidate biomarkers of latent infection in humans. Methodology/Principal Findings We established an assay based on two rounds of in vitro restimulation and intracellular cytokine analysis that detects T-cell responses to antigens expressed during latent M. tuberculosis infection. Comparison between active pulmonary tuberculosis (TB) patients and healthy latently M. tuberculosis-infected donors (LTBI) revealed significantly higher T-cell responses against 7 of 35 tested M. tuberculosis latency-associated antigens in LTBI. Notably, T cells specific for Rv3407 were exclusively detected in LTBI but not in TB patients. The T-cell IFNγ response against Rv3407 in individual donors was the most influential factor in discrimination analysis that classified TB patients and LTBI with 83% accuracy using cross-validation. Rv3407 peptide pool stimulations revealed distinct candidate epitopes in four LTBI. Conclusions Our findings further support the hypothesis that the latency-associated antigens can be exploited as biomarkers for LTBI.
Cholesterol Oxidase Is Indispensable in the Pathogenesis of Mycobacterium tuberculosis  [PDF]
Magdalena Klink, Marta Brzezinska, Izabela Szulc, Anna Brzostek, Michal Kielbik, Zofia Sulowska, Jaroslaw Dziadek
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0073333
Abstract: Despite considerable research effort, the molecular mechanisms of Mycobacterium tuberculosis (Mtb) virulence remain unclear. Cholesterol oxidase (ChoD), an extracellular enzyme capable of converting cholesterol to its 3-keto-4-ene derivative, cholestenone, has been proposed to play a role in the virulence of Mtb. Here, we verified the hypothesis that ChoD is capable of modifying the bactericidal and pro-inflammatory activity of human macrophages. We also sought to determine the contribution of complement receptor 3 (CR3)- and Toll-like receptor 2 (TLR2)-mediated signaling pathways in the development of macrophage responses to Mtb. We found that intracellular replication of an Mtb mutant lacking a functional choD gene (ΔchoD) was less efficient in macrophages than that of the wild-type strain. Blocking CR3 and TLR2 with monoclonal antibodies enhanced survival of ΔchoD inside macrophages. We also showed that, in contrast to wild-type Mtb, the ΔchoD strain induced nitric oxide production in macrophages, an action that depended on the TLR2, but not the CR3, signaling pathway. Both wild-type and mutant strains inhibited the production of reactive oxygen species (ROS), but the ΔchoD strain did so to a significantly lesser extent. Blocking TLR2-mediated signaling abolished the inhibitory effect of wild-type Mtb on ROS production by macrophages. Wild-type Mtb, but not the ΔchoD strain, decreased phorbol myristate acetate-induced phosphorylation of extracellular signal-regulated kinases 1 and 2 (ERK1/2), which are involved in both TLR2- and CR3-mediated signaling pathways. Our finding also revealed that the production of interleukin 10 by macrophages was significantly lower in ΔchoD-infected macrophages than in wild-type Mtb-infected macrophages. However, tumor necrosis factor-α production by macrophages was the same after infection with mutant or wild-type strains. In summary, we demonstrate here that ChoD is required for Mtb interference with the TLR2-mediated signaling pathway and subsequent intracellular growth and survival of the pathogen in human macrophages.
Atherosclerosis: pathogenesis and increased occurrence in individuals with HIV and Mycobacterium tuberculosis infection
Timothy Guilford, Devin Morris, Dennis Gray, et al
HIV/AIDS - Research and Palliative Care , 2010, DOI: http://dx.doi.org/10.2147/HIV.S11977
Abstract: therosclerosis: pathogenesis and increased occurrence in individuals with HIV and Mycobacterium tuberculosis infection Review (5397) Total Article Views Authors: Timothy Guilford, Devin Morris, Dennis Gray, et al Published Date October 2010 Volume 2010:2 Pages 211 - 218 DOI: http://dx.doi.org/10.2147/HIV.S11977 Timothy Guilford1, Devin Morris2,4, Dennis Gray3,4, Vishwanath Venketaraman3,4 1Your Energy Systems, Palo Alto, CA, USA; 2Graduate of College of Biomedical Sciences, 3College of Osteopathic Medicine of the Pacific, 4Western University of Health Sciences, Pomona, CA, USA Abstract: Atherosclerosis is a leading cause of coronary heart disease and stroke. Since 1981, more than 980,000 cases of AIDS have been reported in the United States. According to the Centers for Disease Control, more than 1 million Americans may be infected with HIV. By killing or damaging CD4+ T cells of the body’s immune system, HIV progressively destroys the body’s ability to fight infections. People diagnosed with AIDS often suffer from life-threatening diseases caused by opportunistic infections such as tuberculosis. HIV-infected individuals have increased risks for atherosclerosis. This review summarizes the effects of oxidized low density lipoproteins in impairing macrophage functions in individuals with atherosclerosis (with and without HIV infection) thereby enhancing the susceptibility to Mycobacterium tuberculosis infection.
Factores de virulencia de Mycobacterium tuberculosis Virulence factors of Mycobacterium tuberculosis
Nancy P Maulén
Revista médica de Chile , 2011,
Abstract: Mycobacterium tuberculosis, the etiological agent of human tuberculosis, causes annually three million deaths and latently infects about two billion people. Immunodeficiency caused by malnutrition, senescence or co-infection with HIVenhances the risk of developing active tuberculosis, either from a primary infection or by reactivation of a latent infection. The increasing appearance of multidrug-resistant strains to existing drugs is worrisome, since it leaves patients practically without treatment options. The understanding of the mechanisms of transmission, pathogenesis and virulence of M. tuberculosis is important. The analysis of its genome shows the presence of alternative sigma factors, transcriptional repressors and activators, two component signaling systems, metabolic enzymes and cellular secretory systems, that are associated with virulence in a series of pathogenic micro-organisms. Environmental stimuli such as pH, temperature, osmolality, oxygen availability are processed, activating or repressing virulence genes. The molecular mechanisms of action of these genes have been elucidated in in vitro and in vivo models.
Whole Genome Sequencing of Mycobacterium tuberculosis Reveals Slow Growth and Low Mutation Rates during Latent Infections in Humans  [PDF]
Roberto Colangeli, Vic L. Arcus, Ray T. Cursons, Ali Ruthe, Noel Karalus, Kathy Coley, Shannon D. Manning, Soyeon Kim, Emily Marchiano, David Alland
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0091024
Abstract: Very little is known about the growth and mutation rates of Mycobacterium tuberculosis during latent infection in humans. However, studies in rhesus macaques have suggested that latent infections have mutation rates that are higher than that observed during active tuberculosis disease. Elevated mutation rates are presumed risk factors for the development of drug resistance. Therefore, the investigation of mutation rates during human latency is of high importance. We performed whole genome mutation analysis of M. tuberculosis isolates from a multi-decade tuberculosis outbreak of the New Zealand Rangipo strain. We used epidemiological and phylogenetic analysis to identify four cases of tuberculosis acquired from the same index case. Two of the tuberculosis cases occurred within two years of exposure and were classified as recently transmitted tuberculosis. Two other cases occurred more than 20 years after exposure and were classified as reactivation of latent M. tuberculosis infections. Mutation rates were compared between the two recently transmitted pairs versus the two latent pairs. Mean mutation rates assuming 20 hour generation times were 5.5X10?10 mutations/bp/generation for recently transmitted tuberculosis and 7.3X10?11 mutations/bp/generation for latent tuberculosis. Generation time versus mutation rate curves were also significantly higher for recently transmitted tuberculosis across all replication rates (p = 0.006). Assuming identical replication and mutation rates among all isolates in the final two years before disease reactivation, the u20hr mutation rate attributable to the remaining latent period was 1.6×10?11 mutations/bp/generation, or approximately 30 fold less than that calculated during the two years immediately before disease. Mutations attributable to oxidative stress as might be caused by bacterial exposure to the host immune system were not increased in latent infections. In conclusion, we did not find any evidence to suggest elevated mutation rates during tuberculosis latency in humans, unlike the situation in rhesus macaques.
Transcription of Genes Involved in Sulfolipid and Polyacyltrehalose Biosynthesis of Mycobacterium tuberculosis in Experimental Latent Tuberculosis Infection  [PDF]
Jimmy E. Rodríguez, Ana S. Ramírez, Laura P. Salas, Cecilia Helguera-Repetto, Jorge Gonzalez-y-Merchand, Carlos Y. Soto, Rogelio Hernández-Pando
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0058378
Abstract: The Influence of trehalose-based glycolipids in the virulence of Mycobacterium tuberculosis (Mtb) is recognised; however, the actual role of these cell-wall glycolipids in latent infection is unknown. As an initial approach, we determined by two-dimensional thin-layer chromatography the sulfolipid (SL) and diacyltrehalose/polyacyltrehalose (DAT/PAT) profile of the cell wall of hypoxic Mtb. Then, qRT-PCR was extensively conducted to determine the transcription profile of genes involved in the biosynthesis of these glycolipids in non-replicating persistent 1 (NRP1) and anaerobiosis (NRP2) models of hypoxia (Wayne model), and murine models of chronic and progressive pulmonary tuberculosis. A diminished content of SL and increased amounts of glycolipids with chromatographic profile similar to DAT were detected in Mtb grown in the NRP2 stage. A striking decrease in the transcription of mmpL8 and mmpL10 transporter genes and increased transcription of the pks (polyketidesynthase) genes involved in SL and DAT biosynthesis were detected in both the NRP2 stage and the murine model of chronic infection. All genes were found to be up-regulated in the progressive disease. These results suggest that SL production is diminished during latent infection and the DAT/PAT precursors can be accumulated inside tubercle bacilli and are possibly used in reactivation processes.
Analysis of Mycobacterium tuberculosis-Specific CD8 T-Cells in Patients with Active Tuberculosis and in Individuals with Latent Infection  [PDF]
Nadia Caccamo, Giuliana Guggino, Serena Meraviglia, Giuseppe Gelsomino, Paola Di Carlo, Lucina Titone, Marialuisa Bocchino, Domenico Galati, Alessandro Matarese, Jan Nouta, Michel R. Klein, Alfredo Salerno, Alessandro Sanduzzi, Francesco Dieli, Tom H. M. Ottenhoff
PLOS ONE , 2009, DOI: 10.1371/journal.pone.0005528
Abstract: CD8 T-cells contribute to control of Mycobacterium tuberculosis infection, but little is known about the quality of the CD8 T-cell response in subjects with latent infection and in patients with active tuberculosis disease. CD8 T-cells recognizing epitopes from 6 different proteins of Mycobacterium tuberculosis were detected by tetramer staining. Intracellular cytokines staining for specific production of IFN-γ and IL-2 was performed, complemented by phenotyping of memory markers on antigen-specific CD8 T-cells. The ex-vivo frequencies of tetramer-specific CD8 T-cells in tuberculous patients before therapy were lower than in subjects with latent infection, but increased at four months after therapy to comparable percentages detected in subjects with latent infection. The majority of CD8 T-cells from subjects with latent infection expressed a terminally-differentiated phenotype (CD45RA+CCR7?). In contrast, tuberculous patients had only 35% of antigen-specific CD8 T-cells expressing this phenotype, while containing higher proportions of cells with an effector memory- and a central memory-like phenotype, and which did not change significantly after therapy. CD8 T-cells from subjects with latent infection showed a codominance of IL-2+/IFN-γ+ and IL-2?/IFN-γ+ T-cell populations; interestingly, only the IL-2+/IFN-γ+ population was reduced or absent in tuberculous patients, highly suggestive of a restricted functional profile of Mycobacterium tuberculosis-specific CD8 T-cells during active disease. These results suggest distinct Mycobacterium tuberculosis specific CD8 T-cell phenotypic and functional signatures between subjects which control infection (subjects with latent infection) and those who do not (patients with active disease).
Role of Mycobacterium tuberculosis pknD in the Pathogenesis of central nervous system tuberculosis
Nicholas A Be, William R Bishai, Sanjay K Jain
BMC Microbiology , 2012, DOI: 10.1186/1471-2180-12-7
Abstract: We screened 398 unique M. tuberculosis mutants in guinea pigs to identify genes required for central nervous system tuberculosis. We found M. tuberculosis pknD (Rv0931c) to be required for central nervous system disease. These findings were central nervous system tissue-specific and were not observed in lung tissues. We demonstrated that pknD is required for invasion of brain endothelia (primary components of the blood-brain barrier protecting the central nervous system), but not macrophages, lung epithelia, or other endothelia. M. tuberculosis pknD encodes a "eukaryotic-like" serine-threonine protein kinase, with a predicted intracellular kinase and an extracellular (sensor) domain. Using confocal microscopy and flow cytometry we demonstrated that the M. tuberculosis PknD sensor is sufficient to trigger invasion of brain endothelia, a process which was neutralized by specific antiserum.Our findings demonstrate a novel in vivo role for M. tuberculosis pknD and represent an important mechanism for bacterial invasion and virulence in central nervous system tuberculosis, a devastating and understudied disease primarily affecting young children.Tuberculosis (TB) of the central nervous system (CNS) is a devastating and often fatal disease, primarily affecting young children. Even when treatment is administered in a timely manner, mortality is extraordinarily high, with surviving patients often experiencing severe neurological sequelae. CNS TB comprises approximately 1% of TB disease worldwide, disproportionately affecting children in developing nations [1]. Coinfection with human immunodeficiency virus increases the likelihood of CNS TB [2,3], and the emergence of drug resistant strains further complicates CNS TB due to limited permeability at the blood-brain barrier (BBB) of several second-line TB drugs. Delays in treatment due to drug-susceptibility testing further reduce the efficacy of available patient care [4].The CNS is protected from the systemic circulation by t
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