Expression of Th1-mediated immunity in mouse lungs induces a<i>Mycobacterium tuberculosis</i>transcription pattern characteristic of nonreplicating persistence

Shi, Lanbo; Jung, Yu‐Jin; Tyagi, Sanjay; Gennaro, Maria Laura; North, Robert J.

doi:10.1073/pnas.0136863100

Cited by 240 publications

(228 citation statements)

References 41 publications

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“…The M. tuberculosis genome encodes at least eight proteins of this family (O'Toole & Williams, 2003). Rv2623 contains two UspA typical domains, and it was previously shown to be part of the dormancy regulon and to be upregulated in mouse lungs at the terminal stage of pathology (Florczyk et al, 2001;Shi et al, 2003). Its induction by inhibitory and subinhibitory concentrations of vancomycin suggests its involvement in M. tuberculosis growth control following exposure to stress.…”

Section: Resultsmentioning

confidence: 99%

Global transcriptional response to vancomycin in Mycobacterium tuberculosis

et al. 2009

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In order to gain additional understanding of the physiological mechanisms used by bacteria to maintain surface homeostasis and to identify potential targets for new antibacterial drugs, we analysed the variation of the Mycobacterium tuberculosis transcriptional profile in response to inhibitory and subinhibitory concentrations of vancomycin. Our analysis identified 153 genes differentially regulated after exposing bacteria to a concentration of the drug ten times higher than the MIC, and 141 genes differentially expressed when bacteria were growing in a concentration of the drug eightfold lower than the MIC. Hierarchical clustering analysis indicated that the response to these different conditions is different, although with some overlap. This approach allowed us to identify several genes whose products could be involved in the protection from antibiotic stress targeting the envelope and help to confer the basal level of M. tuberculosis resistance to antibacterial drugs, such as Rv2623 (UspA-like), Rv0116c, PE20-PPE31, PspA and proteins related to toxin-antitoxin systems. Moreover, we also demonstrated that the alternative sigma factor s E confers basal resistance to vancomycin, once again underlining its importance in the physiology of the mycobacterial surface stress response. INTRODUCTIONMycobacterium tuberculosis remains one of the world's most prevalent and serious pathogens. It is estimated that every year 2 million people die as a direct result of tuberculosis and that there is a reservoir of 2 billion cryptically infected people (Dye et al., 1999). Of these asymptomatic carriers, around 5 % will develop active disease at some stage in their lives and in doing so will contribute to the ongoing transmission of infection (Raviglione, 2003). The recent emergence of multidrugresistant (MDR) and extensively drug-resistant (XDR-TB) strains (Gandhi et al., 2006) has raised the importance of searching for alternative targets to develop new antimycobacterial drugs.Due to the importance of its physiological role and its difference from the eukaryotic cell surface, the bacterial cell wall is one of the best candidates in the search for new drug targets. A large number of antibacterial drugs currently in use are directed against surface components or metabolic pathways that are involved in their synthesis. For example, b-lactams, cephalosporins, glycopeptides, phosphomycin, bacitracin and cycloserine inhibit peptidoglycan biosynthesis, while polymyxin interferes with the cell-membrane structure. Moreover, compounds such as isoniazid, pyrazinamide, ethambutol and ethionamide target typical components of the mycobacterial cell surface. In spite of a good knowledge of the chemical composition of the mycobacterial surface, not much is known about its organization and physiology (Barry, 2001). The recent demonstration of the presence of an outer membrane will surely boost research in this field (Hoffmann et al., 2008;Zuber et al., 2008).One strategy to study bacterial surface physiology is to characterize the variation o...

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Section: Resultsmentioning

confidence: 99%

Global transcriptional response to vancomycin in Mycobacterium tuberculosis

et al. 2009

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“…Thus, in contrast to the in vitro results obtained by Yuan et al (1998), these in vivo studies demonstrate that the acr mutation does not impair the growth of M. tuberculosis bacilli in mouse tissues during an acute infection but, on the contrary, results in a state of hypervirulence. The observation that acr expression is upregulated in vitro during hypoxic and stationary-phase growth conditions (Schnappinger et al, 2003;Yuan et al, 1996Yuan et al, , 1998, and in vivo in mouse (Shi et al, 2003;Timm et al, 2003) and human lungs (Timm et al, 2003), suggests that it is an important gene for survival of bacilli under stress and is possibly part of a genetic programme which allows adaptation to hypoxic microenvironments of the host. This adaptation may involve the shutdown of genes necessary for aerobic metabolic pathways, with the ultimate consequence of entering into a state of non-replicative stasis or latency.…”

Section: Discussionmentioning

confidence: 99%

Increased pathology in lungs of mice after infection with an α-crystallin mutant of Mycobacterium tuberculosis: changes in cathepsin proteases and certain cytokines

et al. 2006

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Latency and reactivation are a significant problem that contributes to the incidence, transmission and pathogenesis of tuberculosis. The mechanisms involved in these processes, at the level of both the bacillus and the host, are poorly understood. In Mycobacterium tuberculosis the a-crystallin (acr) gene has been linked to latency, because it is highly expressed during hypoxic growth conditions. Deletion of the acr gene in M. tuberculosis H37Rv (Dacr strain) was previously shown to reduce the intracellular growth of bacilli in macrophages; however, its impact on pathogenesis in vivo was unknown. This study demonstrated that infection of C57BL6 mice with Dacr results in lung bacillary loads 1-2 log units higher in comparison to parental H37Rv. Haematoxylin/eosin staining of lungs revealed exacerbated pathology characterized by extensive obliteration of alveolar air spaces by granulomatous inflammation. RT-PCR analysis and immunostaining of lungs showed that infection with either H37Rv or Dacr results in the differential expression of lysosomal cathepsin proteases. A slight increase in the expression of the matrix-degrading acidic-type cathepsins B, D and H was noted in Dacr-infected mice and was associated with clusters of macrophages within lung granulomas. Dacr-infected mice also showed high serum levels of TNF-a, IFN-c and G-CSF, suggesting that Acr may play a role in modulating the host response to infection.

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“…The use of a broader panel of MTB-and MOTT-associated antigens may aid in dissecting the precise targets of CD4-and CD8-mediated immune responses in MTB patients undergoing therapy (and therefore, potentially alterations in bacterial load). Of particular interest are additional MTB antigens associated with non-replicating mycobacterial persistence and potentially with clinical latency of tuberculosis [33][34][35][36]. Changes in both the magnitude of the response to some antigens and the nature of the T cells responding may allow us to better define the status of the infection.…”

Section: Discussionmentioning

confidence: 99%

MHC class II Tetramer Guided Detection of Mycobacterium tuberculosis‐specific CD4⁺ T Cells in Peripheral Blood from Patients with Pulmonary Tuberculosis

Höhn¹,

Kortsik²,

Zehbe³

et al. 2007

Scand J Immunol

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Novel diagnostic tools are needed to diagnose latent infection and to provide biologically meaningful surrogate markers to define cellular immune responses against Mycobacterium tuberculosis (MTB). Interferon gamma‐based assays have recently been developed in addition to the more than 100‐year‐old tuberculin skin test (TST) for the immune diagnosis of MTB in blood. The advent of soluble MHC/peptide tetramer molecules allows to objectively enumerate antigen‐specific T cells. We identified novel MHC class II‐restricted MTB epitopes and used HLA‐DR4 tetrameric complexes to visualize ex vivo CD4+ T cells directed against the antigens Ag85B and the 19‐kDa lipoprotein, shared between MTB and other Mycobacterium species, and CD4+ T cells which recognize the MTB‐associated ESAT‐6 antigen. MTB‐reactive CD4+ T cells reside predominantly in the CD45RA+ CD28+ and CD45− CD28+ T‐cell subset and recognize naturally processed and presented MTB epitopes. HLA‐DR4‐restricted, Ag85B or ESAT‐6‐specific CD4+ T cells show similar dynamics over time in peripheral blood mononuclear cells (PBMC) when compared with CD8+ T cells directed against the corresponding HLA‐A2‐presented MTB epitopes in patients with pulmonary MTB infection and subsequent successful therapy. This was not found to be true for T‐cell responses directed against the 19‐kDa lipoprotein. The dissection of the cellular immune response in M. tuberculosis infection will enable novel strategies for monitoring MTB vaccine candidates and to gauge CD4+ T cells directed against MTB.

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Expression of Th1-mediated immunity in mouse lungs induces aMycobacterium tuberculosistranscription pattern characteristic of nonreplicating persistence

Cited by 240 publications

References 41 publications

Global transcriptional response to vancomycin in Mycobacterium tuberculosis

Global transcriptional response to vancomycin in Mycobacterium tuberculosis

Increased pathology in lungs of mice after infection with an α-crystallin mutant of Mycobacterium tuberculosis: changes in cathepsin proteases and certain cytokines

MHC class II Tetramer Guided Detection of Mycobacterium tuberculosis‐specific CD4⁺ T Cells in Peripheral Blood from Patients with Pulmonary Tuberculosis

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Expression of Th1-mediated immunity in mouse lungs induces aMycobacterium tuberculosistranscription pattern characteristic of nonreplicating persistence

Cited by 240 publications

References 41 publications

Global transcriptional response to vancomycin in Mycobacterium tuberculosis

Global transcriptional response to vancomycin in Mycobacterium tuberculosis

Increased pathology in lungs of mice after infection with an α-crystallin mutant of Mycobacterium tuberculosis: changes in cathepsin proteases and certain cytokines

MHC class II Tetramer Guided Detection of Mycobacterium tuberculosis‐specific CD4+ T Cells in Peripheral Blood from Patients with Pulmonary Tuberculosis

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MHC class II Tetramer Guided Detection of Mycobacterium tuberculosis‐specific CD4⁺ T Cells in Peripheral Blood from Patients with Pulmonary Tuberculosis