Development of new antituberculous drugs based on bacterial virulence factors interfering with host cytokine networks

Tomioka, Haruaki; Tatano, Yutaka; Sano, Chiaki; Shimizu, Toshiaki

doi:10.1007/s10156-010-0177-y

Cited by 21 publications

(15 citation statements)

References 116 publications

(150 reference statements)

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“…It has been documented that lipid metabolism is a major determinant of virulence in the MTBC either through its role in shaping the proteins and lipids that form the cell wall or in other cell surface modulation independent processes (Sonawane et al 2012; Forrellad et al 2013; Reddy et al 2013). These virulence factors serve as targets for antimicrobial drug development (Tomioka et al 2011; Wang et al 2013; North et al 2013). Here, we found that the most important gene gains in fatty acid and siderophore biosynthesis (Campbell and Cronan 2001; Rodriguez 2006) and carbohydrate membrane transport (Titgemeyer et al 2007; Niederweis 2008) likely took place in the ancestral lineage that led to the pathogenic clade, after the split of M. marinum and M. ulcerans .…”

Section: Discussionmentioning

confidence: 99%

Mycobacterial Phylogenomics: An Enhanced Method for Gene Turnover Analysis Reveals Uneven Levels of Gene Gain and Loss among Species and Gene Families

Librado

Vieira

Sánchez-Gracia

et al. 2014

Genome Biology and Evolution

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Species of the genus Mycobacterium differ in several features, from geographic ranges, and degree of pathogenicity, to ecological and host preferences. The recent availability of several fully sequenced genomes for a number of these species enabled the comparative study of the genetic determinants of this wide lifestyle diversity. Here, we applied two complementary phylogenetic-based approaches using information from 19 Mycobacterium genomes to obtain a more comprehensive view of the evolution of this genus. First, we inferred the phylogenetic relationships using two new approaches, one based on a Mycobacterium-specific amino acid substitution matrix and the other on a gene content dissimilarity matrix. Then, we utilized our recently developed gain-and-death stochastic models to study gene turnover dynamics in this genus in a maximum-likelihood framework. We uncovered a scenario that differs markedly from traditional 16S rRNA data and improves upon recent phylogenomic approaches. We also found that the rates of gene gain and death are high and unevenly distributed both across species and across gene families, further supporting the utility of the new models of rate heterogeneity applied in a phylogenetic context. Finally, the functional annotation of the most expanded or contracted gene families revealed that the transposable elements and the fatty acid metabolism-related gene families are the most important drivers of gene content evolution in Mycobacterium.

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Section: Discussionmentioning

confidence: 99%

Mycobacterial Phylogenomics: An Enhanced Method for Gene Turnover Analysis Reveals Uneven Levels of Gene Gain and Loss among Species and Gene Families

Librado

Vieira

Sánchez-Gracia

et al. 2014

Genome Biology and Evolution

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“…Potential improvement could be obtained by new drug combinations including novel drugs such as the diarylquinoline TMC207 [181], or combinations with immunopotentiators [182,183]. The availability of treatment regimens with equal or better effectiveness that require shorter treatment durations and have fewer interactions with immunosuppressive drugs compared to current anti-TB therapies are desirable for both active disease and LTBI.…”

Section: Improvements On Therapymentioning

confidence: 99%

The risk of tuberculosis in transplant candidates and recipients: a TBNET consensus statement

Bumbăcea

Arend

Eyüboğlu³

et al. 2012

Eur Respir J

228

261

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Tuberculosis (TB) is a possible complication of solid organ and hematopoietic stem cell transplantation. The identification of candidates for preventive chemotherapy is an effective intervention to protect transplant recipients with latent infection with Mycobacterium tuberculosis from progressing to active disease. The best available proxy for diagnosing latent infection with M. tuberculosis is the identification of an adaptive immune response by the tuberculin skin test or an interferon-c based ex vivo assay. Risk assessment in transplant recipients for the development of TB depends on, among other factors, the locally expected underlying prevalence of infection with M. tuberculosis in the target population. In areas of high prevalence, preventive chemotherapy for all transplant recipients may be justified without immunodiagnostic testing while in areas of medium and low prevalence, preventive chemotherapy should only be offered to candidates with positive M. tuberculosis-specific immune responses. The diagnosis of TB in transplant recipients can be challenging. Treatment of TB is often difficult due to substantial interactions between anti-TB drugs and immunosuppressive medications. This management guideline summarises current knowledge on the prevention, diagnosis and treatment of TB related to solid organ and hematopoietic stem cell transplantation and provides an expert consensus on questions where scientific evidence is still lacking. KEYWORDS: Guideline, management, Mycobacterium tuberculosis, transplantation, tuberculosis T uberculosis (TB) is caused by the pathogenic species of the Mycobacterium tuberculosis complex. Only a minority of individuals who develop an adaptive immune response following infection with M. tuberculosis will ever develop TB, with the actual risk depending on the extent to which the host immune system provides a successful or inadequate response [1,2]. Therefore, individuals with impaired immune response, such as solid organ transplant (SOT) and hematopoietic stem cell transplant (HSCT) recipients, are more prone to develop TB than immunocompetent persons. TB in transplant recipients is more frequent compared to the general population (estimates from the last decades state 20-74 times as frequent in SOT [3,4] and twice as frequent in HSCT [5]), and more often fatal (up to 31% in SOT [6] and up to 50% in HSCT recipients [7]), thus adding effectiveness to interventions for its prevention, even in the face of difficulties, with treatment related to adverse drug events and drug-drug interactions. Active TB in transplant recipients can result from latent infection with M. tuberculosis (LTBI) in the transplant candidate or in the donor tissue, or from de novo post-transplant infection. These various scenarios prompt for targeted pre-transplant screening of both recipient and, if possible, donors to allow focused management of recipients selected for preventive intervention in the pre-and/or posttransplant period. The term ''preventive chemotherapy'' is used to denote treatmen...

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“…In general, during the early to middle stages of mycobacterial infections, Th1 cell-mediated immune responses are dominant and play crucial roles in the establishment and expression of antimycobacterial host resistance (Figure 1) [11, 12]. However, in the advanced stages of mycobacterial infections such as TB and M. avium infection, host immune systems tend to adopt a Th2-type immune response through the induction and activation of Th2 cells, thereby resulting in a diminishment of Th1 cell- and activated macrophage-mediated antimycobacterial cellular immunity (Figure 1) [13–17].…”

Section: Introductionmentioning

confidence: 99%

Characteristics of Suppressor Macrophages Induced by Mycobacterial and Protozoal Infections in relation to Alternatively Activated M2 Macrophages

Tomioka

Tatano

Maw

et al. 2012

Clinical and Developmental Immunology

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In the advanced stages of mycobacterial infections, host immune systems tend to change from a Th1-type to Th2-type immune response, resulting in the abrogation of Th1 cell- and macrophage-mediated antimicrobial host protective immunity. Notably, this type of immune conversion is occasionally associated with the generation of certain types of suppressor macrophage populations. During the course of Mycobacterium tuberculosis (MTB) and Mycobacterium avium-intracellulare complex (MAC) infections, the generation of macrophages which possess strong suppressor activity against host T- and B-cell functions is frequently encountered. This paper describes the immunological properties of M1- and M2-type macrophages generated in tumor-bearing animals and those generated in hosts with certain microbial infections. In addition, this paper highlights the immunological and molecular biological characteristics of suppressor macrophages generated in hosts with mycobacterial infections, especially MAC infection.

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Development of new antituberculous drugs based on bacterial virulence factors interfering with host cytokine networks

Cited by 21 publications

References 116 publications

Mycobacterial Phylogenomics: An Enhanced Method for Gene Turnover Analysis Reveals Uneven Levels of Gene Gain and Loss among Species and Gene Families

Mycobacterial Phylogenomics: An Enhanced Method for Gene Turnover Analysis Reveals Uneven Levels of Gene Gain and Loss among Species and Gene Families

The risk of tuberculosis in transplant candidates and recipients: a TBNET consensus statement

Characteristics of Suppressor Macrophages Induced by Mycobacterial and Protozoal Infections in relation to Alternatively Activated M2 Macrophages

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