Isoniazid resistance without a loss of fitness in Mycobacterium tuberculosis

Lee, Jong Hee; Ammerman, Nicole C.; Nolan, Scott T.; Geiman, Deborah E.; Lun, Shichun; Guo, Haidan; Bishai, William R.

doi:10.1038/ncomms1724

Cited by 40 publications

(32 citation statements)

References 24 publications

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“…Johnsson and Schultz [23] subsequently established that INH is a prodrug and requires conversion by the mycobacterial catalaseperoxidase (KatG) encoded by the katG gene. Similarly, a requirement for KatG in the activation of INH during Mtb infection has also been observed in some studies employing in vitro isolated macrophages [24,25], major phagocyte targets involved in the regulation of host/susceptibility to Mtb [26]. Interestingly, it has been recently demonstrated that KatG-activated INH can directly regulate mycobactericidal responses by macrophages [27].…”

Section: Introductionmentioning

confidence: 58%

Isoniazid‐induced control of Mycobacterium tuberculosis by primary human cells requires interleukin‐1 receptor and tumor necrosis factor

et al. 2016

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Proinflammatory cytokines are critical mediators that control Mycobacterium tuberculosis (Mtb) growth during active tuberculosis (ATB). To further inhibit bacterial proliferation in diseased individuals, drug inhibitors of cell wall synthesis such as isoniazid (INH) areemployed. However, whether INH presents an indirect effect on bacterial growth by regulating host cytokines during ATB is not well known. To examine this hypothesis, we used an in vitro human granuloma system generated with primary leukocytes from healthy donors adapted to model ATB. Intense Mtb proliferation in cell cultures was associated with monocyte/macrophage activation and secretion of IL-1β and TNF. Treatment with INH significantly reduced Mtb survival, but altered neither T-cell-mediated Mtb killing, nor production of IL-1β and TNF. However, blockade of both IL-1R1 and TNF signaling rescued INH-induced killing, suggesting synergistic roles of these cytokines in mediating control of Mtb proliferation. Additionally, mycobacterial killing by INH was highly dependent upon drug activation by the pathogen catalase-peroxidase KatG and involved a host PI3K-dependent pathway. Finally, experiments using coinfected (KatG-mutated and H37Rv strains) cells suggested that active INH does not directly enhance host-mediated killing of Mtb. Our results thus indicate that Mtb-stimulated host IL-1 and TNF have potential roles in TB chemotherapy.Keywords: Human r IL-1 r TNF r Isoniazid r Leukocytes r Mycobacterium tuberculosis Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionUpon Mycobacterium tuberculosis (Mtb) exposure, it is estimated that 5-10% of human subjects will develop active tuberculosis Correspondence: Prof. André Báfica e-mail: andre.bafica@ufsc.br (TB) [1], which is characterized by intense pathogen proliferation associated with cellular activation and cell death. Cellular structures known as necrotic granulomas may promote bacterial dissemination and enhance Mtb transmission [2,3]. On the other hand, counter balance is supported by host recognition of Mtb, which induces cytokines such as IL-1β and TNF [4,5], two potent inflammatory mediators that suppress Mtb growth [4,6]. It has C 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol. 2016. 46: 1936-1947 Immunity to infection 1937 been shown that these cytokines regulate intracellular bacterial growth in human macrophages, whether by recruitment of antimicrobial effector molecules [7] or induction of apoptotic cell death [8]. In conjunction with 9], IL-1β, and TNF can provide signals to help differentiation and antigen presentation by macrophages [6,10,11]. Moreover, the adverse outcome of latent TB reactivation observed in clinical trials with anti-TNF therapies, additionally confirmed the essential role of TNF for controlling Mtb growth in humans [12]. In addition to antibiotics, which are major therapeutic tools to promote further suppression of mycobacterial growth [13], host-targeted i...

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Section: Introductionmentioning

confidence: 58%

Isoniazid‐induced control of Mycobacterium tuberculosis by primary human cells requires interleukin‐1 receptor and tumor necrosis factor

et al. 2016

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“…those with a Ser315Thr mutation in the katG gene, which has been recently reported with clustering of MDR-TB [28] and XDR-TB patients [18]. Recent studies have also shown that compensatory mutations in the isoniazid [29] and rifampicin [30] resistance gene conferred high competitive fitness both in vitro and in vivo, favouring the spread of these resistant strains.…”

Section: Discussionmentioning

confidence: 83%

Transmission of multidrug-resistant and extensively drug-resistant tuberculosis in a metropolitan city

Leung

Leung²,

Kam³

et al. 2012

Eur Respir J

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Multidrug-resistant (MDR)-tuberculosis (TB) and extensively drug resistant (XDR)-TB reportedly lead to increased household transmission. This is a retrospective cohort study of active TB occurring among household contacts exposed to MDR-TB.Of 704 contacts in 246 households, initial screening identified 12 (1.7%) TB cases (prevalent cases) and 17 (2.4%) contacts that subsequently developed active TB (secondary cases) after a median (range) duration of 17 (5-62.5) months. Eight prevalent cases and three secondary cases had MDR-TB. TB incidence rates per 100 000 person-years were 254.9 overall and 45.0 for MDR-TB. XDR-TB in the index MDR-TB patient significantly increased the odds of identifying a prevalent TB case to 4.8 (95% CI 1.02-22.5), and the hazard of finding a secondary TB case to 4.7 (95% CI 1.7-13.5). Molecular fingerprinting confirmed household transmission of MDR-TB. Of 20 retrievable isolates from 27 XDR-TB index cases, restriction fragment length polymorphism analysis showed clustering among 13 (65%), with 11 (55%) due to recent transmission by n-1 method and an identifiable household source in only three (27.2%) of the 11 cases.XDR-TB relative to MDR-TB significantly increases household transmission of TB, probably reflecting prolonged/higher infectivity, and indicating a need for prolonged household surveillance. XDR-TB may largely transmit outside of the household settings.

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“…Although the enoyl-acyl carrier protein reductase InhA is the most described, other mechanisms and enzymes may be involved, such as the human arylamine N-acetyltransferase (NAT) polymorphism, the TB NAT that is also required for mycolic acid synthesis, the MDP1 gene, or even the loss of a sigma factor (34)(35)(36)(37)(38). Mycobacterial NudC may also play an important role in the inactivation of INH (39).…”

Section: Discussionmentioning

confidence: 99%

Tuberculosis-Spoligo-Rifampin-Isoniazid Typing: an All-in-One Assay Technique for Surveillance and Control of Multidrug-Resistant Tuberculosis on Luminex Devices

et al. 2013

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e As a follow-up of the "spoligoriftyping" development, we present here an extension of this technique which includes the detection of isoniazid resistance-associated mutations in a new 59-plex assay, i.e., tuberculosis-spoligo-rifampin-isoniazid typing (TB-SPRINT), running on microbead-based multiplexed systems. This assay improves the synergy between clinical microbiology and epidemiology by providing (i) mutation-based prediction of drug resistance profiles for patient treatment and (ii) genotyping data for tuberculosis (TB) surveillance. This third-generation microbead-based high-throughput assay for TB runs on the Luminex 200 system and on the recently launched MagPix system (Luminex, Austin, TX). Spoligotyping patterns obtained by the TB-SPRINT method were 100% (n ‫؍‬ 85 isolates; 3,655/3,655 spoligotype data points) concordant with those obtained by microbead-based and membrane-based spoligotyping. Genetic drug susceptibility typing provided by the TB-SPRINT method was 100% concordant with resistance locus sequencing (n ‫؍‬ 162 for rpoB gene sequencing and n ‫؍‬ 76 for katG and inhA sequencing). Considering phenotypic drug susceptibility testing (DST) as the reference method, the sensitivity and specificity of TB-SPRINT regarding Mycobacterium tuberculosis complex (n ‫؍‬ 162 isolates) rifampin resistance were both 100%, and those for isoniazid resistance were 90.4% (95% confidence interval, 85 to 95%) and 100%, respectively. Used routinely in national TB reference and specialized laboratories, the TB-SPRINT assay should simultaneously improve personalized medicine and epidemiological surveillance of multidrug-resistant (MDR) TB. This assay is expected to play an emerging role in public health in countries with heavy burdens of MDR TB and/or HIV/TB coinfection. Application of this assay directly to biological samples, as well as development for extensively drug-resistant (XDR) TB detection by inclusion of second-line antituberculosis drug-associated mutations, is under development. With bioinformatical methods and data mining to reduce the number of targets to the most informative ones, locally adapted formats of this technique can easily be developed everywhere.

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Isoniazid resistance without a loss of fitness in Mycobacterium tuberculosis

Cited by 40 publications

References 24 publications

Isoniazid‐induced control of Mycobacterium tuberculosis by primary human cells requires interleukin‐1 receptor and tumor necrosis factor

Isoniazid‐induced control of Mycobacterium tuberculosis by primary human cells requires interleukin‐1 receptor and tumor necrosis factor

Transmission of multidrug-resistant and extensively drug-resistant tuberculosis in a metropolitan city

Tuberculosis-Spoligo-Rifampin-Isoniazid Typing: an All-in-One Assay Technique for Surveillance and Control of Multidrug-Resistant Tuberculosis on Luminex Devices

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