HspX knock-out in Mycobacterium tuberculosis leads to shorter antibiotic treatment and lower relapse rate in a mouse model – A potential novel therapeutic target

Hu, Yan; Liu, Alexander; Menéndez, M. Carmen; García, María Jesús García; Oravcova, Katarina; Gillespie, Stephen H.; Davies, Geraint R.; Mitchison, D.A.; Coates, Anthony R. M.

doi:10.1016/j.tube.2014.11.002

Cited by 12 publications

(13 citation statements)

References 24 publications

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“…Deletion or chemical inhibition in vitro of HspX in M. tuberculosis decreased viability in hypoxia 36,38 . When mice were infected by an HspX-deficient strain of M. tuberculosis , the strain grew to a greater organ burden compared with the wild-type parent strain, but was more rapidly cleared upon antibiotic treatment, suggesting that HspX played potentially opposing roles in fitness to the host versus antibiotics in that model 39 . By sorting insoluble protein aggregates to a distinct cellular location, HspX acts to compartmentalize the cell in the absence of membrane-bound organelles.…”

Section: Discussionmentioning

confidence: 99%

HspX promotes the polar localization of mycobacterial protein aggregates

Zhang

Zhu

Wang

et al. 2019

Sci Rep

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Misfolding of translated proteins occurs in all domains of life. In most cells, misfolded proteins coalesce in discrete aggregates at distinct cellular locations. In many bacteria, including mycobacteria, protein aggregates are located at the cellular pole. Yet the mechanism by which aggregates are sorted to the mycobacterial pole is not known. Here, we show that in Mycobacterium smegmatis, the small heat shock protein HspX plays a critical role in the polar localization of aggregates of a model fluorescent misfolded protein, GLR103. HspX itself has a polar localization, which is dependent on its N-terminal domain. In a strain deleted for hspX, GLR103 is less liable to aggregation and no longer localizes to the pole, and redirecting HspX to the septum radically disrupts the normal polar localization of GLR103 aggregates. To further investigate the role of HspX in native protein aggregation, we performed semi-quantitative mass-spectrometry of mycobacterial protein aggregates in wild-type, hspX-deleted and hspX-overexpressing strains. We identified a subset of proteins that appeared to be HspX-dependent for aggregate formation. Furthermore, we demonstrate that for validated native protein aggregates, sorting to the cellular pole following proteotoxic stress required HspX. In summary, we have identified the cellular function of HspX in Mycobacterium smegmatis as both a pro-aggregase and polar sortase.

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Section: Discussionmentioning

confidence: 99%

HspX promotes the polar localization of mycobacterial protein aggregates

Zhang

Zhu

Wang

et al. 2019

Sci Rep

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“…It is characterized by the inoculation of a large number of bacteria intravenously to initiate an infection and the treatment of the disease once the infection has been established (2 to 3 weeks postinfection). In this model, an intensive treatment is able to render mouse organs culture negative on agar plates and in broth culture lacking culture filtrate, but it fails to prevent relapse ( 10 , 11 ). However, these apparently culture-negative organs contained viable bacteria that could be cultivated by supplementing broth media with culture filtrate ( 6 ) containing RPF ( 7 ).…”

Section: Discussionmentioning

confidence: 99%

“…Female BALB/c mice (6 to 8 weeks old) were obtained from Harlan United Kingdom Ltd. A total of 364 mice were infected intravenously via the tail vein with 1.2 × 10 5 CFU of mouse-passaged M. tuberculosis strain H37Rv per mouse as described previously ( 8 , 10 , 11 ). The animal husbandry guidelines and all animal experiments were performed according to the Animals Scientific Procedures Act, 1986 (an Act of the Parliament of the United Kingdom 1986 c. 14) (Home Office Project license Number 70/7077) with approval from the St. George's, University of London, ethics committee.…”

Section: Methodsmentioning

confidence: 99%

Investigation of Elimination Rate, Persistent Subpopulation Removal, and Relapse Rates of Mycobacterium tuberculosis by Using Combinations of First-Line Drugs in a Modified Cornell Mouse Model

Pertinez

Ortega-Muro

et al. 2016

Antimicrob Agents Chemother

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Currently, the most effective tuberculosis control method involves case finding and 6 months of chemotherapy. There is a need to improve our understanding about drug interactions, combination activities, and the ability to remove persistent bacteria using the current regimens, particularly in relation to relapse. We aimed to investigate the therapeutic effects of three main components, rifampin (RMP), isoniazid (INH), and pyrazinamide (PZA), in current drug regimens using a modified version of the Cornell mouse model. We evaluated the posttreatment levels of persistent Mycobacterium tuberculosis in the organs of mice using culture filtrate derived from M. tuberculosis strain H37Rv. When RMP was combined with INH, PZA, or INH-PZA, significant additive activities were observed compared to each of the single-drug treatments. However, the combination of INH and PZA showed a less significant additive effect than either of the drugs used on their own. Apparent culture negativity of mouse organs was achieved at 14 weeks of treatment with RMP-INH, RMP-PZA, and RMP-INH-PZA, but not with INH-PZA, when conventional tests, namely, culture on solid agar and in liquid broth, indicated that the organs were negative for bacteria. The relapse rates for RMP-containing regimens were not significantly different from a 100% relapse rate at the numbers of mice examined in this study. In parallel, we examined the organs for the presence of culture filtrate-dependent persistent bacilli after 14 weeks of treatment. Culture filtrate treatment of the organs revealed persistent M. tuberculosis. Modeling of mycobacterial elimination rates and evaluation of culture filtrate-dependent organisms showed promise as surrogate methods for efficient factorial evaluation of drug combinations in tuberculosis in mouse models and should be further evaluated against relapse. The presence of culture filtrate-dependent persistent M. tuberculosis is the likely cause of disease relapse in this modified Cornell mouse model.

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“…In developing countries implementation of MDR-TB control programmeis challenging. Hence, novel therapeutic targets, especially those associated with M. tuberculosis dormancy that can potentially shorten the duration of chemotherapy and reduce relapse rates would be of great value [21]. …”

Section: Latent Tuberculosismentioning

confidence: 99%

Expression of Alpha Crystallin Protein in Osteoarticular Tuberculosis in Latent Phase: A Review of Evidences

Rizivi¹,

Singh²,

Ali³

et al. 2015

Int Jour of Biomed Res

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Due to scarcity of bacilli, an accurate diagnosis of osteoarticular tuberculosis is always being a challenge. Though conventional methods lack sensitivity and are time consuming, molecular diagnostic modalities are very effective for early diagnosis with high sensitivity and specificity. Timely diagnosis even in latent period will improve the efficacy of the treatment of osteoarticular tuberculosis. Under some stress conditions like hypoxia, nitric oxide stress, long term viability of M. tuberculosis is favoured by alpha crystallin protein (acr), which is adominant protein of latent phase. In this article we focus on protein that shows significant expression in the latent phase of M.tuberculosis. It may be further used as a prognostic biomarker for differentiating latent and active tuberculosis.

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HspX knock-out in Mycobacterium tuberculosis leads to shorter antibiotic treatment and lower relapse rate in a mouse model – A potential novel therapeutic target

Cited by 12 publications

References 24 publications

HspX promotes the polar localization of mycobacterial protein aggregates

HspX promotes the polar localization of mycobacterial protein aggregates

Investigation of Elimination Rate, Persistent Subpopulation Removal, and Relapse Rates of Mycobacterium tuberculosis by Using Combinations of First-Line Drugs in a Modified Cornell Mouse Model

Expression of Alpha Crystallin Protein in Osteoarticular Tuberculosis in Latent Phase: A Review of Evidences

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