Mycobacterium tuberculosis infection induces hypoxic lung lesions in the rat

Heng, YiXiong; Seah, Peck Gee; Siew, Jie Yee; Tay, Hui Chien; Singhal, Amit; Mathys, Vanessa; Kiass, Mehdi; Bifani, Pablo; Dartois, Véronique; Hervé, Maxime

doi:10.1016/j.tube.2011.05.003

Cited by 21 publications

(14 citation statements)

References 8 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, growing evidence has revealed that the extent of hypoxia associated within a given host varies widely based on the size, location, and composition of the microenvironment (31)(32)(33). Our studies modeled quiescent M. tuberculosis using an O 2 environment of 1%, but the metabolic principle revealed may have broader significance, namely, the ability of succinate to serve as a biochemical bridge between oxidative and fermentative metabolic states.…”

Section: Discussionmentioning

confidence: 98%

Multifunctional essentiality of succinate metabolism in adaptation to hypoxia in Mycobacterium tuberculosis

Eoh

Rhee

2013

Proc. Natl. Acad. Sci. U.S.A.

255

330

View full text Add to dashboard Cite

Mycobacterium tuberculosis is a chronic, facultative intracellular pathogen that spends the majority of its decades-long life cycle in a non-or slowly replicating state. However, the bacterium remains poised to resume replicating so that it can transmit itself to a new host. Knowledge of the metabolic adaptations used to facilitate entry into and exit from nonreplicative states remains incomplete. Here, we apply 13 C-based metabolomic profiling to characterize the activity of M. tuberculosis tricarboxylic acid cycle during adaptation to and recovery from hypoxia, a physiologically relevant condition associated with nonreplication. We show that, as M. tuberculosis adapts to hypoxia, it slows and remodels its tricarboxylic acid cycle to increase production of succinate, which is used to flexibly sustain membrane potential, ATP synthesis, and anaplerosis, in response to varying degrees of O 2 limitation and the presence or absence of the alternate electron acceptor nitrate. This remodeling is mediated by the bifunctional enzyme isocitrate lyase acting in a noncanonical role distinct from fatty acid catabolism. Isocitrate lyase-dependent production of succinate affords M. tuberculosis with a unique and bioenergetically efficient metabolic means of entry into and exit from hypoxia-induced quiescence. Q uiescence, or exit from cell cycle, is a physiologic prerogative of all cells, executed irreversibly by some upon terminal differentiation and reversibly by others as they adapt to changing conditions (1). For Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), quiescence has emerged as a hallmark of its pathogenicity. M. tuberculosis infects approximately one in every three people worldwide and is the leading bacterial cause of death. Following infection, M. tuberculosis enters a clinically asymptomatic state of non-or slowly replicating physiology that often lasts decades, if not the lifetime, of the infected host, and exhibits a form of nonheritable resistance to nearly all TB drugs that has hindered mass eradication strategies (2). Clinical TB arises when M. tuberculosis reenters cell cycle and provokes an inflammatory response that inflicts host tissue damage and enables it to transmit itself to a new host. However, some of the M. tuberculosis in active TB is nonreplicating. This is thought to impose the need for chemotherapies that are longer and more complex than for virtually any other bacterial infection (2-7). However, biochemical knowledge of quiescent M. tuberculosis remains highly incomplete.Relieved of the requirement to double biomass, quiescent cells have generally been perceived to have minimal metabolic activity. However, quiescent cells often occupy ecological niches that are highly dynamic and face the challenge of preserving both their viability and their ability to reenter cell cycle. Fibroblasts induced into quiescence by contact inhibition metabolized glucose through all branches of central carbon metabolism at a rate similar to those of proliferating cells (8). Such studies ha...

show abstract

Section: Discussionmentioning

confidence: 98%

Multifunctional essentiality of succinate metabolism in adaptation to hypoxia in Mycobacterium tuberculosis

Eoh

Rhee

2013

Proc. Natl. Acad. Sci. U.S.A.

255

330

View full text Add to dashboard Cite

show abstract

“…The Wayne model is designed to specifically mimic the low-oxygen concentration measured in lung lesions of M. tuberculosis humans and some animal models (Tsai et al, 2006;Via et al, 2008;Heng et al, 2011;Harper et al, 2012). Prolonged hypoxia of inflammatory cells that respond to lung infection likely contributes to individual cell death and lesion necrosis, which releases bacilli from infected cells into the extracellular matrix (Basaraba, 2008).…”

Section: Introductionmentioning

confidence: 99%

Expression of antimicrobial drug tolerance by attached communities ofMycobacterium tuberculosis

et al. 2014

View full text Add to dashboard Cite

There is an urgent need to improve methods used to screen anti-tuberculosis drugs. An in vitro assay was developed to test drug treatment strategies that specifically target drug-tolerant Mycobacterium tuberculosis. The H37Rv strain of M. tuberculosis survived antimicrobial treatment as attached microbial communities when maintained in tissue culture media (RPMI-1640) with or without lysed human peripheral blood leukocytes. When cultured planktonically in the presence of Tween-80, bacilli failed to form microbial communities or reach logarithmic phase growth yet remained highly susceptible to antimicrobial drugs. In the absence of Tween, bacilli tolerated drug therapy by forming complex microbial communities attached to untreated well surfaces or to the extracellular matrix derived from lysed human leukocytes. Treatment of microbial communities with DNase I or Tween effectively dispersed bacilli and restored drug susceptibility. These data demonstrate that in vitro expression of drug tolerance by M. tuberculosis is linked to the establishment of attached microbial communities and that dispersion of bacilli targeting the extracellular matrix including DNA restores drug susceptibility. Modifications of this in vitro assay may prove beneficial in a high throughput platform to screen new anti-tuberculosis drugs especially those that target drug tolerant bacilli.

show abstract

“…Furthermore, we tested the hypothesis that during the chronic phase of infection the Wistar rat could develop hypoxic lesions that may favor dormancy and phenotypic drug tolerance. We did observe a pimonidazole staining within rat granulomas, indicative of low oxygen tension (12). Therefore, the Wistar rat could be a relevant preclinical model to test new chemical entities and evaluate drug response through new innovative biological assays based on the ELISpot assay concept.…”

Section: Discussionmentioning

confidence: 78%

T Cell Monitoring of Chemotherapy in Experimental Rat Tuberculosis

Foo

Tay

Siew

et al. 2011

Antimicrob Agents Chemother

Self Cite

View full text Add to dashboard Cite

Mycobacterium tuberculosis is the causative agent of a pulmonary epidemic that is estimated to infect one-third of the world's population and that has an increased incidence of multidrug resistance. The evaluation of new chemical entities against M. tuberculosis is hampered by the lack of biological tools to help predict efficacy, from early drug development to clinical trials. As the rat is the animal species of choice in the pharmaceutical industry, we have developed a rat model of acute and chronic phases of M. tuberculosis infection for drug efficacy testing. In this model, we have evaluated the impact of tuberculosis drugs on T cell response using the enzyme-linked immunospot assay methodology. Infected rats treated with isoniazid (INH) or rifampin (RIF) responded to therapy, the potency of which was comparable to that seen in the mouse. Peripheral blood mononuclear cells from infected rats produced gamma interferon (IFN-␥) in response to RD-1 antigens, such as the 6-kDa early secretory antigen target (ESAT-6) and the 10-kDa culture filtrate protein (CFP-10). A decrease in IFN-␥ spot-forming cells (SFCs) was consistently observed in response to drug treatment. In both the acute-and chronic-phase models, the T cell response was more sensitive to ESAT-6 than to CFP-10. The SFC count in response to ESAT-6 appears to be an indicator of bacterial killing in the rat. Collectively, our data suggest that the ESAT-6 response could be used as a potential surrogate of drug efficacy in the rat and that such a readout could help shorten drug testing during preclinical development.Mycobacterium tuberculosis infection is among the world's leading infectious diseases, causing about 2 million deaths annually. The emergence of multidrug-resistant M. tuberculosis strains along with the increase of HIV coinfected cases worsens the situation (42). In countries with a high incidence of tuberculosis (TB), TB control programs rely on a diagnostic methods and drugs that have been developed decades ago and that are inadequate to effectively control the epidemic. The urgent need to develop new diagnostic tools as well as new therapeutic interventions is hampered by long clinical trials, where markers of infection and drug response are lacking (38).For decades, the tuberculin skin test (TST) has been used to diagnose TB (18). The TST measures cell-mediated immunity in the form of a delayed-type hypersensitivity response to the purified protein derivative (PPD), a crude mixture of antigens shared among M. tuberculosis, Mycobacterium bovis BCG, and several nontuberculous mycobacteria (NTM). As a result, the TST has lower specificity in populations with high BCG coverage and NTM exposure and shows poor sensitivity in immunocompromised individuals (30). The gamma interferon (IFN-␥) enzyme-linked immunospot (ELISpot) assay has emerged as an alternative to the TST. The assay consists of in vitro stimulation of peripheral blood mononuclear cells (PBMCs) using RD-1 antigens, the 6-kDa early secretory antigen target (ESAT-6) and the 10-kDa cul...

show abstract

Mycobacterium tuberculosis infection induces hypoxic lung lesions in the rat

Cited by 21 publications

References 8 publications

Multifunctional essentiality of succinate metabolism in adaptation to hypoxia in Mycobacterium tuberculosis

Multifunctional essentiality of succinate metabolism in adaptation to hypoxia in Mycobacterium tuberculosis

Expression of antimicrobial drug tolerance by attached communities ofMycobacterium tuberculosis

T Cell Monitoring of Chemotherapy in Experimental Rat Tuberculosis

Contact Info

Product

Resources

About