Experimental Tuberculosis in the Wistar Rat: A Model for Protective Immunity and Control of Infection

Singhal, Amit; Aliouat, El Moukhtar; Hervé, Maxime; Mathys, Vanessa; Kiass, Mehdi; Creusy, Colette; Delaire, Baptiste; Tsenova, Liana; Fleurisse, Laurence; Bertout, Julie; Camacho, Luis R.; Foo, Damian Guang Wei; Tay, Hui Chien; Siew, Jie Yee; Boukhouchi, Warda; Romano, Márta; Mathema, Barun; Dartois, Véronique; Kaplan, Gilla; Bifani, Pablo

doi:10.1371/journal.pone.0018632

Cited by 41 publications

(42 citation statements)

References 30 publications

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“…[12]. We therefore examined whether BCG vaccination could induce complete clearance of Mtb W4 in lungs in a larger number of infected rat.…”

Section: Resultsmentioning

confidence: 99%

“…The strain was cultured in stationary Sauton medium in 500 ml cellular culture flasks to mid-log phase, washed, pelleted, re-suspended in phosphate-buffered saline (PBS), vortexed with 2 mm glass beads and prepared for infection as described [12]. For vaccination, M. bovis BCG strain Pasteur was cultured in Dubos broth base (Difco) supplemented with 10% Dubos medium albumin at 37°C.…”

Section: Methodsmentioning

confidence: 99%

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BCG Induces Protection against Mycobacterium tuberculosis Infection in the Wistar Rat Model

et al. 2011

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Our understanding of the correlation of Mycobacterium bovis Bacille Calmette-Guerin (BCG)-mediated immune responses and protection against Mycobacterium tuberculosis (Mtb) infection is still limited. We have recently characterized a Wistar rat model of experimental tuberculosis (TB). In the present study, we evaluated the efficacy of BCG vaccination in this model. Upon Mtb challenge, BCG vaccinated rats controlled growth of the bacilli earlier than unvaccinated rats. Histopathology analysis of infected lungs demonstrated a reduced number of granulomatous lesions and lower parenchymal inflammation in vaccinated animals. Vaccine-mediated protection correlated with the rapid accumulation of antigen specific CD4+ and CD8+ T cells in the infected lungs. Immunohistochemistry further revealed higher number of CD8+ cells in the pulmonary granulomas of vaccinated animals. Evaluation of pulmonary immune responses in vaccinated and Mtb infected rats by real time PCR at day 15 post-challenge showed reduced expression of genes responsible for negative regulation of Th1 immune responses. Thus, early protection observed in BCG vaccinated rats correlated with a similarly timed shift of immunity towards the Th1 type response. Our data support the importance of (i) the Th1-Th2 balance in the control of mycobacterial infection and (ii) the value of the Wistar rats in understanding the biology of TB.

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“…[12]. We therefore examined whether BCG vaccination could induce complete clearance of Mtb W4 in lungs in a larger number of infected rat.…”

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

BCG Induces Protection against Mycobacterium tuberculosis Infection in the Wistar Rat Model

et al. 2011

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“…Our group has recently shown that Wistar rats can form organized granulomas. We have also observed that the Wistar rat can develop subclinical manifestations of human disease with no detectable CFU in the lung, where bacilli can be reactivated upon immunosuppression (32). 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.…”

Section: Discussionmentioning

confidence: 99%

“…It has also helped to identify markers of disease and surrogate markers of drug response in chronic inflammation and age-related diseases (2,17,26). Recent studies, including some from our group, have also shown that M. tuberculosis-infected rats develop organized granulomas within the lungs while controlling the infection over time (32). This suggests that the rat may be a good alternative to the mouse model for in vivo drug efficacy studies (4,34).…”

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confidence: 97%

T Cell Monitoring of Chemotherapy in Experimental Rat Tuberculosis

Foo

Tay

Siew

et al. 2011

Antimicrob Agents Chemother

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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...

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“…Foamy macrophages have been observed in a number of inflammatory conditions, including infectious and noninfectious diseases, such as natural and experimental TB in particular (11)(12)(13)(14)(15)(16). M. tuberculosis slows its multiplication rate in foamy macrophages and accumulates LD in its own cytoplasm.…”

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Mycobacteria and the Greasy Macrophage: Getting Fat and Frustrated

Neyrolles

2014

Infect Immun

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In the current issue of Infection and Immunity, Caire-Brändli and coworkers (Infect. Immun. 82:476 -490, 2014, doi:10.1128 /IAI.01196-13) describe a novel cell system for studying mycobacterial interactions with foamy macrophages and provide a magnificent series of electron microscopy-based observations providing major insight into the microbiology and cell biology of these interactions. With nearly 9 million new cases and 1.3 million deaths each year, as indicated by the World Health Organization (WHO) in its 2013 global report (1), tuberculosis (TB) remains a leading cause of mortality due to a single bacterial pathogen, namely Mycobacterium tuberculosis. The development of new tools for controlling, and possibly even eradicating TB, such as new antimicrobial drugs, a more effective vaccine than Mycobacterium bovis BCG, and innovative host-targeted strategies (2), is hampered primarily by the incomplete nature of our understanding of the molecular and cellular aspects of host-pathogen interactions in TB.Pulmonary macrophages are the primary host cells for the TB bacillus (3, 4). M. tuberculosis thrives in these cells during the first few weeks of infection, until adaptive immunity kicks in, helping the body to control the proliferation of the pathogen through cytokine-mediated macrophage activation and other mechanisms (5). The continued recruitment of T and B lymphocytes to the site of infection and the concomitant death of infected macrophages leads to the formation of a complex structure with a well-organized architecture, the granuloma, a hallmark of TB (6-8). M. tuberculosis can persist for decades within the granuloma, in a dormant state referred to as "latency." It has been estimated that up to 2 billion individuals may carry such latent infection and that the disease will reactivate in about 10% of these individuals, at some point in their lifetime.One of the most striking features of the TB granuloma is the presence around the lesion of a specific population of histiocytes/ macrophages enriched in lipid droplets (LD) and known as foamy macrophages (9, 10). Foamy macrophages have been observed in a number of inflammatory conditions, including infectious and noninfectious diseases, such as natural and experimental TB in particular (11-16). M. tuberculosis slows its multiplication rate in foamy macrophages and accumulates LD in its own cytoplasm. It has been suggested that foamy macrophages (i) constitute a reservoir of nutrients for the pathogen during latency, supplying carbon and energy, in particular, via various lipids, including triacylglycerol (TAG) (9, 10), and (ii) participate in the formation of the caseous center of the granuloma after the death of the macrophages, releasing their lipid content (10,17). The mechanisms by which mycobacteria induce foam cell differentiation and by which LD accumulate in the bacterial cytoplasm within infected cells remain interesting areas of investigation. In particular, the way in which the intracellular mycobacterial vacuole, or phagosome, interacts with the ...

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Experimental Tuberculosis in the Wistar Rat: A Model for Protective Immunity and Control of Infection

Cited by 41 publications

References 30 publications

BCG Induces Protection against Mycobacterium tuberculosis Infection in the Wistar Rat Model

BCG Induces Protection against Mycobacterium tuberculosis Infection in the Wistar Rat Model

T Cell Monitoring of Chemotherapy in Experimental Rat Tuberculosis

Mycobacteria and the Greasy Macrophage: Getting Fat and Frustrated

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