The American cotton rat: A novel model for pulmonary tuberculosis

Elwood, Robert L.; Wilson, Samuel; Blanco, Jorge C. G.; Yim, Kevin C.; Pletneva, Luba; Никоненко, Б. В.; Samala, Rowena; Joshi, Swati; Hemming, Val G.; Trucksis, Michele

doi:10.1016/j.tube.2006.07.001

Cited by 38 publications

(38 citation statements)

References 18 publications

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“…In recent years, there are many reports on rat M. tuberculosis infection models for investigating immunology and pathology of tuberculosis [12–15, 19]. A report indeed showed that granulomas in M. tuberculosis infected American cotton rats [12] exhibit caseous central necrosis similar to humans thereby adding additional value to the animal model.…”

Section: Discussionmentioning

confidence: 99%

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Aerosol Infection Model of Tuberculosis in Wistar Rats

Gaonkar

Srinivasan

Kumar

et al. 2010

International Journal of Microbiology

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We explored suitability of a rat tuberculosis aerosol infection model for investigating the pharmacodynamics of new antimycobacterial agents. Infection of rats via the aerosol route led to a reproducible course of M. tuberculosis infection in the lungs. The pulmonary bacterial load increased logarithmically during the first six weeks, thereafter, the infection stabilized for the next 12 weeks. We observed macroscopically visible granulomas in the lungs with demonstrable acid-fast bacilli and associated histopathology. Rifampicin (RIF) at a dose range of 30 to 270 mg/kg exhibited a sharp dose response while isoniazid (INH) at a dose range of 10 to 90 mg/kg and ethambutol (EMB) at 100 to 1000 mg/kg showed shallow dose responses. Pyrazinamide (PZA) had no dose response between 300 and 1000 mg/kg dose range. In a separate time kill study at fixed drug doses (RIF 90 mg/kg, INH 30 mg/kg, EMB 300 mg/kg, and PZA 300 mg/kg) the bactericidal effect of all the four drugs increased with longer duration of treatment from two weeks to four weeks. The observed infection profile and therapeutic outcomes in this rat model suggest that it can be used as an additional, pharmacologically relevant efficacy model to develop novel antitubercular compounds at the interface of discovery and development.

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Section: Discussionmentioning

confidence: 99%

“…In recent years, several rat strains like Lewis, American cotton rats [12], and diabetic rat strains [13] have been successfully used to develop infection model of tuberculosis, particularly for investigating pathology and immune responses [14, 15]. However, there are no reports on therapy of tuberculosis in rat infection model.…”

Section: Introductionmentioning

confidence: 99%

Aerosol Infection Model of Tuberculosis in Wistar Rats

Gaonkar

Srinivasan

Kumar

et al. 2010

International Journal of Microbiology

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“…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). The rat offers the additional advantage of providing larger volumes of body fluids and larger numbers of PBMCs than the mouse, which makes the model attractive to study the response of circulating immune cells as it is performed in tuberculosis patients.…”

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confidence: 87%

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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“…A small animal model that is susceptible to infection with both pathogens could lead to development of treatments and vaccines that can target more efficiently this unparalleled problem for the population of third world countries. The natural history of TB infection in S. hispidus and S. fulviventer has been studied (Elwood et al, 2007). The relatively short life span of the cotton rat (12-18 months) makes it possible to study TB infections throughout the entire life span of the animal.…”

Section: The Cotton Rat Model Of Tuberculosismentioning

confidence: 99%

“…Gross inspection of TB-infected cotton rat lungs show whitish nodular lesions and large numbers of TB (1 X 10 5-7 cfu) were cultured from granulomas, spleen, and occasionally in smaller numbers from liver and bone marrow. Tuberculous lesions may also be seen in the adrenal glands (other organs remain to be examined) (Elwood et al, 2007). Established granulomas in some cases underwent central necrosis and calcification and cytokine genes are more highly expressed in the granuloma than in the unaffected areas of the lung.…”

Section: The Cotton Rat Model Of Tuberculosismentioning

confidence: 99%