Tuberculosis of Rabbits Induced by Droplet Nuclei Infection

Ratcliffe, Herbert L.; Wells, W. F.

doi:10.1084/jem.87.6.575

Cited by 17 publications

(14 citation statements)

References 3 publications

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“…Fewer than 30 inhaled bacilli of M. bovis results in a progressive infection that eventually leads to the death of the rabbit (8,9,33). One to 2 orders of magnitude more inhaled bacilli of H37Rv M. tuberculosis are needed to create one visible pulmonary tubercle at 5 weeks (3,10,23,24).…”

Section: Discussionmentioning

confidence: 99%

Different Strains ofMycobacterium tuberculosisCause Various Spectrums of Disease in the Rabbit Model of Tuberculosis

Manabe¹,

Dannenberg

Tyagi³

et al. 2003

Infect Immun

142

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The rabbit model of tuberculosis has been used historically to differentiate between Mycobacterium tuberculosis and Mycobacterium bovis based on their relative virulence in this animal host. M. tuberculosis infection in market rabbits is cleared over time, whereas infection with M. bovis results in chronic, progressive, cavitary disease leading to death. Because of the innate resistance of commercial rabbits to M. tuberculosis, 320 to 1,890 log-phase, actively growing inhaled bacilli were required to form one grossly visible pulmonary tubercle at 5 weeks. The range of inhaled doses required to make one tubercle allows us to determine the relative pathogenicities of different strains. Fewer inhaled organisms of the M. tuberculosis Erdman strain were required than of M. tuberculosis H37Rv to produce a visible lesion at 5 weeks. Furthermore, with the Erdman strain, only 7 of 15 rabbits had healed lesions at 16 to 18 weeks; among the other animals, two had chronic, progressive cavitary disease, a phenotype usually seen only with M. bovis infection. Genotypic investigation of the Erdman strain with an H37Rv-based microarray identified gene differences in the RD6 region. Southern blot and PCR structural genetic analysis showed significant differences between M. tuberculosis strains in this region. Correlation of the relative pathogenicity, including disease severity, in the rabbit model with the strain genotype may help identify stage-specific M. tuberculosis genes important in human disease.Tuberculosis continues to be a leading cause of infectious disease mortality. Because of the complex pathogenesis of the disease, the development of animal models for specific stages of disease such as latency and cavitation remains a priority. The murine model is the most widely used animal model because of its economy, the extensive characterization of inbred strains, and the commercial availability of immunologic reagents (31). The guinea pig is another well-researched model of tuberculosis and has the advantages of remarkable susceptibility to low doses of aerosolized Mycobacterium tuberculosis and the development of a strong delayed-type hypersensitivity response (11,36,37,40).The rabbit model offers certain advantages over both the murine and guinea pig models. First, when infected with M. tuberculosis or Mycobacterium bovis, rabbits have a spectrum of disease that represents many of the specific stages of human disease. In general, rabbits are able to contain disease caused by virulent M. tuberculosis. Over time, the number of pulmonary bacilli decline and the lesions regress (22). With M. bovis infection, rabbits form chronic fibrosing pulmonary cavities (8). Both of these are prominent features in human disease. Finally, rabbit lung granulomas, with their caseous centers, closely resemble the human granuloma. Lurie and colleagues have found a remarkable similarity between the spectrum of rabbit tuberculosis and that found in humans (23).In the era before genomics and before the biochemical property differences were elucid...

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Section: Discussionmentioning

confidence: 99%

Different Strains ofMycobacterium tuberculosisCause Various Spectrums of Disease in the Rabbit Model of Tuberculosis

Manabe¹,

Dannenberg

Tyagi³

et al. 2003

Infect Immun

142

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“…The importance of presensitization was further elucidated by Ratcliffe and Wells in their demonstration that more numerous cavities develop after reinfection with high-dose M. bovis following an initial primary low-dose aerosolized infection (23). Yamamura et al reliably produced lung cavities in rabbits 30 to 60 days after intrathoracic injection of live or heat-killed mycobacteria when the rabbits were sensitized by repeated subcutaneous injections of heat-killed bacilli (34).…”

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confidence: 99%

Extrapulmonary Dissemination of Mycobacterium bovis but Not Mycobacterium tuberculosis in a Bronchoscopic Rabbit Model of Cavitary Tuberculosis

Nedeltchev¹,

Raghunand

Jassal

et al. 2009

Infect Immun

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The rabbit model of tuberculosis is attractive because of its pathophysiologic resemblance to the disease in humans. Rabbits are naturally resistant to infection but may manifest cavitary lung lesions. We describe here a novel approach that utilizes presensitization and bronchoscopic inoculation to reliably produce cavities in the rabbit model. With a fixed inoculum of bacilli, we were able to reproducibly generate cavities by using Mycobacterium bovis Ravenel, M. bovis AF2122, M. bovis BCG, M. tuberculosis H37Rv, M. tuberculosis CDC1551, and the M. tuberculosis CDC1551 ⌬sigC mutant. M. bovis infections generated cavitary CFU counts of 10 6 to 10 9 bacilli, while non-M. bovis species and BCG yielded CFU counts that ranged from 10 4 to 10 8 bacilli. Extrapulmonary dissemination was almost exclusively noted among rabbits infected with M. bovis Ravenel and AF2122. Though all of the species yielded secondary lesions at intrapulmonary sites, M. bovis infections led to the most apparent gross pathology. Using the M. tuberculosis icl and dosR gene expression patterns as molecular sentinels, we demonstrated that both the cavity wall and cavity lumen are microenvironments associated with hypoxia, upregulation of the bacterial dormancy program, and the use of host lipids for bacterial catabolism. This unique cavitary model provides a reliable animal model to study cavity pathogenesis and extrapulmonary dissemination.Tuberculosis (TB) continues to be a global public health problem, with approximately one-third of the world's population latently infected (14). Nine million active infections are diagnosed annually, and approximately two million people died of the disease last year (33). Cavitary pulmonary lesions are key means of disease transmission (1, 21). The lesions present an ideal environment for tremendous bacillary growth, with up to 10 7 to 10 9 organisms being able to be routinely cultured from a single cavity (4). High titers of bacilli also lead to an increased likelihood of antimicrobial resistance due to spontaneous mutations (11).For these reasons, animal models of cavity formation and TB disease transmission have been sought. The murine model is limited because mice form cellular granuloma-like lesions which usually lack necrosis, caseation, and cavitation (16). Guinea pigs form necrotic granulomas with caseation but rarely produce cavitary lesions after aerosol Mycobacterium tuberculosis exposure (27). However, rabbits form caseating, necrotic granulomas which, under the correct conditions, may liquefy and cavitate.Early investigations by Wells and Lurie yielded cavity formation in rabbits presensitized with heat-killed M. bovis and challenged with aerosolized low-dose M. bovis (32). The importance of presensitization was further elucidated by Ratcliffe and Wells in their demonstration that more numerous cavities develop after reinfection with high-dose M. bovis following an initial primary low-dose aerosolized infection (23). Yamamura et al. reliably produced lung cavities in rabbits 30 to 60 days after in...

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“…Previous sensitization has been shown to enhance the development of these lesions (Wells and Lurie, ; Ratfliffe and Wells, ; Yamamura et al., ; Yamamura, ). Such sensitization involves administering heat‐killed M. bovis (Wells and Lurie, ; Yamamura et al., ; Yamamura, ) or live M. bovis in a low dose through the aerogenous route (Ratfliffe and Wells, ). Afterwards, challenges may be carried out by intrathoracic infection of M. bovis at low dose (Wells and Lurie, ) or high dose (Ratfliffe and Wells, ).…”

Section: Infection By Mycobacterium Tuberculosis Complexmentioning

confidence: 99%

“…Such sensitization involves administering heat‐killed M. bovis (Wells and Lurie, ; Yamamura et al., ; Yamamura, ) or live M. bovis in a low dose through the aerogenous route (Ratfliffe and Wells, ). Afterwards, challenges may be carried out by intrathoracic infection of M. bovis at low dose (Wells and Lurie, ) or high dose (Ratfliffe and Wells, ). Recently, sensitization with heat‐killed M. bovis has shown to be necessary to generate lung cavities by bronchoscopic injection (Jassal et al., ).…”

Section: Infection By Mycobacterium Tuberculosis Complexmentioning

confidence: 99%

Mycobacterial Infections in Rabbits: From the Wild to the Laboratory

Arrazuria

Juste

Elguezabal

2016

Transbound Emerg Dis

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Tuberculous mycobacterial diseases such as leprosy and tuberculosis are ancient diseases that currently continue threatening human health in some countries. Non-tuberculous mycobacterial (NTM) infections cause a series of well-defined pathological entities, as well as some opportunistic diseases that have also increased worldwide, being more common among immunocompromised patients but rising also in immunocompetent individuals. Reports on natural infections by mycobacteria in rabbits are scarce and mainly involve NTM such as Mycobacterium avium subsp. avium in pigmy rabbits in the United States and Mycobacterium avium subsp. paratuberculosis in wild rabbits in Europe. Rabbits have been used as laboratory animals through the years, both to generate immunological reagents and as infection models. Mycobacterial infection models have been developed in this animal species showing different susceptibility patterns to mycobacteria in laboratory conditions. The latent tuberculosis model and the cavitary tuberculosis model have been widely used to elucidate pathogenic mechanisms and to evaluate chemotherapy and vaccination strategies. Rabbits have also been used as bovine paratuberculosis infection models. This review aimed to gather both wildlife and experimental infection data on mycobacteriosis in rabbits to assess their role in the spread of these infections as well as their potential use in the experimental study of mycobacterial pathogenesis and treatment.

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Tuberculosis of Rabbits Induced by Droplet Nuclei Infection

Cited by 17 publications

References 3 publications

Different Strains ofMycobacterium tuberculosisCause Various Spectrums of Disease in the Rabbit Model of Tuberculosis

Different Strains ofMycobacterium tuberculosisCause Various Spectrums of Disease in the Rabbit Model of Tuberculosis

Extrapulmonary Dissemination of Mycobacterium bovis but Not Mycobacterium tuberculosis in a Bronchoscopic Rabbit Model of Cavitary Tuberculosis

Mycobacterial Infections in Rabbits: From the Wild to the Laboratory

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