Guinea pig model of Mycobacterium tuberculosis latent/dormant infection (original) (raw)
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Lessons from experimental Mycobacterium tuberculosis infections
Microbes and Infection, 2006
Mycobacterium tuberculosis is the cause of enormous human morbidity and mortality each year. Although this bacterium can infect and cause disease in many animals, humans are the natural host. For the purposes of studying the pathogenesis of M. tuberculosis, as well as the protective and immunopathologic host responses against this pathogen, suitable animal models must be used. However, modeling the human infection and disease in animals can be difficult, and interpreting the data from animal models must be done carefully. In this paper, the animal models of tuberculosis are discussed, as well as the limitations and advantages of various models. In particular, the lessons we have learned about tuberculosis from the mouse models are highlighted. The careful and thoughtful use of animal models is essential to furthering our understanding of M. tuberculosis, and this knowledge will enhance the discovery of improved treatment and prevention strategies.
Infection and Immunity, 2003
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.
Pathogenesis of mycobacterium tuberculosis in rabbits (Experimental Model for Human Disease)
2011
Experimental model using adult rabbits to investigate pathogenesis and ill effect of M.tuberculosis was worked up. Three groups of rabbits used each group eight in number. Animals in groups one and two were injected intraperitoneally with 1mg/ml/animal of the bacterium containing 2x10 CFU/ml. The third groups were left as control. Pathological changes were seen after sixty days of infection in the visceral organs in both groups infected. Immediately following the appearance of lesions, animals of groups one treated with Isoniazide and Rifampicine for two months. Sacrification of rabbits after 120,130 &140 days post infection of both groups envisages no typical lesions of tuberculosis in group one in contrast to the formation of clear and evident typical tubercles in group two. Histopathology revealed well established allergic inflammation and histiocytic granulomas of atypical tuberculosis infection predominantly in some internal organs (lung, liver. spleen & lymph nodes) in group o...
Location of Persisting Mycobacteria in a Guinea Pig Model of Tuberculosis Revealed by R207910
Antimicrobial Agents and Chemotherapy, 2007
The lengthy chemotherapy of tuberculosis reflects the ability of a small subpopulation of Mycobacterium tuberculosis bacteria to persist in infected individuals. To date, the exact location of these persisting bacteria is not known. Lung lesions in guinea pigs infected with M. tuberculosis have striking similarities, such as necrosis, mineralization, and hypoxia, to natural infections in humans. Guinea pigs develop necrotic primary lesions after aerosol infection that differ in their morphology compared to secondary lesions resulting from hematogenous dissemination. In infected guinea pigs conventional therapy for tuberculosis during 6 weeks reduced the bacterial load by 1.7 logs in the lungs and, although this completely reversed lung inflammation associated with secondary lesions, the primary granulomas remained largely unaffected. Treatment of animals with the experimental drug R207910 (TMC207) for 6 weeks was highly effective with almost complete eradication of the bacteria throughout both the primary and the secondary lesions. Most importantly, the few remnants of acid-fast bacilli remaining after R207910 treatment were to be found extracellular, in a microenvironment of residual primary lesion necrosis with incomplete dystrophic calcification. This zone of the primary granuloma is hypoxic and is morphologically similar to what has been described for human lung lesions. These results show that this acellular rim may, therefore, be a primary location of persisting bacilli withstanding drug treatment.
The Stringent Response Is Required for Full Virulence ofMycobacterium tuberculosisin Guinea Pigs
The Journal of Infectious Diseases, 2010
During human latent tuberculosis infection, Mycobacterium tuberculosis likely resides within the nutrientstarved environment of caseous lung granulomas. The stringent response alarmone (p)ppGpp is synthesized by Rel in response to nutrient starvation, thus enabling tubercle bacilli to restrict growth and shut down metabolism in a coordinated fashion. In this study, we investigated the virulence of a rel-deficient M. tuberculosis mutant in the guinea pig model. Quantitative reverse-transcription polymerase chain reaction was used to study the effect of (p)ppGpp deficiency on expression of key cytokine and chemokine genes in guinea pig lungs. The rel-deficient mutant showed impaired initial growth and survival relative to the wild-type strain. Loss of Rel was associated with the striking absence of tubercle lesions grossly and of caseous granulomas histologically. The attenuated phenotype of the rel-deficient mutant was not associated with increased expression of genes encoding the proinflammatory cytokines interferon-g and tumor necrosis factor a in the lungs 28 days after infection.
Clinical & …, 2002
Mycobacterium tuberculosis produces latent infection or progressive disease. Indeed, latent infection is more common since it occurs in one-third of the world's population. We showed previously, using human material with latent tuberculosis, that mycobacterial DNA can be detected by in situ PCR in a variety of cell types in histologically-normal lung. We therefore sought to establish an experimental model in which this phenomenon could be studied in detail. We report here the establishment of such a model in C57Bl/6 × DBA/2 F1 hybrid mice by the intratracheal injection of low numbers of virulent mycobacteria (4000). Latent infection was characterized by low and stable bacillary counts without death of animals. Histological and immunological study showed granulomas and small patches of alveolitis, with high expression of tumour necrosis factor alpha (TNFα), inducible nitiric oxide synthase (iNOS), interleukin 2 (IL-2) and interferon gamma (IFNγ). In contrast, the intratracheal instillation of high numbers of bacteria (1 × 106) produced progressive disease. These animals started to die after 2 months of infection, with very high bacillary loads, massive pneumonia, falling expression of TNF-α and iNOS, and a mixed Th1/Th2 cytokine pattern. In situ PCR to detect mycobacterial DNA revealed that the most common positive cells in latently-infected mice were alveolar and interstitial macrophages located in tuberculous lesions, but, as in latently-infected human lung, positive signals were also seen in bronchial epithelium, endothelial cells and fibroblasts from histologically-normal areas. Our results suggest that latent tuberculosis is induced and maintained by a type 1 cytokine pattern plus TNFα, and that mycobacteria persist intracellularly in lung tissue with and without histological evidence of a local immune response.
Evidence, Challenges, and Knowledge Gaps Regarding Latent Tuberculosis in Animals
Microorganisms
Mycobacterium bovis and other Mycobacterium tuberculosis complex (MTBC) pathogens that cause domestic animal and wildlife tuberculosis have received considerably less attention than M. tuberculosis, the primary cause of human tuberculosis (TB). Human TB studies have shown that different stages of infection can exist, driven by host–pathogen interactions. This results in the emergence of heterogeneous subpopulations of mycobacteria in different phenotypic states, which range from actively replicating (AR) cells to viable but slowly or non-replicating (VBNR), viable but non-culturable (VBNC), and dormant mycobacteria. The VBNR, VBNC, and dormant subpopulations are believed to underlie latent tuberculosis (LTB) in humans; however, it is unclear if a similar phenomenon could be happening in animals. This review discusses the evidence, challenges, and knowledge gaps regarding LTB in animals, and possible host–pathogen differences in the MTBC strains M. tuberculosis and M. bovis during in...
The Pathology of Mycobacterium tuberculosis Infection
Veterinary Pathology, 2012
Mycobacterium tuberculosis is an old enemy of the human race, with evidence of infection observed as early as 5000 years ago. Although more host-restricted than Mycobacterium bovis, which can infect all warm-blooded vertebrates, M. tuberculosis can infect, and cause morbidity and mortality in, several veterinary species as well. As M. tuberculosis is one of the earliest described bacterial pathogens, the literature describing this organism is vast and overwhelming. This review strives to distill what is currently known about this bacterium and the disease it causes for the veterinary pathologist.
A Mouse Model for Latent Tuberculosis
Scandinavian Journal of Infectious Diseases, 1998
The aim of the study was to establish a reproducible murine model for latent tuberculosis. We propose an operational definition of latent murine tuberculosis as a stable Mycobacterium tuberculosis count in lungs and spleens without clinical signs or obvious histopathological changes in the lungs over a long period of time and without spontaneous reactivation of disease. B6D2F1Bom mice were inoculated with a wide range of Mycobacterium tuberculosis doses intraperitoneally or intravenously and followed for a long period to determine suitable conditions to produce latent infection. No anti-tuberculosis drug treatment was used. Microbiological and histopathological studies were carried out. Corticosterone challenge was used to reactivate the latent infection. Mice infected with 4× 10 4 and 4×10 5 bacilli i.p. were followed up to 107 weeks without spontaneous reactivation. The present model is discussed in comparison with previous latent tuberculosis mouse models as well as the possible mechanisms of shift to stationary phase from multiplying bacilli.