Differential Virulence and Disease Progression following Mycobacterium tuberculosis Complex Infection of the Common Marmoset (Callithrix jacchus)

ABSTRACTExisting small-animal models of tuberculosis (TB) rarely develop cavitary disease, limiting their value for assessing the biology and dynamics of this highly important feature of human disease. To develop a smaller primate model with pathology similar to that seen in humans, we experimentally infected the common marmoset (Callithrix jacchus) with diverse strains ofMycobacterium tuberculosisof various pathogenic potentials. These included recent isolates of the modern Beijing lineage, the Euro-American X lineage, andM. africanum. All three strains produced fulminant disease in this animal with a spectrum of progression rates and clinical sequelae that could be monitored in real time using 2-deoxy-2-[18F]fluoro-d-glucose (FDG) positron emission tomography (PET)/computed tomography (CT). Lesion pathology at sacrifice revealed the entire spectrum of lesions observed in human TB patients. The three strains produced different rates of progression to disease, various extents of extrapulmonary dissemination, and various degrees of cavitation. The majority of live births in this species are twins, and comparison of results from siblings with different infecting strains allowed us to establish that the infection was highly reproducible and that the differential virulence of strains was not simply host variation. Quantitative assessment of disease burden by FDG-PET/CT provided an accurate reflection of the pathology findings at necropsy. These results suggest that the marmoset offers an attractive small-animal model of human disease that recapitulates both the complex pathology and spectrum of disease observed in humans infected with variousM. tuberculosisstrain clades.

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The Common Marmoset (Callithrix jacchus) as a Model in Toxicology

Toxicologic Pathology ◽

10.1080/01926230390175002 ◽

2003 ◽

Vol 31 (1_suppl) ◽

pp. 123-127 ◽

Cited By ~ 61

Author(s):

U. Zühlke ◽

G. Weinbauer

Keyword(s):

Animal Model ◽

Current Knowledge ◽

Common Marmoset ◽

Callithrix Jacchus ◽

Human Reproduction ◽

Background Information ◽

Reproductive Toxicology ◽

Primate Model ◽

Wide Range ◽

The Common

The common marmoset, Callithrix jacchus, is the smallest nonhuman primate commonly used in biomedical research. Marmoset characteristics and propensities have enabled them to be used in a wide range of research as a model of human disease, physiology, drug metabolism, general toxicology, and reproductive biology. This paper provides a general overview of the marmoset with special emphasis on the benefits and disadvantages of this species as a model for inclusion in preclinical drug development programmes. In view of its small size in comparison with other nonrodent species marmosets have become of value for toxicology studies with biotechnology products where compound supply is limited. In general toxicology studies, marmosets have been successfully used to meet regulatory endpoints also for specific investigatory purposes. The widespread use of this species has allowed extensive background information to become available and a summary of the most frequently measured parameters are presented. Marmosets apparently represent an interesting animal model for comparative research on primate reproductive physiology. However, several basic aspects of reproductive processes exhibit cardinal discrepancies to those described for macaques and human. Thus, from the viewpoint of reproductive toxicology, the relevance of the marmoset primate model for human reproduction remains unclear to date and further research is obviously needed. Given our current knowledge of marmoset reproductive features, the use of this animal model cannot be recommended for reproductive toxicology assessment.

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Characterization of lethal inhalational infection with Francisella tularensis in the common marmoset (Callithrix jacchus)

Journal of Medical Microbiology ◽

10.1099/jmm.0.020669-0 ◽

2010 ◽

Vol 59 (9) ◽

pp. 1107-1113 ◽

Cited By ~ 17

Author(s):

Michelle Nelson ◽

Mark S. Lever ◽

Rachel E. Dean ◽

Victoria L. Savage ◽

F. Javier Salguero ◽

...

Keyword(s):

Francisella Tularensis ◽

Immunological Response ◽

Common Marmoset ◽

Callithrix Jacchus ◽

Post Challenge ◽

Primate Model ◽

Immunological Parameters ◽

Suitable Animal Model ◽

The Common ◽

Schu S4

The intracellular Gram-negative pathogen Francisella tularensis is the causative agent of tularaemia and is prevalent in many countries in the northern hemisphere. To determine whether the common marmoset (Callithrix jacchus) would be a suitable non-human primate model of inhalational tularaemia, a pathophysiology study was undertaken. Ten animals were challenged with ∼102 c.f.u. F. tularensis strain SCHU S4 (F. tularensis subsp. tularensis). To look for trends in the infection, pairs of animals were sacrificed at 24 h intervals between 0 and 96 h post-challenge and blood and organs were assessed for bacteriology, pathology and haematological and immunological parameters. The first indication of infection was a raised core temperature at 3 days post-challenge. This coincided with a number of other factors: a rapid increase in the number of bacteria isolated from all organs, more pronounced gross pathology and histopathology, and an increase in the immunological response. As the disease progressed, higher bacterial and cytokine levels were detected. More extensive pathology was observed, with multifocal lesions seen in the lungs, liver and spleen. Disease progression in the common marmoset appears to be consistent with human clinical and pathological features of tularaemia, indicating that this may be a suitable animal model for the investigation of novel medical interventions such as vaccines or therapeutics.

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A Sterilizing Tuberculosis Treatment Regimen Is Associated with Faster Clearance of Bacteria in Cavitary Lesions in Marmosets

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00115-15 ◽

2015 ◽

Vol 59 (7) ◽

pp. 4181-4189 ◽

Cited By ~ 31

Author(s):

Laura E. Via ◽

Kathleen England ◽

Danielle M. Weiner ◽

Daniel Schimel ◽

Matthew D. Zimmerman ◽

...

Keyword(s):

Drug Combination ◽

Bacterial Load ◽

Common Marmoset ◽

Drug Regimen ◽

Content Type ◽

Positron Emission ◽

Cavitary Disease ◽

Drug Regimens ◽

The Common ◽

Relapse Rates

ABSTRACTShortening the lengthy treatment duration for tuberculosis patients is a major goal of current drug development efforts. The common marmoset develops human-like disease pathology and offers an attractive model to better understand the basis for relapse and test regimens for effective shorter duration therapy. We treatedMycobacterium tuberculosis-infected marmosets with two drug regimens known to differ in their relapse rates in human clinical trials: the standard four-drug combination of isoniazid, rifampin, pyrazinamide, and ethambutol (HRZE) that has very low relapse rates and the combination of isoniazid and streptomycin that is associated with higher relapse rates. As early as 2 weeks, the more sterilizing regimen significantly reduced the volume of lung disease by computed tomography (P= 0.035) and also significantly reduced uptake of [18F]-2-fluoro-2-deoxyglucose by positron emission tomography (P= 0.049). After 6 weeks of therapy, both treatments caused similar reductions in granuloma bacterial load, but the more sterilizing, four-drug regimen caused greater reduction in bacterial load in cavitary lesions (P= 0.009). These findings, combined with the association in humans between cavitary disease and relapse, suggest that the basis for improved sterilizing activity of the four-drug combination is both its faster disease volume resolution and its stronger sterilizing effect on cavitary lesions. Definitive data from relapse experiments are needed to support this observation.

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