Guinea pig model of Mycobacterium tuberculosis latent/dormant infection

Abstract

Most experimental studies of latent or dormant tuberculosis infection have been conducted in murine models. Although guinea pigs are considered one of the animals that best reproduce human tuberculosis, surprisingly little data exist describing latent or dormant infection in these animals. The present work addresses this issue and shows that guinea pigs infected with a streptomycin auxotrophic mutant of Mycobacterium tuberculosis (strain 18b) replicate most of the known clinical, immunological, and pathological manifestations of this phase of the infectious process in humans. To establish infection, animals were inoculated with the mutant followed by administration of streptomycin for three weeks. Withdrawal of streptomycin caused microbial dormancy and few microorganisms remained viable and could be recovered from the animals' lungs and spleen several months later. Guinea pigs with dormant infection steadily gained weight and presented no clinical signs (scuff fur and lethargy) of active disease. The histopathology of the tuberculous lesions mimicked human lesions well. In addition, PBMC from infected animals strongly responded to stimulation with PPD or soluble culture filtrate proteins of M. tuberculosis throughout the duration of the experiment (six months). Finally, the tuberculin skin test (a clinical hallmark of latent infection) performed in guinea pigs infected with the auxotrophic mutant remarkably reproduced the response of humans to this test. Together, these findings confirm that infection of guinea pigs with M. tuberculosis strain 18b results in an infectious process that can be used as an interesting alternative model of latent or dormant tuberculosis infection in this animal specie.

De Novo Emergence of Genetically Resistant Mutants of Mycobacterium tuberculosis from the Persistence Phase Cells Formed against Antituberculosis Drugs In Vitro

“…Sputum and blood samples from TB patients under treatment and with destructive cavities in the lungs showed the presence of persistent tubercle bacilli (11)(12)(13)(14)(15). Among the animal models, Mycobacterium tuberculosis persister cells have been found against anti-tuberculosis drugs in the lungs and spleen of mice (16)(17)(18)(19)(20), guinea pigs (21)(22)(23)(24)(25)(26)(27), macrophages (28,29), in vitro cultures (30)(31)(32), and the environment (33). These antibiotic persister cells from human tissue samples and the animal models could be cultured to get an infectious, drugsusceptible population of tubercle bacilli (13,18,19,34).…”

Simple Model for Testing Drugs against Nonreplicating Mycobacterium tuberculosis

“…The molecular reason for this unique phenotype was investigated, and insertion of a cytosine in the 530 loop of the 16S rRNA, known to be involved in STR resistance, was found to be associated with the dependency (13). Recent vaccine work exploited M. tuberculosis 18b for establishing dormant infection in mouse and guinea pig models (16,17). Notably, those authors demonstrated that the strain replicates in the lungs and spleens of animals injected with STR, whereas it no longer grows and it enters the nonreplicating state upon STR withdrawal, thus leading to the conclusion that it mimics dormancy.…”

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“…Moreover, some studies claims the presence of latent bacilli in guinea pig lungs and spleen and shown a positive TST test. All these findings suggest guinea pigs may be used as a reliable animal model of LTBI 48 .…”