Model systemsStrain-dependent CNS dissemination in guinea pigs after Mycobacterium tuberculosis aerosol challenge
Introduction
Central nervous system tuberculosis (CNS TB) is the most severe and debilitating form of TB. Primarily affecting children in developing nations, diagnosis and management of CNS TB is tremendously challenging due to non-specific clinical presentation, poor diagnostics, and limited availability of adequate clinical resources. By the time of diagnosis, the patient often exhibits progressive disease, with hydrocephalus and vasculitis leading to infarction.1
Over the course of more than a century of TB research, many models have been employed as tools for the study of TB pathogenesis and disease mechanisms.2 However, the majority of model systems for CNS TB have employed direct inoculation of bacilli into the cerebrospinal fluid (CSF) or cerebrum.3, 4 Although such models are useful for the study of acute and chronic meningitis, they do not simulate the natural course of disease, typified by bacillary dissemination via blood. In the current study, we describe a guinea pig model of extrapulmonary dissemination and utilize it to study CNS dissemination of three different laboratory strains of Mycobacterium tuberculosis after an aerosol infection.
Section snippets
Extrapulmonary and CNS dissemination of M. tuberculosis
On day 1 after infection, pulmonary log10 colony forming units (CFU) were 3.1 ± 0.1, 2.2 ± 0.3, and 3.0 ± 0.3 in animals infected with M. tuberculosis CDC1551, H37Rv JHU, and H37Rv TAMU, respectively. Pulmonary bacillary burdens reached a plateau 14 days after infection, which were not significantly different between the 3 strains (P > 0.3). Complete lung CFU data for these animals have been described previously by Ahmad et al.5
Extrapulmonary dissemination was first observed 14 days after
Discussion
We developed a guinea pig model of extrapulmonary dissemination and utilized it to study CNS dissemination of three different laboratory strains of M. tuberculosis after an aerosol infection. Although all three strains evaluated in this study grew exponentially in the lungs and had similar bacterial burdens at the time of extrapulmonary dissemination (day 14), M. tuberculosis CDC1551 disseminated to the CNS significantly more than the two H37Rv strains. Brain CFU counts were higher than CFU in
M. tuberculosis strains and media
Three strains were used in this study: a CDC1551 strain which was twice-passaged through mice, an H37Rv strain also twice-passaged in mice (H37Rv JHU – obtained from Johns Hopkins University), and an H37Rv strain, which was not animal-passaged (H37RV TAMU – obtained from Dr. David McMurray, Texas A&M University). All cultures were grown at 37 °C in 7H9 liquid broth (Difco) supplemented with oleic acid albumin dextrose catalase (BD), 0.5% glycerol, and 0.05% Tween 80.
Aerosol infection and processing of guinea pigs
Outbred Hartley guinea pigs
Acknowledgments
Financial support was provided by Bill and Melinda Gates Foundation #48793 and #42851, NIH Director's New Innovator Award OD006492, CFAR Pilot Developmental Program (Johns Hopkins), and NIH contract and grant N01 30036 and AI79590 respectively. Financial sponsors had no role in the study design, collection, analysis, or interpretation of data.
References (23)
Experimental models used to study human tuberculosis
Adv Appl Microbiol
(2010)- et al.
Vaccine-induced cytokine responses in a guinea pig model of pulmonary tuberculosis
Tuberculosis (Edinb)
(2005) - et al.
Disseminated disease severity as a measure of virulence of Mycobacterium tuberculosis in the guinea pig model
Tuberculosis (Edinb)
(2008) - et al.
Specific bacterial genotypes of Mycobacterium tuberculosis cause extensive dissemination and brain infection in an experimental model
Tuberculosis (Edinb)
(2010) - et al.
Bacillus Calmette-Guérin sequestered in the brain parenchyma escapes immune recognition
J Neuroimmunol
(1998) - et al.
Demyelination in the central nervous system following a delayed-type hypersensitivity response to bacillus Calmette-Guérin
Neuroscience
(1995) - et al.
Responses of guinea pig pups during isolation in a novel environment may represent stress-induced sickness behaviors
Physiol Behav
(2004) - et al.
Pathogenesis of central nervous system tuberculosis
Curr Mol Med
(2009) - et al.
Virulence of selected Mycobacterium tuberculosis clinical isolates in the rabbit model of meningitis is dependent on phenolic Glycolipid produced by the bacilli
J Infect Dis
(2005) - et al.
A New murine model to study the pathogenesis of tuberculous meningitis
J Infect Dis
(2007)
Biphasic kill curve of isoniazid reveals the presence of drug-tolerant, not drug-resistant, Mycobacterium tuberculosis in the guinea pig
J Infect Dis
Cited by (14)
Experimental animal models of central nervous system tuberculosis: A historical review
2018, TuberculosisCitation Excerpt :After determining the microbial load, this strain was compared to the reference strain H37Rv as a control, and there was a difference of 103 CFU between day 21 and the endpoint of the experiment. In a similar manner, there were no histopathological changes in the brain of infected guinea pigs, and there were low concentrations of the proinflammatory cytokines TNF-α and IL-1β, as determined by ELISA [34]. These findings are the opposite of those observed in humans, where anatomopathological changes, such as tuberculoma and tuberculous abscesses, were evident during active infection.
Spontaneous latency in a rabbit model of pulmonary tuberculosis
2012, American Journal of PathologyCitation Excerpt :Even in the rabbit, not all Mtb strains are cleared spontaneously. Thus, the nature of the infecting Mtb strain significantly affects the host-pathogen interactions and determines the outcome of infection in these and other animal species.14,67,68 Thus far, only Mtb CDC1551 infection of rabbits has consistently resulted in complete clearance of the bacilli from the lungs.
Microglia activation in a pediatric rabbit model of tuberculous meningitis
2016, DMM Disease Models and MechanismsAffinity of Mycobacterium tuberculosis strains for M059K microglial cells after migration through A549 alveolar epithelium
2021, European Journal of Clinical Microbiology and Infectious DiseasesOne Size Fits All? Not in In Vivo Modeling of Tuberculosis Chemotherapeutics
2021, Frontiers in Cellular and Infection Microbiology