Specific bacterial genotypes of Mycobacterium tuberculosis cause extensive dissemination and brain infection in an experimental model

Hernández-Pando, Rogelio; Aguilar, Diana; Cohen, Ingrid; Guerrero, Martha Inírida; Ribón, Wellman; Acosta, Patrícia; Orozco, Héctor; Marquina, Brenda; Salinas, Citlal; Rembao, Daniel; Espitia, Clara

doi:10.1016/j.tube.2010.05.002

Cited by 50 publications

(50 citation statements)

References 38 publications

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“…For example, quite a number of recent studies have demonstrated variability among what were assumed to be clinical isolates in terms of virulence in animal models (54)(55)(56)(57)(58)(59). Without pointing to any study in particular, it seems reasonable to assume that all of the isolates in question (including a number that were East Asian/Beijing isolates) would have been held in liquid culture for at least the length of time it takes to prepare gDNA, genotype the strains, and then prepare suitable inocula for carrying out the infections.…”

Section: Discussionmentioning

confidence: 99%

Origins of a 350-Kilobase Genomic Duplication in Mycobacterium tuberculosis and Its Impact on Virulence

et al. 2014

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bIn the present study, we have investigated the evolution and impact on virulence of a 350-kb genomic duplication present in the most recently evolved members of the Mycobacterium tuberculosis East Asian lineage. In a mouse model of infection, comparing HN878 subclones HN878-27 (no duplication) and HN878-45 (with the 350-kb duplication) revealed that the latter is impaired for in vivo growth during the initial 3 weeks of infection. Furthermore, the median survival time of mice infected with isolate HN878-45 is significantly longer (77 days) than that of mice infected with HN878-27. Whole-genome sequencing of both isolates failed to reveal any mutational events other than the duplication that could account for such a substantial difference in virulence. Although we and others had previously speculated that the 350-kb duplication arose in response to some form of hostapplied selective pressure ( , here we show that this large chromosomal amplification event is very rapidly selected within standard in vitro broth cultures in a range of isolates. Indeed, subclones harboring the duplication were detectable after just five rounds of in vitro passage. In contrast, the duplication appears to be highly unstable in vivo and is negatively selected during the later stages of infection in mice. We believe that the rapid in vitro evolution of M. tuberculosis is an underappreciated aspect of its biology that is often ignored, despite the fact that it has the potential to confound the data and conclusions arising from comparative studies of isolates at both the genotypic and phenotypic levels.

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Section: Discussionmentioning

confidence: 99%

Origins of a 350-Kilobase Genomic Duplication in Mycobacterium tuberculosis and Its Impact on Virulence

et al. 2014

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“…Microglia, the resident immune cells in the brain, are the primary host cells of Mycobacterium tuberculosis and release pro-inflammatory cytokines when activated as a result of TB infection (Curto et al, 2004; Hernandez Pando et al, 2010; Rock et al, 2005; Yang et al, 2007, 2009; Zucchi et al, 2012). Microglia are not only involved with host-defense (Rock et al, 2004), but also have a crucial role in neurodevelopment.…”

Section: Introductionmentioning

confidence: 99%

Microglia activation in a pediatric rabbit model of tuberculous meningitis

Tucker

Pokkali

Zhi

et al. 2016

Disease Models &Amp; Mechanisms

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Central nervous system (CNS) tuberculosis (TB) is the most severe form of extra-pulmonary TB and disproportionately affects young children where the developing brain has a unique host response. New Zealand white rabbits were infected with Mycobacterium tuberculosis via subarachnoid inoculation at postnatal day 4-8 and evaluated until 4-6 weeks post-infection. Control and infected rabbit kits were assessed for the development of neurological deficits, bacterial burden, and postmortem microbiologic and pathologic changes. The presence of meningitis and tuberculomas was demonstrated histologically and by in vivo magnetic resonance imaging (MRI). The extent of microglial activation was quantified by in vitro immunohistochemistry as well as non-invasive in vivo imaging of activated microglia/macrophages with positron emission tomography (PET). Subarachnoid infection induced characteristic leptomeningeal and perivascular inflammation and TB lesions with central necrosis, a cellular rim and numerous bacilli on pathologic examination. Meningeal and rim enhancement was visible on MRI. An intense microglial activation was noted in M. tuberculosis-infected animals in the white matter and around the TB lesions, as evidenced by a significant increase in uptake of the tracer 124I-DPA-713, which is specific for activated microglia/macrophages, and confirmed by quantification of Iba-1 immunohistochemistry. Neurobehavioral analyses demonstrated signs similar to those noted in children with delayed maturation and development of neurological deficits resulting in significantly worse composite behavior scores in M. tuberculosis-infected animals. We have established a rabbit model that mimics features of TB meningitis in young children. This model could provide a platform for evaluating novel therapies, including host-directed therapies, against TB meningitis relevant to a young child's developing brain.

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“…There are few reports of MTC in foxes (Bruning-Fann et al 2001, Delahay et al 2007, Millán et al 2008. In animals, the infection caused by these agents has only been reported in the brain of rabbits, mice, and pigs in an experimental model infection (Hernandez Pando et al 2010). In humans, tuberculosis infections of the central nervous system, caused by M. tuberculosis, are a serious and often fatal disease, predominantly impacting young children (Bartzatt 2011).…”

Section: Ycobacterium Tuberculosis Complex (Mtc) Includesmentioning

confidence: 99%

“…In humans, tuberculosis infections of the central nervous system, caused by M. tuberculosis, are a serious and often fatal disease, predominantly impacting young children (Bartzatt 2011). This is a severe type of extrapulmonary disease that is thought to begin with respiratory infection, followed by hematogenous dissemination and brain infection (Hernandez Pando et al 2010).…”

Section: Ycobacterium Tuberculosis Complex (Mtc) Includesmentioning

confidence: 99%

Disseminated Mycobacterium bovis Infection in Red Foxes (Vulpes vulpes) with Cerebral Involvement Found in Portugal

Matos

Figueira

Martins

et al. 2014

Vector-Borne and Zoonotic Diseases

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A total of 49 road-killed red foxes were used for the detection of Mycobacterium tuberculosis complex (MTC) in Portugal. MTC infection was detected by PCR in 10 red foxes (20.4%; 95% confidence interval [CI] 8.8-31.2%) and confirmed in three (6.1%; 95% CI 0.0-7.9%) of them by microbiological culture. The complex was detected in 20 tissues out of 441 by PCR techniques (4.5%; 95% CI 16.3-23.7%) and in seven tissues out of 441 (1.6%; 95% CI 4.6-9.4%) by culture. MTC was most frequently detected in the brain (8.2%) and in the mediastinal lymph nodes (8.2%). The seven cultures obtained were positive for M. bovis by PCR-based genotyping of the MTC targeting genomic deletions. This study confirms the presence of disseminated M. bovis in red foxes in Portugal, and it is the first report in the world of the natural infection in the animals' brains.

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Specific bacterial genotypes of Mycobacterium tuberculosis cause extensive dissemination and brain infection in an experimental model

Cited by 50 publications

References 38 publications

Origins of a 350-Kilobase Genomic Duplication in Mycobacterium tuberculosis and Its Impact on Virulence

Origins of a 350-Kilobase Genomic Duplication in Mycobacterium tuberculosis and Its Impact on Virulence

Microglia activation in a pediatric rabbit model of tuberculous meningitis

Disseminated Mycobacterium bovis Infection in Red Foxes (Vulpes vulpes) with Cerebral Involvement Found in Portugal

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