Microglia activation in a pediatric rabbit model of tuberculous meningitis

Elizabeth W. Tucker; Supriya Pokkali; Zhi Zhang; Vincent P. DeMarco; Mariah Klunk; Elizabeth S. Smith; Alvaro A. Ordonez; Marie-France Penet; Zaver Bhujwalla; Sanjay K. Jain; Sujatha Kannan

doi:10.1242/dmm.027326

Disease Models & Mechanisms (Dec 2016)

Microglia activation in a pediatric rabbit model of tuberculous meningitis

Elizabeth W. Tucker,
Supriya Pokkali,
Zhi Zhang,
Vincent P. DeMarco,
Mariah Klunk,
Elizabeth S. Smith,
Alvaro A. Ordonez,
Marie-France Penet,
Zaver Bhujwalla,
Sanjay K. Jain,
Sujatha Kannan

Affiliations

Elizabeth W. Tucker: Department of Anesthesiology and Critical Care Medicine, Division of Pediatric Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
Supriya Pokkali: Center for Infection and Inflammation Imaging Research, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
Zhi Zhang: Department of Anesthesiology and Critical Care Medicine, Division of Pediatric Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
Vincent P. DeMarco: Center for Infection and Inflammation Imaging Research, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
Mariah Klunk: Center for Infection and Inflammation Imaging Research, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
Elizabeth S. Smith: Department of Anesthesiology and Critical Care Medicine, Division of Pediatric Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
Alvaro A. Ordonez: Center for Infection and Inflammation Imaging Research, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
Marie-France Penet: JHU ICMIC Program, Division of Cancer Imaging Research, The Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
Zaver Bhujwalla: JHU ICMIC Program, Division of Cancer Imaging Research, The Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
Sanjay K. Jain: Center for Infection and Inflammation Imaging Research, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
Sujatha Kannan: Department of Anesthesiology and Critical Care Medicine, Division of Pediatric Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA

DOI: https://doi.org/10.1242/dmm.027326
Journal volume & issue: Vol. 9, no. 12
pp. 1497 – 1506

Abstract

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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.

Published in Disease Models & Mechanisms

ISSN: 1754-8403 (Print); 1754-8411 (Online)
Publisher: The Company of Biologists
Country of publisher: United Kingdom
LCC subjects: Medicine: Pathology
Website: https://journals.biologists.com/dmm

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