title: Microglia activation in a pediatric rabbit model of tuberculous meningitis.
abstract: 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 tracer124I-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.
authors.affiliation: 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.|Center for Infection and Inflammation Imaging Research, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.|Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.|Center for Nanomedicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.|Department of Anesthesiology and Critical Care Medicine, Division of Critical Care Medicine, Johns Hopkins All Children's Hospital, St. Petersburg, FL 33701, USA.
authors.forename: Elizabeth W
authors.initials: EW
authors.lastname: Tucker
authors.affiliation: Center for Infection and Inflammation Imaging Research, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.|Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.|Department of Pediatrics, Division of Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
authors.forename: Supriya
authors.initials: S
authors.lastname: Pokkali
authors.affiliation: 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.|Center for Nanomedicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
authors.forename: Zhi
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Center for Infection and Inflammation Imaging Research, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.|Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.|Department of Pediatrics, Division of Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
authors.forename: Vincent P
authors.initials: VP
authors.lastname: DeMarco
authors.affiliation: Center for Infection and Inflammation Imaging Research, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.|Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.|Department of Pediatrics, Division of Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
authors.forename: Mariah
authors.initials: M
authors.lastname: Klunk
authors.affiliation: 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.|Center for Nanomedicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
authors.forename: Elizabeth S
authors.initials: ES
authors.lastname: Smith
authors.affiliation: Center for Infection and Inflammation Imaging Research, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.|Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.|Department of Pediatrics, Division of Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
authors.forename: Alvaro A
authors.initials: AA
authors.lastname: Ordonez
authors.affiliation: 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.|Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
authors.forename: Marie-France
authors.initials: MF
authors.lastname: Penet
authors.affiliation: 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.|Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
authors.forename: Zaver
authors.initials: Z
authors.lastname: Bhujwalla
authors.affiliation: Center for Infection and Inflammation Imaging Research, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA sjain5@jhmi.edu skannan3@jhmi.edu.|Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.|Department of Pediatrics, Division of Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
authors.forename: Sanjay K
authors.identifier: 0000-0001-9620-7070
authors.initials: SK
authors.lastname: Jain
authors.affiliation: 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 sjain5@jhmi.edu skannan3@jhmi.edu.|Center for Nanomedicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
authors.forename: Sujatha
authors.initials: S
authors.lastname: Kannan
mesh_terms: D000081:Acetamides / Q000737:chemistry; D000818:Animals; D001522:Behavior, Animal; D001921:Brain / Q000382:microbiology / Q000473:pathology; D002648:Child; D004195:Disease Models, Animal; D005122:Exudates and Transudates; D005260:Female; D005682:Gadolinium / Q000737:chemistry; D006801:Humans; D007249:Inflammation / Q000473:pathology; D007457:Iodine Radioisotopes / Q000737:chemistry; D007700:Kinetics; D008168:Lung / Q000382:microbiology / Q000473:pathology; D008262:Macrophage Activation; D008279:Magnetic Resonance Imaging; D008297:Male; D017628:Microglia / Q000473:pathology*; D009043:Motor Activity; D009169:Mycobacterium tuberculosis / Q000254:growth & development; D000072078:Positron Emission Tomography Computed Tomography; D011720:Pyrazoles / Q000737:chemistry; D011743:Pyrimidines / Q000737:chemistry; D011817:Rabbits; D014390:Tuberculosis, Meningeal / Q000000981:diagnostic imaging / Q000382:microbiology / Q000473:pathology* / Q000503:physiopathology
chemical_list: D000081:Acetamides; D007457:Iodine Radioisotopes; C507091:N,N-diethyl-2-(2-(4-methoxyphenyl)-5,7-dimethyl-pyrazolo(1,5-a)pyrimidin-3-yl)-acetamide; D011720:Pyrazoles; D011743:Pyrimidines; D005682:Gadolinium
keywords: Meningitis; Microglia; PET; Pediatric; TSPO; Tuberculosis