Nos2−/− mice infected with M. tuberculosis develop neurobehavioral changes and immunopathology mimicking human central nervous system tuberculosis

Abstract

<jats:title>Background</jats:title> <jats:p>Understanding the pathophysiology of central nervous system tuberculosis (CNS-TB) is hampered by the lack of a good pre-clinical model that mirrors the human CNS-TB infection. We developed a murine CNS-TB model that demonstrates neurobehavioral changes with similar immunopathology with human CNS-TB.</jats:p> </jats:sec><jats:sec> <jats:title>Methods</jats:title> <jats:p>We injected two <jats:italic>Mycobacterium tuberculosis</jats:italic> (<jats:italic>M.tb</jats:italic>) strains, H37Rv and CDC1551, respectively, into two mouse strains, C3HeB/FeJ and <jats:italic>Nos2</jats:italic><jats:sup>−/−</jats:sup> mice, either into the third ventricle or intravenous. We compared the neurological symptoms, histopathological changes and levels of adhesion molecules, chemokines, and inflammatory cytokines in the brain induced by the infections through different routes in different strains.</jats:p> </jats:sec><jats:sec> <jats:title>Results</jats:title> <jats:p>Intra-cerebroventricular infection of <jats:italic>Nos2</jats:italic><jats:sup>−/−</jats:sup> mice with <jats:italic>M.tb</jats:italic> led to development of neurological signs and more severe brain granulomas compared to C3HeB/FeJ mice. Compared with CDC1551 <jats:italic>M.tb</jats:italic>, H37Rv <jats:italic>M.tb</jats:italic> infection resulted in a higher neurobehavioral score and earlier mortality. Intra-cerebroventricular infection caused necrotic neutrophil-dominated pyogranulomas in the brain relative to intravenous infection which resulted in disseminated granulomas and mycobacteraemia. Histologically, intra-cerebroventricular infection of <jats:italic>Nos2</jats:italic><jats:sup><jats:italic>−/−</jats:italic></jats:sup> mice with <jats:italic>M.tb</jats:italic> resembled human CNS-TB brain biopsy specimens. H37Rv intra-cerebroventricular infected mice demonstrated higher brain concentrations of inflammatory cytokines, chemokines and adhesion molecule ICAM-1 than H37Rv intravenous-infected mice.</jats:p> </jats:sec><jats:sec> <jats:title>Conclusions</jats:title> <jats:p>Intra-cerebroventricular infection of <jats:italic>Nos2</jats:italic><jats:sup>−/−</jats:sup> mice with H37Rv creates a murine CNS-TB model that resembled human CNS-TB immunopathology, exhibiting the worst neurobehavioral score with a high and early mortality reflecting disease severity and its associated neurological morbidity. Our murine CNS-TB model serves as a pre-clinical platform to dissect host–pathogen interactions and evaluate therapeutic agents for CNS-TB.</jats:p> </jats:sec>