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

Abstract

Background 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. Methods We injected two Mycobacterium tuberculosis (M.tb) strains, H37Rv and CDC1551, respectively, into two mouse strains, C3HeB/FeJ and Nos2−/− 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. Results Intra-cerebroventricular infection of Nos2−/− mice with M.tb led to development of neurological signs and more severe brain granulomas compared to C3HeB/FeJ mice. Compared with CDC1551 M.tb, H37Rv M.tb 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 Nos2−/− mice with M.tb 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. Conclusions Intra-cerebroventricular infection of Nos2−/− 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.

Tuberculosis: The success tale of less explored dormant Mycobacterium tuberculosis

“…Heat shock protein gene hspX which encodes alpha-crystallin with a role in adaptation to stimuli such as hypoxia and nitric oxide is also induced during the stationary growth phase ( Timm et al., 2003 ). The mice model C3HeB/FeJ (Kramnik mice) closely replicates the human granuloma features, as it is hyper-susceptible to M.tb infection due to the presence of super susceptibility to tuberculosis 1 ( sst1 ) locus ( Poh et al., 2022 ). Research conducted by Harper et al.…”

MMPs and NETs are detrimental in human CNS-tuberculosis and MMP inhibition in a mouse model improves survival

“…000658) (Jackson Laboratory) were infected with M. tb H37Rv at seven days after brain cannulation, via intra-cerebroventricular (i.c.vent.) route as previously described 10 . Briefly, a motorized stereotaxic instrument (Neurostar) was used to implant a 26-gauge guide cannula (RWD) into the third ventricle (coordinates from the bregma: − 1.6 mm posterior, 0 mm lateral, − 2.5 mm ventral) of mice at one week before infection.…”

“…To better understand the immunopathogenesis in CNS-TB, we first studied human clinical samples and then developed a murine CNS-TB model that recapitulated the brain pathology and neurological symptoms observed in humans 10 . Concurrently, we examined the role of MMPs and NETs in human CNS-TB immunopathology in driving CNS-TB disease severity.…”

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

“…Following the publication of the original article [ 1 ], it was noted that the ESM video 10 has been processed incorrectly. That is, the ESM video 9 was duplicated in ESM video 10 mistakenly.…”

“…The correct Videos of 9 and 10 (Additional files: Video S9 and S10) have been included in this correction, and the original article [ 1 ] has been corrected.…”