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Investigating host immune responses in astrocytes during central nervous system-tuberculosis infection

S. Geyer (1), A. Walters (1), N.J. Hsu (1), R Keeton (1), M. Jacobs (1, 2, 3); (1) Division of Immunology, Department of Pathology and Institute of Infectious Disease and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, South Africa; (2) National Health Laboratory Service, Johannesburg, South Africa; (3) Immunology of Infectious Disease Research Unit, University of Cape Town, South; Africa.

Tuberculosis (TB) is a major health concern causing 1,2 million deaths in 2018 worldwide. Dissemination of Mycobacterium tuberculosis (Mtb) to the central nervous system (CNS-TB) is the severest clinical extra-pulmonary manifestation of the disease which constitutes approximately 1% of global TB cases. Substantial complications present in survivors including neurological sequelae, motor impairment, optic atrophy, ophthalmoplegia and hearing impairment. Although microglia are the prime resident immune-effector cells in the CNS, increasing evidence indicates that astrocytes regulate innate and adaptive immunity in CNS disease and injury. This study therefore evaluates the potential immunological role of astrocytes in CNS-TB by exploring their interactions and regulation of CNS inflammation following Mtb challenge.

To investigate the direct interaction between astrocytes and Mtb, primary astroglial cultures were inoculated with virulent H37Rv and attenuated BCG bacilli and analyzed by immunocytochemistry. The immune regulatory role of astrocytes were assessed through microarray analysis, flow cytometry and ELISA. To validate this in an animal model, flow cytometry analysis and immunohistochemistry was performed on mouse brains following H37Rv intracerebral infection. Orthogonal views of confocal fluorescent images demonstrate that astrocytes can internalize Mtb ex vivo. Bacterial uptake by astrocytes was further supported by CFU enumeration. In intracerebrally infected mice flow cytometry analysis of astrocytes showed an upregulation of IL1B and IL10, compared to saline controls. Our data supports the regulatory role of astrocytes to maintain a delicate balance through promoting cellular responses whilst limiting inflammation during CNS-TB infection. Characterizing Mtb infection of astrocytes and identifying mechanisms that are associated with neurological complications offer the potential to improve diagnostics and therapeutic strategies, leading to better prognosis.