Astrocyte-mediated immune modulation during mycobacterial infection

Geyer, Sohair

Astrocyte-mediated immune modulation during mycobacterial infection

Thesis / Dissertation

2023

Abstract

Central nervous system tuberculosis (CNS-TB) is the severest clinical extra-pulmonary manifestation of tuberculosis (TB) disease and constitutes approximately 1% of global cases. Little is known about the cells that regulate immune responses during CNS-TB infection. Microglia are the prime resident immune-effector cells in the CNS; astrocytes however also regulate innate and adaptive immunity in CNS disease and injury. Astrocytes play a progressive role in maintaining the structural and functional integrity of the CNS while supporting neuronal function and participating in host protection during infection of the CNS. These cells exist as distinct populations with complex morphological identities and functional modifications suited to their micro-environment. The principal aim of this study was to elucidate the genomic profile and cellular immune responses of astrocytes to characterise their immunomodulatory potential during CNS-TB infection. The ability of astrocytes to internalise mycobacteria was evaluated by immunocytochemistry and immunohistochemistry. The immune regulatory role of astrocytes was assessed through transcriptomic profiling, flow cytometry and Luminex analysis. Outcomes were validated in mouse models, through flow cytometric analysis of infected brain cells. The novel findings presented here collectively demonstrate the sophistication and complexity of astrocyte activity and behaviour during host immunity. For the first time, astrocytes showed internalisation of M. bovis BCG and M. tuberculosis bacilli, demonstrating that astrocytes are target cells for non-virulent and virulent mycobacterial strains. Extensive transcriptomic analysis of astrocytes revealed elevated expression of multiple pathways in infected cells, particularly those involved in inflammation and immune regulation, and emphasised the innate immune component. Notably, various pro-inflammatory cytokines essential to host defence during CNS-TB infection, such as IL-1b and TNF, were upregulated by astrocytes following the mycobacterial challenge. The data suggests that astrocytes may modulate host immune responses by regulating blood-brain barrier permeability and facilitating immune cell recruitment and activation at the site of infection. This potential was demonstrated by their enhanced expression and production of well-described pro- and anti-inflammatory factors as well as chemotactic factors following mycobacterial infection. Furthermore, increased expression of neurotrophic factors by astrocytes was observed, which can assist in the recovery and repair of the CNS during CNS-TB. By supporting the survival and function of neurons and modulating immune cell activity, astrocyte-derived neurotrophic factors can help to limit infection-induced damage and promote the resolution of inflammation. The dichotomous behaviour of astrocytes during CNS-TB was demonstrated, as they can contribute to the maintenance and protection of CNS function and host immune responses while potentially enhancing pathology during infection. This study explored astrocyte contributions to host immune responses during CNS-TB infection by examining their regulation of CNS inflammation in the presence of mycobacterial challenges, and highlighted the intricate interplay of cytokines/chemokines that need careful modulation to achieve optimal outcomes. These findings demonstrated that astrocytes are crucial regulators of host immunity during mycobacterial infection and play a progressive role in maintaining the structural and functional integrity of the CNS

Keywords

Clinical Sciences and Immunology

Reference:

Collections

PhD / Doctoral

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