Intracerebral Mycobacterium tuberculosis infection induces robust myeloid and lymphocytic immunity in the central nervous system

Abstract

Abstract Central nervous system tuberculosis (CNSTB) is a rare, highly devastating manifestation of extra-pulmonary tuberculosis. To date, research has focused on pulmonary tuberculosis, with no significant advancements being made in understanding the mechanisms associated with CNSTB. This study uses a small animal model of CNSTB that permits us to investigate the immune responses following CNS Mycobacterium tuberculosis infection. We use intracerebral infection of mice with Mtb H37rv which has been fluorescently tagged with tdTomato, allowing us to track it in vivo, and analyze the cellular composition of the subsequent immunological response in the brain. Starting at 7 days post-infection (PI), we show a robust infiltration of immune cells into the brain including the infiltration of CD11chigh dendritic cells, CD11b+ monocytes, and an IFNγ dominated T cell response. Mtb-containing granulomatous lesions develop starting at 1 week and continue to form until 7 weeks PI. Granuloma composition in the brain is dominated by CD11chigh dendritic cells, CD11b+ monocytes, CD4+ T cells and to a lesser extent, Tmem119+ microglia. We show robust immune cell infiltration in the choroid plexus during infection indicating a potential route for secondary dissemination and immune cell infiltration into the brain. We also discovered that anti-Mtb immunity in the brain develops as early as 1 week following intracerebral inoculation of Mtb, earlier than following peripheral inhalation infection in the lung. Finally, robust anti TB immunity leads to infection control in the brain at 7 weeks post-infection. This study provides new knowledge into the pathogenesis of CNSTB, and could provide possible treatment strategies to lessen its destructive outcome.