Intracerebral Mycobacterium tuberculosis infection-induced immune response in the central nervous system

Abstract

The World Health Organization declared a tuberculosis (TB) global emergency. Central nervous system (CNS) TB is a rare, highly devastating manifestation of extra-pulmonary TB. To date, research has focused on pulmonary TB, with no significant advancements being made in understanding the mechanisms associated with CNS TB. This study uses a small animal model of CNS TB that permits us to investigate the immune responses following CNS Mycobacterium tuberculosis (Mtb) infection. We use intracranial infection of mice with the H37Rv strain of Mtb which has been fluorescently tagged with a TdTomato plasmid, allowing us to track it in vivo, and analyzed the cellular composition of the subsequent immunological response in the brain. At 7 days post infection (PI), we show a robust infiltration of immune cells into the CNS including the infiltration of CD11c+ dendritic cells. We can also see Mtb-containing granuloma-like lesions. We adoptively transferred Mtb-specific P25 CD4+ T and found that these cells also accumulate in the brain and were found activated in the peripheral lymphoid tissue, including the spleen and cervical draining lymph nodes. The P25 T cells present in the brain display extensive proliferation. Moreover, P25 T cells present in the peripheral lymphoid organs of Mtb infected mice show increased proliferation when compared to non-infected controls suggesting a systemic sampling of CNS Mtb antigen. We also show that at 7 days PI there is a significantly higher percentage of activated, INFγ producing, CD4+ T in the brain. Both INFγ and IL-17 producing T cell populations increase in size by day 21. This study will provide knowledge into the pathogenesis of CNS TB, and provide possible treatment strategies to lessen its destructive outcome.