Dendritic cells as potential mediators of Mycobacterium tuberculosis infection of the central nervous system in a MHC class II-deficient mouse model.

Mycobacterium tuberculosis (Mtb) infection of the central nervous system (CNS) in a rare, but deadly form of TB affecting immune-compromised individuals. Due to the HIV-AIDS epidemic this population has recently increased, however the pathway by which Mtb gains access to the CNS is poorly understood. Our work seeks to understand the potential ability of dendritic cells to traffic Mtb to the CNS. Preliminarily, we established the importance of mycobacterium infected dendritic cells to the formation of nervous system infection in MHC class II-deficient mice. In this model we used bone marrow derived dendritic cells (BMDC) from a dendritic cell reporter mouse strain (CD11c-eYFP). These cells increased the dissemination of Mtb 6020 to the brain by one log compared to Mtb 6020 alone, though the systemic infection remained the same. When GM-CSF BMDCs were infected with tdTomato H37Rv Mtb and injected IV into MHC class II-deficient mice CFU was detected in the brain, cervical lymph nodes and lung with no Mtb observed in the liver and superficial lymph nodes. After infection with tdTomato Mtb, BMDCs matured using GM-CSF or FLT3 had increased expression of CD11c, eYFP, CD40 and CD86 as detected by flow cytometry. These immunocompromised mice, whose phenotype reflects aspects of immunodeficiency seen in human populations, have a predisposition to CNS infection when BMDCs are directly infected with mycobacterium, suggesting the ability of dendritic cells to facilitate the movement of Mtb across the BBB or choroid plexus to initiate infection. These data support the use of MHC class II-deficient mice as a model for future work.