Therapeutic potential of targeting glia as an inflammatory mediator source and bacterial reservoir

ABSTRACT Bacterial infections of the central nervous system (CNS) are associated with a high degree of mortality and serious neurological deficits. While inflammation is often a crucial component in host defense against infectious organisms, such responses can have devastating consequences in the CNS and astrocytes and microglia play a major role in the initiation and propagation of bacteria-associated neuroinflammation. Furthermore, bacteria pathogens, including Borrelia burgdorferi, can invade and persist in glia. Bacteria sequestered intracellularly may exacerbate glial inflammatory responses and provide a reservoir for chronic infections. As such, developing novel treatment strategies that can limit both intracellular CNS bacterial burden and glia-driven neuroinflammation is of considerable importance. In this exploratory and developmental R21 project, we will employ a novel non-immunostimulatory nucleic acid-based linear nano-scaffold, developed by our research team, combined with an appropriate carrier molecule, to deliver an anti-inflammatory therapeutic nucleic acid cargo and/or an anti- microbial agent into resident CNS cells and assess its therapeutic benefits following direct administration of B. burgdorferi into the CNS. These nanoparticles will be functionalized to target the master inflammatory gene transcription regulator NF-kB with RNAi and decoy DNA oligonucleotides, or be co-functionalized with the antimicrobial agent LL-37 to limit bacterial burden and associated neuroinflammation. The successful attenuation of neuroinflammation or bacterial burden with such functionalized nanoparticle-carrier formulations will support the therapeutic potential of targeting glial cells as a source of inflammatory mediators, or as a bacterial reservoir, to limit neurological damage and/or extend the effective window for antibiotic treatment during bacterial CNS infections.