Inflammation is a foundational cause of brain injury during central nervous system (CNS) infections and the reason why anti-inflammatory therapy is used along with antibiotics during infections such as meningitis. Corticosteroids are the only anti-inflammatory treatment currently approved for bacterial infections of the CNS. However, corticosteroids are sub-optimal as their benefit is restricted to individuals in high-income countries, to infections with certain bacteria, and ultimately do not improve long-term neurological outcomes. Thus, new therapies are needed that will ameliorate inflammatory pathology and deliver more positive patient outcomes. MicroRNA (miR) are short, non-coding RNA expressed in myeloid cells that have key roles as modulators of innate and adaptive immune responses. Our data suggest several miR, e.g. miR-155, are up-regulated in cerebrospinal fluid (CSF) of patients with bacterial meningitis as well as in the brains of mice infected with the neurotropic bacterium, L. monocytogenes (Lm). miR-155 up-regulation coincides with up-regulation of pro-inflammatory cytokines and recruitment of inflammatory leukocytes into the brain. Notably, preliminary data presented here show miR-155-/- mice recruit more Ly-6Chigh monocytes and neutrophils to the brain than do normal mice suggesting miR-155 limits inflammation during infection. The goals of this proposal are to establish the novel finding that miR-155 has a role in reducing brain inflammation during infection and to identify the mechanisms by which infection induces brain expression of miR that are found both in patients with meningitis and in experimental mouse infection.
Specific Aims of this proposal include:
Aim 1. Elucidate the mechanisms leading to increased inflammatory cell influxes in the brains of miR-155-/- mice during Lm infection. Our working hypothesis is that loss of miR-155 leads to increased production of monocyte and neutrophil-attracting chemokines in the brain during CNS infection.
Aim 2. To identify key biological stimuli that up-regulate miR expression in the brain during CNS infection. Our working hypothesis is that the initial miR up-regulation in the brain is driven by cytokines produced during Lm infection. Experiments will be performed in part using the mouse model of Lm infection as well as with novel techniques including bone marrow chimeras and organotypic brain slice cultures. Successful completion of these aims will establish for the first time that a specific miR influences brain inflammation during bacterial infection and will gauge the potential benefit of targeting miRs or specific miR-expressing inflammatory cells as novel adjunctive treatment for CNS infections. This is a necessary first step towards discovering new molecular targets for modulating CNS inflammation.
Bacterial meningitis is a severe infection that causes high rates of death and disability around the world. Current studies show that advances in antibiotics and medical care have improved survival only marginally over the past 50 years and that anti-inflammatory therapy with corticosteroids offers little to no benefit for most patients. Studies in this proposal will test the extent to which microRNA control brain inflammation during bacterial infection of the central nervous system and could be used as new therapies to suppress harmful inflammation.