Molecular mechanisms underlying glial inflammatory responses to Neisseria meningitidis: A pilot study - Project Summary Neisseria meningitidis is the causative agent of meningococcal meningitis, which can lead to epidemics with a fatality rate of up to 50% in untreated patients. In addition, up to 20% of survivors of such infections show permanent CNS deficits due to severe neuroinflammation, a hallmark of meningitis. It is now appreciated that resident glial cells, including microglia and astrocytes, play a key role in initiating such damaging inflammation and do so following the recognition of conserved N. meningitidis motifs using an assortment of cell surface and membrane-associated pattern recognition receptors (PPRs). Furthermore, the production of inflammatory mediators by glial cells following the recognition of pathogen associated molecular patterns (PAMPs) can serve as host environmental cues that direct changes in the bacterial transcriptome to promote further colonization and virulence. For example, Neisseria expression and/or release of the lipooligosaccharide (LOS) and peptidoglycan (PGN) stimulates host cell production of inflammatory mediators, and these bacteria can modify the lipid A component of LOS and release different amounts/profiles of PGN fragments that have been demonstrated to influence host cell recognition and responses in non-CNS cell types. Intriguingly, N. meningitidis has been reported to bind and import host cytokines that then drive changes in gene expression, suggesting that cytokine responses serve as environmental cues to promote N. meningitidis virulence. To date, the effect of specific LOS modifications and PGN fragment release on glial recognition and responses has not been determined. Accordingly, this R03 pilot study will begin to address the hypothesis that N. meningitidis PAMPs initiate glial immune responses that, in turn, feedback to regulate bacterial gene expression to further exacerbate infection. These pilot studies are an essential first step in dissecting the intimate relationship between N. meningitidis and glial cells that underlies the development of detrimental neuroinflammation and will provide a solid rationale for future comprehensive investigations.
