Mechanisms Underlying Control of Anti-Microbial Immunity by Acetylcholinesterase Inhibition

Ray M. Esam Al-Barazie


Inflammation is a crucial defense mechanism that protects the body from the devastating effects of invading pathogens. However, an unrestrained inflammatory reaction may result in systematic manifestations with dire consequence to the host. The extent of activation of the inflammatory response is tightly regulated through immunological and neural pathways. Previously, we demonstrated that cholinergic stimulation confers enhanced protection in experimental animals orally infected with a lethal dose of Salmonella typhymurium. In this study, we investigated the mechanism by which this enhanced protection takes place. We showed that cholinergic stimulation enhanced host survival following oral-route infection, which correlated with significantly reduced bacterial load in target organs, including livers and spleens. Enhanced protection was not due to increased gut motility or rapid bacterial clearance from the GI tract. Moreover, protection against bacterial infection was lost when the animals were infected systematically, suggesting that the acetylcholine-mediated protective effect was mostly confined to the gut mucosal tissue. In vivo imaging demonstrated more localized infection and delay in bacterial dissemination into systemic organs in mice pre-treated with acetylcholinesterase inhibitors. Morphological analysis of the small intestine (ileum) showed that acetylcholinesterase inhibition induced the degranulation of goblet cells and Paneth cells, two specialized secretory cells involved in innate immunity. Our findings demonstrated a crucial pathway between neural and immune systems that acts at the mucosal interface to protect the host against invading pathogens.