Initiation and regulation of cytosolic innate immunity during sepsis

The innate immune system recognizes pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) through a set of germline-encoded proteins called pattern recognition receptors (PRRs). Depending on the ligand, inflammasome activation can occur through either canonical or non-canonical inflammasome activation pathways. Gram-positive bacteria such as Staphylococcus aureus (SA) and Group B streptococcus (GBS) are the primary causal organisms of adult and neonatal sepsis. Molecular mechanisms through which these bacteria activate the inflammasome pathways are poorly understood. The principal aim of this thesis was to investigate the molecular mechanisms involved in the activation of inflammasome pathways induced by SA and GBS. In human macrophages, Gram-positive bacteria activate the canonical inflammasome pathway via an upstream pathway involving stimulator of interferon genes (STING) but independent of the DNA sensor cyclic GMP-AMP synthase (cGAS). Small RNA aptamers are being delivered through multilamellar lipid bodies (MLBs) secreted by Gram-positive bacteria in turn activating STING. The expression of the CDN binding small regulatory RNAs is dependent on the accessory gene regulatory (AGR) system of SA. Moreover, we report that staphyloxanthin types of lipids are present in the multilamellar lipid bodies of SA that target the microbial RNA for the cytosolic activation of the inflammasome. Collectively, this work outlines the mechanism involved in Gram-positive bacteria mediated inflammasome activation for the release of IL-1β and progranulin. Gram-positive sepsis patients demonstrated RNA mediated inflammasome activation and substantial accumulation of progranulin and caspase-5 mediation inflammasome activation. Thus, these findings contribute to a new panorama for the pathogenicity of Gram-positive sepsis in man.