The role of the inflammasome in chronic infection. (360G-Wellcome-089590_Z_09_Z)

Immune homeostasis in the gastrointestinal tract is tightly regulated in order to provide protective immunity from pathogens, whilst concurrently suppressing excessive reactivity directed towards the commensal micro-flora. In humans, perturbation of this balanced immune response presents as inflammatory bowel diseases (IBD), including Crohn's disease and ulcerative colitis, which are characterized by chronic inflammation of the intestinal tract [1]. Similarly, chronic viral infection often leads to host-mediated immunopathology and associated organ loss-of-function, including hepatitis and liver dysfunction in chronic Hepatitis C virus (HCV) infection [2]. Mammalian detection of invading pathogens is dependent upon several families of germ-line encoded pattern recognition receptors (PRR) able to bind a vast array of microbial-associated molecular patterns (MAMP), including RNA, DNA and cell wall components [3]. Multiple PRR families, including cell-surface Toll-like receptors (TLR), cytosolic Nod-like receptors (NLR) and Rig-I like receptors (RLR), play complementary roles in inducing optimal immune responses [4]. This is best illustrated for the pro-inflammatory cytokines IL-1? and IL-18, where TLR activation enhances production of the inactive cytosolic forms of these cytokines and NLR activation leads to the formation of multi-molecular platforms, termed inflammasomes, that activate Caspase-1, resulting in cleavage and secretion of active IL-1? and IL-18 [5]. Several NLR, including NLRP3 and NLRC4, can promote inflammasome formation in response to a wide range of pathogen-derived or host stress signals. In humans, polymorphisms in NLR genes have been associated with a range of auto-inflammatory diseases termed CAPS (Cryopyrin-associated periodic syndromes) that have been successfully treated with IL-1R antagonist [6]. In addition, distinct polymorphisms in NLR, such as NOD2 and NLRP3, have been associated with susceptibility to IBD, but despite intensive investigation, the mechanisms involved remain unclear [7, 8]. Equally, polymorphisms in the IL-18 promoter and in IL-18 binding protein are associated with HCV clearance [9, 10], whilst a body of evidence suggest a role for IL-18 in promoting pathology following experimental liver injury [11], as well as increased IL-18 levels in the serum of HCV infected patients [12]. Despite the emerging links between NLR and inflammasome activation in chronic inflammation, the precise roles of IL-1? and IL-18 in protective versus pathogenic responses remain unclear. Indeed, recent studies suggest that inflammasomes may play a crucial role in maintaining intestinal homeostasis following chemical-induced epithelial injury [13, 14]. The aim of this investigation is to characterise the role of the inflammasome in established models of chronic bacterial colitis and viral hepatitis, and determine how the pro-inflammatory cytokines IL-1 and IL-18 influence disease progression and outcome. Our study will focus on the inflammasome components and cell types required for IL-1 and IL-18 activation in response to model bacterial and viral infections and the cellular targets upon which they act to drive protective immunity and/or immunopathology