The immunoregulatory role of Nod proteins

To combat and respond to infection, the immune system initially requires recognition of exogenous and endogenous signals by way of complex cellular and humoral processes. The mechanisms and molecular effectors to detect microbial-derived signals are highly conserved in diverse hosts, and rely on analogous regulatory mechanisms by sensing of pathogen-associated molecular patterns (PAMPs) by germ-line encoded molecules, termed pattern recognition molecules (PRMs). PAMP-PRM engagement induces specific downstream signalling events providing immediate first-line protection of the host from invading pathogens and instructs and shapes antigen-specific adaptive immunity. Several PRMs such as Toll-like receptors (TLR) have been characterized, during the last decade, and many microbial motifs sensed by TLRs have been deciphered, and their impact on first- line host response induction has been demonstrated. However, depending on the cell type and molecule, the localization of TLRs seems to be restricted to the cell surface or specialized cell organelles, especially the endolysosomal compartment. Conversely, bacteria use a variety of strategies to escape these compartments entertaining the idea that the cytosolic location of a pathogen may provide optimal protection from immune recognition and response. Recent findings now indicate that mammals have also evolved strategies to recognize bacteria inside the cell via members of the NACHT-LRR protein family (NLRs), Nod1 and Nod2, respectively, representing a means of cytosolic surveillance. Several studies have shown that the host cell recognizes the microbial cell-wall component peptidoglycan (PGN) via Nod1 and Nod2, and the relevance of these recognition events for antimicrobial immunity has recently been demonstrated by studies with Nod-deficient animals. The role of Nod proteins in balancing host immune responses has further been supported by observations describing polymorphisms in Nod genes linked to increased susceptibility to asthma, inflammatory bowel disease (IBD) and atopic eczema, inflammatory barrier diseases with imbalanced effector arms of immunity. These findings therefore suggest that the pathogenesis of these diseases is likely related to an abnormal long-term response to microbial components. This research proposal aims to investigate if the observed inverse correlation between the incidence of microbial infections and exaggerated barrier disorders is related to altered antigen-specific responses. The results will give insight into how Nod proteins are activated by microbial components and how this then translates into an antimicrobial long-term response in the host. Findings generated by this work will certainly aid in our understanding of how inflammatory conditions like IBD and asthma develop and may impact on the treatment and prevention of these diseases.