Pathogen Associated Molecular Patterns, Pattern Recognition Receptorsand Pediatric Sepsis

摘要

The mortality of septic shock in the pediatric population has improved over the last 2 decades with bettersupportive care however it still remains unacceptably high. Exaggerated inflammatory responses early in septic shockhave been associated with poor outcomes. Regulation of the magnitude of the early inflammatory response is not wellunderstood. The earliest aspect of the inflammatory response to pathogens is the innate immune response which isimportant to pathogen containment. Elements of the innate immune system activate the adaptive immune system in anantigen-specific way which leads to pathogen-specific protection and lasting immunologic memory to prevent subsequentinfection. Pattern recognition receptors (PRRs) are evolutionarily conserved receptors on multiple types of innate immunecells and are capable of responding to highly conserved components of pathogens called pathogen associated molecularpatterns (PAMPs). Numerous PRRs have been defined and are present on the cell surface as well as in the cytosol. Thesereceptors fall into several classes called Toll-like receptors which are expressed on the cell surface or on the endosomalplasma membrane, C type lectin receptors and scavenger receptors which are only present on the cell surface. Other PRRsare present in the cytosol and including NOD-like receptors which can aggregate to form inflammasomes and RIG1 likereceptors. Pathogenic microorganisms are extremely diverse however there are some common patterns repeated incomponents of structures such as the cell wall. PRRs can respond to PAMPs comprised of proteins, lipids, andcarbohydrates, DNA and RNA. Numerous PAMPs have been described for many classes of pathogenic microorganismssuch as Gram negative bacteria, Gram positive bacteria, viruses, fungi, and protozoa. The interactions between PRRs andPAMPs comprise the earliest immune responses to foreign substances and are critical for pathogen containment andamplification of the full repertoire of the immune response. There are developmental differences in the immune systemsof infants and children compared to adults. The innate immune system matures much earlier than the adaptive immuneresponse and as a result infants and young children may be more reliant on their innate immune system. For this reason itimportant to fully understand the key elements of the innate immune response including the many categories of PRRs andtheir cognate PAMPs. As these interactions are very early in the immune response, they are particularly relevant targetsfor therapeutic intervention. Below is a discussion of the major classes of PRRs, their expression, ligands, and signalingpathways as well as the major classes of PAMPs that activate them.