Pathogen Associated Molecular Patterns, Pattern Recognition Receptors and Pediatric Sepsis

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