PAMPs are conserved residues that activate innate immune responses downstream of germline-encoded PRRs, including TLRs, NLRs, RLRs, and CLRs. Extracellular TLRs typically recognize pathogen cell wall components, including lipoproteins and lipopolysaccharides, whereas endosomal TLRs recognize nucleic acids. Sensing of PAMPs by TLRs initiates downstream signaling cascades, which converge upon intracellular signal-potentiating enzymes such as MAP kinase (MAPK), IKK complex, and TANK-binding kinase 1 (TBK1). These kinases activate, often via phosphorylation, downstream transcription factors including AP-1, NF-kB, and interferon regulatory factors (IRFs), thereby facilitating their nuclear translocation, from where they can bind to consensus sequences on promoters of genes encoding proinflammatory cytokines, chemokines, and IFN-I. Engagement of RNA-sensing cytosolic RLRs, including RIG-I and MDA5, and cytosolic DNA sensors, such as cGAS, triggers similar downstream signaling pathways. Rather than MyD88/Toll/IL-1R domain-containing adaptor-inducing IFN-β (Trif), RNA and DNA sensors signal via the adaptor proteins mitochondrial antiviral signaling protein (MAVS) and STING, respectively. CLRs, including Dectin-1 and -2 and Mincle, recognize carbohydrate moieties and have been implicated in so-called trained immunity, whereby prior exposure to molecules including β-glucan and bacille Calmette-Guerin (BCG) augments secondary immune responses to heterologous pathogens via induction of epigenetic modifications.
