The Three Flavors of Danger

To survive as a species, all organisms must protect their genome integrity from invaders. Several billion years ago, archaebacteria evolved selective defenses such as CRISPR-Cas to specifically cut DNA sequences in invading bacteriophage. Multicellular eukaryotes like us needed to evolve new defenses to protect our genome integrity against intracellular infections such as retroviruses, to defend against extracellular infections (e.g., bacteria, fungi); and to recognize and repair sterile tissue damage (e.g. trauma). To differentiate these three broad categories of “danger”, we evolved an innate immune system that uses several families of “pattern recognition receptors” to “taste” their environment for the presence of molecules that are associated with these three fundamental flavors of danger: i) intracellular infections (e.g., retroviruses); ii) extracellular infections (e.g., bacteria, fungi); and iii) sterile tissue damage. Activation of different subsets of pattern recognition receptors in innate immune cells causes the activation of threat-appropriate adaptive immune defenses to eradicate infection and promote homeostasis and tissue healing. Recent discoveries have provided fresh insights into how these systems normally cooperate to keep us healthy, how their failure can lead to autoimmune diseases and to cancer, and how therapeutic manipulation of pattern recognition receptors can be applied to treat disease.