Welcome Letter from Dr. Zasloff.

It is a fact that we live in harmony with microbes. Our epithelial surfaces are populated by a highly diverse population of bacteria, fungi, viruses, and protozoa, and yet exhibit no visible signs of disease, most of the time. Consider the diversity of microbes that are contained within the walls of the colon, or those that come into contact with the epithelial surfaces within the oral cavity, or on our skin. Is it not surprising that these surfaces appear indifferent to their presence? The surprise in recent decades has been the discovery of the depth of protection afforded by the clinically silent component of innate immunity provided by antimicrobial peptides and proteins. Antimicrobial peptides and proteins are produced by the epithelial surfaces of plants and animals in contact with microbes, and by professional microbe hunting phagocytic cells that roam the tissues of vertebrates and invertebrates. They include the 1,000 or so different antimicrobial peptides described in plants and animals that can discriminate differences in the design and lipid composition of the plasma membranes of microbe and host, and cause rapid damage to the former. In general every organism maintains two ‘‘sets’’ of antimicrobial peptides and proteins. One set is constitutively produced, preformed and stored for rapid deployment should a microbe gain access to ‘‘restricted’’ anatomy, the response of the system being more rapid than the time required for the organism to gain a foothold. Breach of this first barrier generally triggers the induction of a second battery, often a set of different peptides and proteins with a different spectrum of anti-infective activity, a process that furthers hardens the defensive barrier. Remarkably, ‘‘hard-wired’’ sensors exist on the host cells that participate in this ‘‘second-wave’’ of defense that can recognize specific determinants characteristic of classes of microbe, such as Gram negative or Gram positive bacteria, fungi, or viruses. In a sense the host can ‘‘recognize’’ the type of microbe that threatens and, consequently, a set of antimicrobial peptides and proteins most effective against that microbe is induced. In addition, at least in vertebrates, antimicrobial peptides secreted from the epithelial site exhibit independent chemokine activities, including the attraction of phagocytic cells to the site of the breach, and, in some cases, the attraction of certain classes of dendritic cell, thereby facilitating the education of the adaptive immune system. Antimicrobial peptides and proteins are never used to ‘‘sterilize the outside world.’’ On epithelial surfaces, they are not produced in amounts that could achieve effective antimicrobial concentrations except within the local microenvironments. For example, in the human intestine, the peptides produced by both Paneth cells and enterocytes, create an anti-bacterial barrier in the thin fluid space between the epithelial surface and the overriding mucous layer. An organism that ventured from the lumen through the mucous layer would encounter a diverse mixture of antimicrobial peptides and proteins at a concentration that would likely kill it before it had the opportunity to either attach or replicate. Perhaps it is not surprising that the microbes that now populate our gut are those that remain M. Zasloff (&) Department of Surgery, Transplant Institute, Georgetown University School of Medicine, Washington, USA e-mail: maz5@georgetown.edu