When αand β-defensins are first synthesized, they contain a signal peptide (not shown); a pro-region (blue), which is shorter in the β-defensins; and an amphipathic domain (AMPH, green–yellow); the pro-region represses the membrane-inserting properties of the amphipathic domain. After defensins are released from the cell, or into phagosomes, they undergo cleavage by proteases, which releases the amphipathic domain in active form. Newly synthesized cathelicidins contain a signal peptide, a cathelin domain, a short pro-region, and an amphipathic domain; they, too, are activated by proteolytic cleavage. RegIII contains a C-type lectin domain (CTLD), also known as a carbohydrate-recognition domain (CRD). After release of the signal peptide, further proteolytic cleavage of RegIII also regulates its antimicrobial activity.
A class of antimicrobial peptides called histatins are constitutively produced in the oral cavity by the parotid, sublingual, and submandibular glands. These short, histidine-rich, cationic peptides are active against pathogenic fungi such as Cryptococcus neoformans and Candida albicans. More recently histatins were found to promote the rapid wound healing that is typical in the oral cavity, but the mechanism of this effect is unclear.
Another type of bactericidal proteins made by epithelia is carbohydrate-binding proteins, or lectins. C-type lectins require calcium for the binding activity of their carbohydrate-recognition domain (CRD), which provides a variable interface for binding carbohydrate structures. C-type lectins of the RegIII family include several bactericidal proteins expressed by intestinal epithelium in humans and mice, comprising a family of ‘lecticidins.’ In mice, RegIIIγ is produced by Paneth cells and secreted into the gut, where it binds to peptidoglycans in bacterial cell walls and exerts direct bactericidal activity. Like other bactericidal peptides, RegIIIγ is produced in inactive form but is cleaved by the protease trypsin, which removes a short amino-terminal fragment to activate the bactericidal potential of RegIIIγ within the intestinal lumen (see Fig. 2.11). Human RegIIIα (also called HIP/PAP for hepatocarcinomaintestine-pancreas/pancreatitis-associated protein) kills bacteria directly by forming a hexameric pore in the bacterial membrane (Fig. 2.12). RegIII family proteins preferentially kill Gram-positive bacteria, in which the peptidoglycan is exposed on the outer surface (see Fig. 2.9). In fact, the LPS of Gram-negative bacteria inhibits the pore-forming ability of RegIIIα, further enforcing the selectivity of RegIII proteins for Gram-positive bacteria.
Summary.
The mammalian immune response to invading organisms proceeds in three phases, beginning with immediate innate defenses, then the induced innate defenses, and finally adaptive immunity. The first phase of host defense consists of those mechanisms that are present and ready to resist an invader at any time. Epithelial surfaces provide a physical barrier against pathogen entry, but they also have other more specialized strategies. Mucosal surfaces have a protective barrier of mucus. Through particular cell-surface interactions, highly differentiated epithelia protect against both microbial colonization and invasion. Defense mechanisms of epithelia include the prevention of pathogen adherence, secretion of antimicrobial enzymes and bactericidal peptides, and the flow caused by the actions of cilia. Antimicrobial peptides and the bactericidal lectins of the RegIII family are made as inactive proproteins that require