The Vitamin D–antimicrobial Peptide Pathway and Its Role in Protection against Infection

Adrian F Gombart

Disclosures

Future Microbiol. 2009;4(9):1151-1165. 

In This Article

Cathelicidins, Defensins & Innate Immunity

Cathelicidins are synthesized as a prepropeptide consisting of an N-terminal signal peptide, a conserved prosequence (cathelin domain) and a highly variable C-terminal cationic AMP.[45] In neutrophils, proteolytic cleavage generates the mature AMP.[46] While some mammals express numerous cathelicidins, humans possess a single cathelicidin gene[47,48] called CAMP, also known as hCAP18/LL-37/FALL39 (humans) and CRAMP/CNLP/MCLP (mice). Throughout this paper the gene and mRNA is referred to as CAMP, the proprotein as cathelicidin or hCAP18 (human) or CRAMP (mouse) and the processed peptide as LL-37 (human).

The hCAP18/CRAMP protein is synthesized and secreted in significant amounts by those tissues constantly exposed to environmental microbes,[49] as well as other tissues[50–53] and fluids,[50,52,54–56] and is expressed by a wide array of immune cells.[57–59] Other lines of evidence similarly indicate that hCAP18/CRAMP has important functions in host defense.[60–62] Mice deficient in CRAMP are more susceptible to skin infection than wild-type mice,[63] and CRAMP secretion is induced by bacteria and protects the murine urinary tract against invasive bacterial infection.[64] Decreased expression of hCAP18 is reported in human diseases whose common denominator is enhanced susceptibility to infection.[65–67] Collectively, these data strongly implicate a key role for CAMP in maintaining adequate host defenses.

The defensins are antimicrobial peptides with a characteristic β-sheet-rich fold resulting from a framework of six disulfide-linked cysteines.[68] They are expressed by leukocytes and various epithelial cells that come in contact with environmental microbes. Expression is both constitutive and inducible depending on the tissue.[68] Both cathelicidins and defensins disrupt the integrity of the bacterial cell membrane, resulting in the death of the microbe.[68]

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