LA JOLLA, CALIF—Mammalian peptides known as cathelicidins have previously shown bactericidal activity in vitro. Targeted deletion of a mouse cathelicidin gene Cnlp now demonstrates the peptide’s protective role against infection with group A streptococci (GAS) in vivo.[1]

“We’ve shown that this previously unappreciated component of the immune system is a vital part of defense against microbes,” Richard L. Gallo, MD, PhD, told PULMONARY REVIEWS. Although cathelicidins’ in vivo function in signaling was known, their role as antibiotics remained unproven. Dr. Gallo, Associate Professor of Medicine and Pediatrics at University of California, San Diego, and colleagues subcutaneously injected GAS into wild-type mice as well as mice lacking the Cnlp gene. The resulting necrotic lesions grew more rapidly, attained larger maximal size, and persisted longer in mice lacking Cnlp than in wild-type mice, while heterozygous mice with only one copy of Cnlp grew lesions of intermediate size.

PEPTIDES PUNCTURE BACTERIA

Cathelicidins probably kill by integrating into bacterial membranes to disrupt membrane integrity. “Within a couple of minutes, there’s a loss of membrane potential,” said Dr. Gallo. Because resistance to such a mode of killing would require restructuring bacterial membranes, such peptides may surpass conventional antibiotics in forestalling resistance.

Dr. Gallo and colleagues developed mutant GAS laboratory strains insensitive to cathelicidins and tested their virulence in vivo. The strains produced lesions larger in size and longer lasting than those caused by nonresistant GAS, highlighting cathelicidins’ role in limiting infection. Why haven’t cathelicidin-resistant strains evolved in the wild? “Bacteria which are resistant ... develop more slowly, so apparently there’s a cost to such adaptations,” Dr. Gallo offered.

In response to microbial invasion and inflammation, cathelicidins are appropriately expressed within the cell types that provide a first line of defense against infection, Dr. Gallo pointed out. “In this case, they are secreted by keratinocytes. But they are also made by pulmonary epithelial cells,” thus presumably guarding against lung infections as well. Secreted cathelicidins also attract neutrophils, monocytes, and some T cells to the site.

CATHELICIDINS IN DISEASE

In diseases such as cystic fibrosis (CF), infection correlates with reduced peptide activity, said Dr. Gallo. “One of the reasons for decreased antimicrobial action is that the cathelicidins are inactivated by very high salt concentrations” surrounding respiratory epithelia of CF patients. Thus, he added, “in a mouse model of CF, overexpression of cathelicidins was able to combat infection.” And in human gut epithelium, Shigella down-regulated expression of a cathelicidin and another peptide, ß-defensin, a possible mechanism for virulence.

Cathelicidins may soon be used as therapeutic antimicrobial agents, according to Dr. Gallo. “An oral synthetic analogue of the pig cathelicidin protegrin is now in phase III trials for human mucositis,” he noted.

—Mimi Zucker, PhD

Reference
1. Nizet V, Ohtake T, Lauth X, et al. Innate antimicrobial peptide protects the skin from invasive bacterial infection. Nature. 2001;414:454-457.

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