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Nature Reviews Microbiology
2,
727-738
(2004);
doi:10.1038/nrmicro976
PRIMATE DEFENSINS
Robert I. Lehrer
about the author
Abstract
Defensins are endogenous, cysteine-rich antimicrobial peptides that contribute to host defence against bacterial, fungal and viral infections. There are three subfamilies of defensins in primates:  -defensins are most common in neutrophils and Paneth cells of the small intestine;  -defensins protect the skin and the mucous membranes of the respiratory, genitourinary and gastrointestinal tracts; and  -defensins, which are expressed only in Old World monkeys, lesser apes and orangutans, are lectins with broad-spectrum antiviral efficacy. Here, their discovery and recent advances in understanding their properties and functions are described.
Summary
- Endogenous antimicrobial peptide molecules of less than 100 amino acids are an important component of innate immunity. The type and number of antimicrobial peptides varies from species to species. In humans and other primates, defensins (cationic antimicrobial peptides that are rich in cysteine residues) contribute to host defence against bacterial, fungal and viral infections.
- Three families of defensins —
 ,  and  — are found in primates. The -defensins, which were first discovered in the 1960s but not sequenced until almost 20 years later, are most prominent in neutrophils and Paneth cells in the small intestine. -defensins were initially identified in cattle. Later (in 1995) they were found in humans, and reported to protect the skin and the mucous membranes of the respiratory, genitourinary and gastrointestinal tracts. - and -defensins differ from each other in the spacing and pairing of their six conserved cysteines. -defensins were first identified in 1999 and are expressed only in PMNs and bone marrow in Old World monkeys, lesser apes and orangutans. - Unsurprisingly, some bacteria that infect humans can resist the antimicrobial activities of defensins. In Salmonella enterica serovar Typhimurium, the PhoP–PhoQ regulon controls the transcription of many genes involved in resistance to defensins and other antimicrobial molecules. Several factors that contribute to defensin resistance have been identified in Staphylococcus aureus, including MprF, a lysylphosphatidylglycerol synthase, which functions by decreasing the negative charge of the bacterial membrane, thereby decreasing binding of cationic defensins. Neisseria gonorrhoeae are naturally resistant to -defensins.
- The antimicrobial activity of defensins is mainly due to permeabilization of the target cell membrane. However, defensins also have a range of other important activities, including involvement in chemotaxis of monocytes, T cells and dendritic cells; the release of histamine from mast cells; opsonization; interaction with complement; and wound repair.
- The antiviral properties of defensins are beginning to be studied more, and this research has led to the discovery that many -defensins have lectin-like properties. The -defensins, the latest defensin family to be discovered, also have lectin-like properties and show broad-spectrum antiviral efficacy. The genes encoding these molecules (DEFT) are mutated -defensin genes that arose in an Old World monkey. Humans, chimpanzees and gorillas do not express -defensin peptides because their DEFT genes acquired a mutation that introduced a premature stop codon into the signal sequence. A synthetic -defensin, retrocyclin 2, has activity against HIV-1 and HSV-2 and acts by inhibiting viral entry. The role of endogenous human -defensins in resistance to HIV/AIDS is not yet clear.
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