MINIREVIEW SERIES

Multifunctional host defense peptidesPierre Nicolas1 and Yvonne Rosenstein2

1 Biogenese des Signaux Peptidiques, ER3-UPMC, Universite Pierre et Marie Curie, France

2 Instituto de Biotecnologia, Universidad Nacional Autonoma de Mexico, Cuernavaca, Mor. Mexico

Host defense peptides (HDPs) are central effectors ofinnate immunity that are conserved in all forms of life.So far, more than 1200 HDPs have been isolated or pre-dicted. HDPs rapidly kill a broad range of bacteria,fungi, yeasts and protozoa by compromising the struc-tural and functional integrity of the plasma membrane ofthe target cells and ⁄or inactivating intracellular targets.HDPs also trigger and tune immunomodulatory pro-cesses on host cells, by inducing chemotaxis, leukocyteactivation and cytokine release, and wound repair, andenhancing angiogenesis. Their abnormal expression cor-relates with disease, revealing their participation in thepreservation of homeostasis. With their obvious poten-tial as novel therapeutic agents, understanding the physi-ological processes that are controlled by HDPs, as wellas the relationships between structure and mode ofaction of these molecules, is essential for the developmentof novel peptide-based antibiotics and immunotherapeu-tic tools. This minireview series discusses differentaspects of recent progress in the field, from advances inunraveling the structural basis of their antimicrobial andimmunomodulatory activity and specificity to the devel-opment of efficient antiparasitic therapeutic drugs.Determination of the 3D structures of HDPs, and

their oligomerization state, membrane orientation anddynamics when complexed with phospholipids, is fun-damental for understanding the underlying mechanismof microbial membrane permeation ⁄disruption and thedevelopment of novel antibiotics. The first minireview,by Bhattacharjya and Ramamoorthy, models magaininanalogs to provide an overview of novel functionaland mechanistic insights obtained by the use of solu-tion-state and solid-state NMR in environments thatmimic the inner and outer membranes of bacteria.

HDPs are able to act on a variety of pathogens,including protozoa that are the causative agents ofmalaria, leishmaniasis, amebiasis, and Chagas disease.The second minireview, by Mor, summarizes recentefforts to assess the antiparasitic properties of HDPswhile focusing on possible mechanisms by which thesepeptides kill the parasites at different stages of theirlife cycle. It introduces evidence that the antiparasiticactivity of HDPs emanates from interactions with mul-tiple targets, some of these peptides being endowedwith the ability to cross several membranes before spe-cifically reaching and killing the intracellular parasite.

There is increasing speculation that HDPs may alsoaffect microbial viability by entering the cells and inter-fering with their metabolic functions. In the third mini-review, Nicolas questions some widely held views aboutintracellular-targeting HDPs. The possibility that micro-bial cell entry and ⁄or membrane damage associatedwith membrane phase ⁄ transient pore or long-lived tran-sitions can be a feature common to intracellular-target-ing HDPs and mammalian cell-penetrating peptidesthat have biased amino acid composition is discussed.

In the final minireview, Auvynet and Rosensteinfocus on the role of human HDPs in modulating theimmune response and disease. They highlight some ofthe elaborate feedback mechanisms and signalingpathways through which HPDs control immune cells,stimulating innate immunity but controlling adaptiveimmunity by reducing endotoxemia and inflammation,ultimately maintaining homeostasis. The participationof HPDs in disease illustrates the potential of thesepeptides as therapeutic agents to control sepsis as wellas to function as adjuvants and thus improve the effec-tiveness of vaccines.

Pierre Nicolas received his PhD from the Universite Pierre et Marie Curie, Paris, where he is currently Professor of

Biochemistry. From 1980 to 1982, he conducted postdoctoral work in the laboratory of Choh Hao Li at UCSF, USA, to

investigate structure–function relationships of b-endorphin. In 1986, he was appointed Professor of Neurobiology at the

Faculte des Sciences, Rouen, France, and established his research group at the Institut Jacques Monod, Paris, where

he worked until 2004. His research interests encompass the molecular evolution and structure–function relationships of

peptides from frog skin, with emphasis on antimicrobial peptides.

Yvonne Rosenstein obtained her bachelor degree from the Universidad Nacional Autonoma de Mexico (UNAM) in

Mexico, and her PhD from the Universite Pierre et Marie Curie, Paris. As a postdoctoral fellow and Instructor in

Pathology in Steven Burakoff’s laboratory at the Dana Farber Cancer Institute in Boston (1986–1994), she contributed to

the identification of receptor–ligand pairs involved in lymphocyte adhesion and activation. In 1994, she joined the

Instituto de Biotecnologia ⁄ UNAM, where she was appointed professor in 2000. Her scientific interests are focused on

the molecular mechanisms triggered by coreceptor molecules that regulate lymphocyte activation, and on the immuno-

modulatory properties of antimicrobial peptides.

doi:10.1111/j.1742-4658.2009.07356.x

6464 FEBS Journal 276 (2009) 6464 ª 2009 The Authors Journal compilation ª 2009 FEBS