Cathelicidins Revisited: Molecular Evolution, Structure and Functional Implications

Cathelicidins Revisited: Molecular Evolution, Structure and Functional Implications

Athanasia Pavlopoulou (Biomedical Research Foundation, Academy of Athens, Athens, Greece)
DOI: 10.4018/ijsbbt.2013040102
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Abstract

Cathelicidins constitute important antimicrobial peptides of innate immunity. In order to elucidate the evolutionary history of cathelicidins, the author performed comprehensive phylogenetic analyses of cathelicidin homologs in all available genomes including those completed recently. The organization of cathelicidin genes, as well as the secondary and tertiary structures of the inferred proteins are conserved. Based on integrated genomic, structural, and functional data, the author identified the last common ancestor of the cathelicidin family in lampreys, thus tracing the evolutionary origin of cathelicidins 550 million years ago. The author’s data suggest that cathelicidins arose concordantly with the adaptive immune system, a new organismal function first acquired in lampreys. The appearance of cathelicidins at the junction of innate and adaptive immunity may explain their dual roles as signal transducing molecules and as antimicrobial peptide precursors. Conserved regulatory elements associated with functions of the immune system were identified in cathelicidin gene promoter sequences invariably from fishes to humans.
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Introduction

The innate immune system developed before the separation of vertebrates and invertebrates. In contrast to the acquired immune response, the innate immune system confers broad specificity, and provides immediate and effective defense against infection without previous exposure to a pathogen (Kimbrell & Beutler, 2001). Nonetheless, in the absence of innate immunity, the adaptive immune response offers weak protection against infection (Kimbrell & Beutler, 2001). Antimicrobial peptides (AMPs), including cathelicidins, constitute an integral part of innate immunity. More specifically, cathelicidins provide the first line of defense against a broad spectrum of invading pathogens including both Gram-positive and Gram-negative bacteria, fungi and viruses (Barbeiro et al., 2013; Veldhuizen, Brouwer, Schneider, & Fluit, 2013; Wantha et al., 2013; Zanetti, 2005).

Cathelicidin peptides have been identified thus far in vertebrates, like mammals including humans (Gudmundsson et al., 1996) and primates (Zelezetsky et al., 2006), mouse (Gallo et al., 1997), guinea pig (Nagaoka, Tsutsumi-Ishii, Yomogida, & Yamashita, 1997), bovine (Skerlavaj et al., 1996), pig (C. Zhao, Ganz, & Lehrer, 1995), dog (Sang et al., 2007), rabbit (Tossi, Scocchi, Skerlavaj, & Gennaro, 1994), horse (Scocchi et al., 1999), sheep and goat (Shamova et al., 1999), panda (Yan et al., 2012), tammar wallaby (Daly et al., 2008), birds including chicken (Goitsuka et al., 2007; Xiao et al., 2006), and pheasant (Wang et al., 2011), reptiles including snakes (Wang et al., 2008; H. Zhao et al., 2008), amphibia (Hao et al., 2012) and fish including cod and salmon (Chang, Zhang, Zou, Nie, & Secombes, 2006; Scocchi, Pallavicini, Salgaro, Bociek, & Gennaro, 2009). The evolutionarily basal (closest to the origin) cathelicidins were identified in the primitive Atlantic hagfish Myxine glutinosa (Uzzell, Stolzenberg, Shinnar, & Zasloff, 2003).

Cathelicidins exert direct microbicidal effects but also mediate various immune-modulatory functions including stimulation of components of the adaptive immune system, chemoattraction of neutrophils, angiogenesis and wound repair (Hancock & Sahl, 2006). Due to these pleiotropic functions, cathelicidins are also referred to as “alarmins” (Oppenheim & Yang, 2005).

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