Antimicrobial peptides AMPs

The humoral immune response culminates in the production of effector molecules that kill invading microbes. One well-studied class of effector

Gram-negative bacteria and Bacillus

Other PGRPs, GNBPs

Antimicrobial peptides

Eater, Nimrods

Gram-negative bacteria and Bacillus

Other PGRPs, GNBPs

Eater, Nimrods

Antimicrobial peptides

Fungi i

Figure 13.2 A schematic illustration of an idealized D. melanogaster immune-responsive cell illustrating prominent proteins required for the activation of a humoral immune response and receptors involved in defensive phagocytosis. Proteins whose gene families have experienced considerable genomic turnover within the genus Drosophila and among Drosophila, Anopheles, Aedes, Apis, and Tribolium are outlined in heavy black. Grey-shaded proteins have been implicated as evolving adaptively at the amino acid sequence level in D. melanogaster and/or D. simulans. Reproduced with permission from Lazzaro (2008). Cact, cactus; DIF, Dorsal-related immune factor; GNBP, Gram-negative-binding protein; IKK, I-kB kinase; JNK, c-Jun N-terminal kinase; Nec, Necrotic; PGRP, peptidoglycan-recognition protein; SPE, Spätzle-processing enzyme; Spz, Spätzle; TEP, thioester-containing protein.

Fungi i

Figure 13.2 A schematic illustration of an idealized D. melanogaster immune-responsive cell illustrating prominent proteins required for the activation of a humoral immune response and receptors involved in defensive phagocytosis. Proteins whose gene families have experienced considerable genomic turnover within the genus Drosophila and among Drosophila, Anopheles, Aedes, Apis, and Tribolium are outlined in heavy black. Grey-shaded proteins have been implicated as evolving adaptively at the amino acid sequence level in D. melanogaster and/or D. simulans. Reproduced with permission from Lazzaro (2008). Cact, cactus; DIF, Dorsal-related immune factor; GNBP, Gram-negative-binding protein; IKK, I-kB kinase; JNK, c-Jun N-terminal kinase; Nec, Necrotic; PGRP, peptidoglycan-recognition protein; SPE, Spätzle-processing enzyme; Spz, Spätzle; TEP, thioester-containing protein.

molecules is AMPs. Most AMPs are short cationic peptides whose microbicidal activity is mediated by direct interaction with the negatively charged lipid membranes of bacteria and fungi (Zasloff, 2002; Lemaitre and Hoffmann, 2007; Yeaman and Yount, 2007). AMPs drew early attention as potential sites of host-pathogen co-evolution (Clark and Wang, 1997; Date et al., 1998; Ramos-Onsins and Aguade, 1998) because of their direct role in the lysis and targeted killing of pathogens. However, systematic study of AMP genes, first in D. mela-nogaster and more recently across six Drosophila species, has failed to uncover evidence of adaptive evolution at the amino acid level (e.g. Lazzaro and Clark, 2003; Jiggins and Kim, 2005; Sackton et al, 2007). Drosophila AMP genes do, however, show extremely high rates of gene family expansion and contraction (Sackton et al, 2007). This high rate of genomic turnover extends to other taxa and is characteristic of most AMPs (Figure 13.2). In fact, the majority of Drosophila AMPs have no identifiable homologues in the genomes of mosquitoes, honey bees, or Tribolium (Christophides et al., 2002; Evans et al, 2006; Waterhouse et al, 2007; Zou et al, 2007).

Phosphorylation complex

Caspase complex

IKK,

D. melanogaster

Dredd

IKK melanogaster group melanogaster group _

did dd dFADD

^ melanogaster subgroup cc cc cc did did dd tp(pp (p ipppsglp C dp Cp ippp | NF-kB I Spacer I IkB |

Relish melanogaster subgroup

Figure 13.3 Adaptive evolution in the Relish complex. Caspase cleavage of the phosphorylated Relish spacer region allows the nuclear factor kB (NF-kB) domain to be translocated to nucleus, where it drives expression of immune response genes. IKKY and IKKP form a complex through interaction at coiled-coil domains, and IKKP phosphorylates Relish. The caspase Dredd is activated by dFADD via interaction at death-inducing domains and forms a complex with Relish. Putative Relish activation domains are indicated in grey. Positively selected sites (posterior probability >0.75) are indicated (*=significant at P<0.01; ^significant at P<0.02) and reflect selection along the D. melanogaster branch (Relish, IKKp, or dFADD) or across the melanogaster (Dredd) species group (Sackton et al., 2007). Taxonomic lineages where these genes appear to have evolved adaptively are indicated beneath each gene name (Begun and Whitley, 2000; Schlenke and Begun, 2003; Jiggins and Kim, 2007; Sackton et al., 2007). C, caspase cleavage site; CC, coiled-coil domain; DD, death domain; DID, death-inducing domain; IKK, I-kB kinase; IkB, inhibitory kB; P, phosphorylation site.

Instead, these insects each have their own unique peptide families (Bulmer and Crozier, 2004; Evans et al, 2006; Waterhouse et al, 2007; Zou et al, 2007). In some cases, AMP families in different species converge independently on similar tertiary structures and presumably functions (Broekaert et al, 1995). Thus, whereas AMPs as a functional class of protein are ubiquitous among higher eukaryotes, there appears to be little homologous retention of peptides over evolutionary time.

The levels of sequence constraint seen in Drosophila do not characterize AMP evolution in all taxa. Genomic duplication of AMP genes is occasionally coupled with adaptive diversification at the amino acid level, presumably reflecting functional divergence (Tennessen, 2005; Yeaman and Yount, 2007). Genes encoding a termite-specific class of AMPs, termicins, have independently duplicated or triplicated in several termite species, with one duplicate typically sustaining mutations that decrease the polarity of the peptide (Bulmer and

Crozier, 2004). These changes, which are driven by positive selection on amino acid sequence, result in peptides with divergent charges. Similarly, the mosquito A. gambiae has duplicated members within the defensin family (Dassanayake et al, 2007). Again, expansion is coupled with elevated rates of amino acid substitutions that change polarity, suggesting adaptive value to having two defensins with slightly different polar affinities. Previous studies in vertebrate AMP families have also found evidence of duplication coupled with positive selection, although in these cases peptide charge is maintained (reviewed in Tennessen, 2005; Yeaman and Yount, 2007). There is compelling evidence from insects and vertebrates that gene-family expansion can sometimes allow adaptive diversification of peptide function (Tennessen, 2005).

AMPs are remarkably efficient at combating infection. Resistance in microbes is seldom observed in nature, and, when it is, it tends to arise in specialized pathogens that are likely to be under strong selective pressure to resist this form of defence (see Samakovlis et al., 1990; Zasloff, 2002). There are several possible explanations for why it may be difficult for most bacteria to evolve resistance. One common AMP mechanism is to disrupt membrane integrity though biochemically simple mechanisms, such as forming open pores (Zasloff, 2002; Yeaman and Yount, 2007). The ability of microbes to evolve resistance to such activities may be limited. However, heritable variation for resistance can be created and selected upon in microbial populations in the laboratory (Perron et al, 2006). In natural contexts, hosts simultaneously produce an array of AMPs that differ in charge, hydrophobi-city, structure, and activity, probably ensuring that most pathogens are susceptible to at least a subset of them. This is conceptually similar to the application of multiple antibiotics in clinical settings and may serve to delay or eliminate the evolution of resistance (Yeaman and Yount, 2007). If pathogens are slow or fail to evolve resistance to peptides, there may be little selective pressure on insect hosts to adapt their AMPs at the amino acid level over modest evolutionary time. However, divergent bacteria and fungi display a range of susceptibilities to individual peptides (Zasloff, 2002), so diversification in AMP function may be selectively favoured in instances when a host shifts to a new ecological niche and is immediately presented with a novel and distinct set of pathogen pressures.

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