Melanization a conserved immune response based on speciesspecific regulatory modules

Melanization is an important, ancient defence reaction of arthropods that may be triggered by pathogens or wounding (see Chapter 3). Like immune signalling, melanization is structured into sequential phases: molecular pattern recognition produces signals that must be modulated before activating effector mechanisms. The melanization cascade is tightly regulated as it generates toxic byproducts, including ROS. It is positively and negatively regulated by a network of specific clipdomain serine proteases (CLIPBs), enzymically incompetent homologues (CLIPAs), CTLs, and serine protease inhibitors (SRPNs). Reverse genetics in Anopheles has identified a large set of regulators for melanization of the rodent malaria parasite Plasmodium berghei or Sephadex beads (Volz et al., 2005, 2006; Paskewitz et al., 2006; Barillas-Mury, 2007). Remarkably, all the regulators are members of mosquito-specific expansions, none has a definitive 1:1:1 orthologue, and only SRPN2 has a clear Aedes orthologue. Thus, while the melanization reaction is conserved among insects, its critical regulatory modules appear to be almost entirely species-specific.

On activation, proteolytic cleavage of proph-enoloxidases (proPOs) into active POs initiates conversion of tyrosine to melanin with the assistance of additional enzymes, culminating with cross-linking the wound or the invader in a melan-otic capsule. The family of proPOs has expanded greatly in mosquitoes compared to Drosophila and larger model insects. Only one mosquito ortholo-gous pair clusters with Drosophila proPOs; the remaining mosquito proPOs form a distinct extensive clade, created by reduplication events both before and since the Anopheles/Aedes divergence. The invariable catalytic activity of proPOs suggests that their observed expansions may accommodate differential regulation such as temporal, developmental, or topological activation. Indeed, several proPOs do show developmental or physiological specificity (Li et al., 2005).

In A. gambiae, several genes have been implicated in the outcome of infections with the rodent malaria model parasite, P. berghei, and are classified as antagonist (negative) or agonist (positive) factors (Osta et al., 2004) (see Chapter 7). The most important parasite antagonists are TEP1, member of a family of complement-like thioester-containing proteins (Blandin et al, 2004), and members of a leucine-rich-repeat protein family (Osta et al., 2004; Riehle et al., 2006). The leucine-rich-repeat immune protein (LRIM) family appears as a mosquito evolutionary novelty and is discussed below. The TEP family is related to the vertebrate complement factors C3/C4/C5 and pan-protease inhibitors, the a2-macroglobulins (Blandin and Levashina, 2004). It exhibits only one orthologous trio, and otherwise shows two clades: one with both fruit fly and mosquito TEPs, and a mosquito-specific group that includes AgTEP1. Melanization or lysis are thought to be initiated when TEP1 kills parasites after binding to their surface (Blandin et al.,

2004). TEP1 also binds to bacteria, promoting their phagocytosis (Levashina et al., 2001; Moita et al.,

2005). Melanization usually disposes of malaria parasites that have been killed by TEP1 binding (Blandin et al, 2004). However, depending on the genetic background, melanization may itself cause parasite killing (Volz et al., 2006).

Components of the critical regulatory modules appear to have been selected from large reservoirs of independently expanded gene families, in a so-called mix-and-match mode of evolution, giving rise to related but distinct sets of proteins that control the melanization response in each species.

It would appear therefore, that the specificity of the otherwise ubiquitous process of melanization derives from its tight regulation by genetic modules that probably co-evolve with pathogens. The modular mix-and-match evolution hinders detailed knowledge transfer between species, but elegantly illustrates the flexibility of the immune system to correctly identify specific threats and then activate a potent immune response.

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