Melanogenesis and associated cytotoxic reactions: Applications to insect innate immunity

doi:10.1016/j.ibmb.2005.01.014

Insect Biochemistry and Molecular Biology

Volume 35, Issue 5, May 2005, Pages 443-459

https://doi.org/10.1016/j.ibmb.2005.01.014 Get rights and content

Abstract

Insects transmit the causative agents for such debilitating diseases as malaria, lymphatic filariases, sleeping sickness, Chagas’ disease, leishmaniasis, river blindness, Dengue, and yellow fever. The persistence of these diseases provides testimony to the genetic capacity of parasites to evolve strategies that ensure their successful development in two genetically diverse host species: insects and mammals. Current efforts to address the problems posed by insect-borne diseases benefit from a growing understanding of insect and mammalian immunity. Of considerable interest are recent genomic investigations that show several similarities in the innate immune effector responses and associated regulatory mechanisms manifested by insects and mammals. One notable exception, however, is the nearly universal presence of a brown-black pigment accompanying cellular innate immunity in insects. This response, which is unique to arthropods and certain other invertebrates, has focused attention on the elements involved in pigment synthesis as causing or contributing to the death of the parasite, and has even prompted speculation that the enzyme cascade mediating melanogenesis constitutes an ill-defined recognition mechanism. Experimental evidence defining the role of melanin and its precursors in insect innate immunity is severely lacking. A great deal of what is known about melanogenesis comes from studies of the process occurring in mammalian systems, where the pigment is synthesized by such diverse cells as those comprising portions of the skin, hair, inner ear, brain, and retinal epithelium. Fortunately, many of the components in the metabolic pathways leading to the formation of melanin have been found to be common to both insects and mammals. This review examines some of the factors that influence enzyme-mediated melanogenic responses, and how these responses likely contribute to blood cell-mediated, target-specific cytotoxicity in immune challenged insects.

Section snippets

Insect innate immunity

Vertebrate species possess both innate and adaptive immune mechanisms to detect and eliminate aberrant cells and pathogens, whereas invertebrates rely solely on innate immunity to combat infections (Janeway and Medzhitov, 2002; Ratcliffe and Whitten, 2004). Comparative cellular, molecular, and biochemical investigations have shown innate immunity to be a conserved mechanism of defense, involving common cell-signaling pathways, transcriptional elements, and cytotoxic effector responses (Beutler,

Melanogenesis

Melanin is derived from the oxidation of monophenols and diphenols and the ensuing polymerization of their respective orthoquinones, a cascade of reactions initiated by, or at least involving the participation of, certain host blood cells or hemocytes (Sugumaran, 2002). Little is known of the molecular mechanisms that activate hemocytes and initiate melanogenesis in response to infections. Typically, parasite-induced melanogenic responses are cell-mediated, very site-specific, and do not

Melanogenesis in insects

TYRs are widespread throughout the plant and animal kingdoms, and are often referred to in different groups as polyphenoloxidases, POs, phenolases, diphenol oxidases, or catechol oxidases. Unfortunately, these designations do not distinguish TYR from laccases, which catalyze the oxidation of both o-diphenols and p-diphenols, and also are frequently referred to as a polyphenoloxidases, or from catechol oxidases, which are binuclear type 3 copper proteins that only oxidize o-diphenols. In

Cytotoxic and cytoprotective properties of melanin

ROI and RNI generated during melanogenesis have been implicated, along with pigment precursors, in the killing of parasites by insects (Fritsche et al., 2001; Kumar et al., 2003; Lanz-Mendoza et al., 2002; Nappi and Ottaviani, 2000; Nappi and Sugumaran, 1993; Nappi and Vass, 1993; Nappi et al., 1995, Nappi et al., 2000; Whitten et al., 2001). As redox-active polymers, melanins engage in electron transfer processes with a variety of reducing or oxidizing species (O’Brien, 1991). Depending on the

Interactions of melanin intermediates with ROI and RNI

Autoxidations in biological systems frequently progress via univalent reductions, as a result of which O₂⁻ is produced by the leakage of electrons to molecular oxygen. This radical, which can spawn more reactive oxygen species, normally is produced in electron transport chains, in activated phagocytic cells via plasma membrane NADPH oxidase, and in the course of the activity of certain other enzymes, including xanthine oxidase, aldehyde oxidase, and cytochrome P450 (Fig. 4). Parasite-induced

Melanogenesis, cytotoxicity, and host and parasite strategies

The NADPH oxidase-mediated production of O₂⁻ and ensuing reactions of SOD to produce H₂O₂ represent critical early events in establishing immune competence. Accordingly, the virulence of a parasite may reside in its ability to directly or indirectly interfere with the production of O₂⁻ and H₂O₂. In many prokaryotic and eukaryotic organisms, antioxidant protection is provided by antioxidant enzymes (e.g., SOD; catalase, CAT; glutathione peroxidase, GP) and thiol reducing systems that shuttle

Metalloenzymes and site-specificity of cytoxic responses

The transport, activation, and metabolism of oxygen are critical processes that are mediated primarily by metalloproteins containing iron or copper (Chevion et al., 1999). Investigations of the interactions of SQ⁻ with metalloenzymes may define a mechanism for target-specific killing during melanogenesis. Enzyme-specific binding to substrate-like molecules expressed on foreign surfaces would localize any cytotoxic molecules generated by the active enzyme. In this context, tyrosine residues in

Concluding remarks

The molecular and biochemical changes that appear to be crucial to the host in establishing resistance, or to the parasite for its virulence, are merely temporal features of an ongoing struggle involving the interacting genomes of co-evolving combatants. Innate immunity is the sole mechanism of defense used by invertebrates to destroy infectious agents and rogue cells. Invertebrate blood cells or hemocytes exhibit macrophage-like activity and use ROI and RNI to destroy pathogens. These

Acknowledgements

The work of AJN was supported by the National Science Foundation (IBN 0342304) and the National Institutes of Health (GM 059774), and of BMC by the National Institutes of Health (AI 19769, AI 46032, and AI 53772). We thank M. Mastore and L. Kohler for their assistance with the manuscript, and the anonymous referees for their helpful comments and suggestions.

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Melanogenesis and associated cytotoxic reactions: Applications to insect innate immunity

Abstract

Section snippets

Insect innate immunity

Melanogenesis

Melanogenesis in insects

Cytotoxic and cytoprotective properties of melanin

Interactions of melanin intermediates with ROI and RNI

Melanogenesis, cytotoxicity, and host and parasite strategies

Metalloenzymes and site-specificity of cytoxic responses

Concluding remarks

Acknowledgements

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