Immunity has, for obvious reasons of practical application, been studied most intensely in vertebrates. The vast bulk of animals must rely on their own innate, inducible, broad-spectrum, nonspecific immunity, and a few model invertebrate systems have been studied in detail, with some information available from others as well. Generally, although many invertebrates have short lives and high repro-ductivity (r strategies) as a possible defense mechanism—for the species, not the individual—even these organisms can be destroyed by pathogens and they have evolved protective defenses to combat them. In invertebrates the system relies on phagocytosis or encapsulation of the pathogen.
Most insects are r strategists that reproduce rapidly and have short generation times. They are also mobile. From this point of view, insect species might in principle be able to survive pathogens by reproducing fast enough to tolerate heavy loss of individuals or might be mobile enough to readily escape predation. However, some insects are relatively immobile, or large, or long-lived, so we cannot invoke generic evolutionary strategy arguments with regard to their immune capabilities.
Insect immune mechanisms begin with their hard exoskeleton, which serves as a first line of defense against pathogens or injury. The peritrophic membrane that sep arates the gut epithelium from the lumen (the passageway of the gut) also serves to inhibit infection by separating the contents of the lumen from the body interior, as does the lining of the trachea (Khush and Lemaitre 2000). Insects maintain a low pH and accumulate digestive enzymes and antibacterial lysozymes in their midguts as well, creating an unfavorable environment for most pathogens. However, we should note that in mammals the stomach is an acidic environment not usually hospitable to pathogens but to which a group (helicobacters) have adapted.
If an insect is wounded, or a pathogen evades the structural defenses, insects are able to mount a fast, strong response, both humoral and cellular. The system is not adaptive, nor does it have memory. It is likely that the antimicrobial response is based on the binding of receptors on circulating antibacterial proteins to general microbial epitopes (sites on these molecules that antibacterial proteins recognize and bind). The involvement of several different pathways has been described (Lee et al. 2001), but neither the receptor genes nor the mechanism that initiates insect response to wounding are as yet well understood.
Two immediate responses to wounding, infection, or the presence of other foreign objects in insects are the release of phenoloxidase and clotting of the hemolymph. Phenoloxidase induces the formation of melanin, which surrounds the wound and encapsulates parasites. Within a few hours of infection, a number of antibacterial proteins and peptides begin to build up in the hemolymph. More than 150 of these have been identified (Chung and Ourth 2000). The most significant is a family of peptides called cecropins, which quickly lyse bacteria. Another group of bacterici-dals is the defensins (with vertebrate homologs), which act more slowly but also per-meabilize microbial or fungal cell membranes, and a third group is the attacin-like molecules, which disrupt dividing cells of Escherichia coli and other bacteria, causing the breakdown of their outer membrane. Genes coding a number of these antibac-terials are known (Lee, Cho et al. 2001).
The regulatory regions for these peptides contain binding sites for transcription factors containing the Rel domain, and some of these Rel proteins are homologs of transcription factors with similar roles in immunity in mammals, the NFkB family. The insect gene Toll does not function in microbe recognition but is activated on an immune challenge. A number of TLRs, in addition to Toll, have been identified in Drosophila, and these do interact directly with microbes (Khush and Lemaitre 2000).
As in vertebrates, the immune response in insects is activated by recognition of common proteins on microbes by PRRs. Peptidoglycan recognition protein (PGRP), for example, has been identified in the moth Trichoplusia ni (Khush and Lemaitre 2000). It binds to Gram-positive bacteria, as does peptidoglycan recognition protein in vertebrates. Gram-negative binding proteins (GNBP) have also been isolated from insects, again with homologies to proteins in vertebrates that recognize Gram-negative bacteria and initiate an immune response (Ochiai and Ashida 1999).
Inside the body invading microbes are attacked by hemocytes, that is, phagocytic cells in the hemolymph. Antibacterials and antifungals are produced in the fat body, the functional equivalent of the mammalian liver. The genes that encode these pep-tides, including cecropins, attacins, diptericin, defensin, drosocin, drosomycin, andropin, and diptiricin-like protein, are induced by intracellular signaling cascades with homologies to the activation of NFkB in mammalian immunity (Lagueux et al. 2000). Other antimicrobial responses include the production of nitric oxide, which is toxic to some parasites, and perhaps sequestration of iron to limit bacterial infection (Khush and Lemaitre 2000).
Activation of the immune response in an insect, either because of microbial infection or wounding, also causes systemic and behavioral changes including reduced feeding, and developmental delay, and there is even a possible febrile response, marked by the insect's pursuit of warmer locations in its environment (Hultmark 1993). The type of immune response an insect mounts depends on the type of microbe against which it must defend. Fungi and bacteria elicit different responses in insects, as they do in vertebrates.
mollusks and Other invertebrates
Studies in mollusks show that at least some of the mechanisms found in insects have earlier origins. Two members of the insect defensin family of antibacterial peptides are found in mollusks (Charlet et al. 1996). PRPs specific to molecules on the surface of pathogens initiate the immune system in these animals, as in the vertebrate and invertebrate systems. Among other responses, PRPs initiate the prophenoloxidase (ProPO) cascade, the same melanin release system found in insects. The ProPO system recognizes nonself proteins and targets them with antimicrobial peptides and other toxic metabolites.
Some of the immune response of these animals relies on clotting, and the clotting protein has been cloned and found to be a member of the vitellogenin family. Echinoderms have a complement system, somewhat analogous to that of vertebrates.
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