TRENDSin Immunology Vol.22 No.6 June 2001 http://immunology.trends.com 1471-4906/01/$ – see front matter © 2001 Elsevier Science Ltd. All rights reserved. PII: S1471-4906(01)01895-6 285 Research Update Research Update Research Update Research News Research on the innate immune response of mammals has revealed similarities w ith the invertebrate immune system. Thus, insects have developed an acute response resembling that seen in humans, implicating similar effectors,receptors and regulation of gene expression. Mussels have developed intracellular phagocytosis resembling that seen in mammalian neutrophils, using cationic antibacterial peptides in phagolysosomes. Leeches, like amphibians, contain antibacterial peptides and immune stimulators that derive from the processing of neuropeptide precursors. This pattern of similarities suggests that the vertebrate innate immune response resembles a patchwork of those responses seen in several invertebrate models. Over more than three billion years, bacteria have developed a variety of survival mechanisms that have led to the appearance of antibiotic-resistant bacteria 1 . This raises the question: how are bacteria kept in check by multicellular organisms? Research on the immune systems of invertebrates, such as insects, has shown that they have developed a battery of natural antibacterial peptides, such as defensin and cecropins 2,3 , as part of their innate response to bacteria. In addition, antibacterial peptides have been identified in the glandular cells of amphibian skin (e.g. magainins, dermaseptins and ranalexin), humans (e.g. defensins, hadrurin and hepcidin) and plants [e.g. thionins, snaking-1 and antifungal peptides from seeds of Phytolacca americana (PAFP-s)], reflecting the universal nature of such natural defense mechanisms 4–9 . However, although these antibacterial peptides are present throughout the living kingdom, it is interesting to see how they have evolved. Human antimicrobial responses In humans, some antimicrobial peptides are produced by the epithelial cells that line the respiratory, gastrointestinal and urogenital tracts and the skin 9 . Epithelial granulocytes of the small intestine contribute to the barrier function of the gastric mucosa by the apical release of granules containing a variety of antimicrobial products, including human α-defensin-5 and -6 (Ref. 5). Other similar peptides are found in the glandular secretions that moisten and lubricate such surfaces 2 . Others, such as human β-defensins, are abundant in certain migratory phagocytic cells that can surround, ingest and kill microbial invaders 9 . Invertebrate immune responses Insects, such as Drosophila, respond to septic injuries by rapidly synthesizing antimicrobial peptides (Fig. 1). These peptides are predominantly produced in the fat body; they are then secreted into the hemolymph and participate in a systemic response 10 . Seven distinct antimicrobial peptides (plus isoforms) have been described for Drosophila. Interestingly, they appear to have distinct target specificities, and induction of the expression of the various peptides depends on the type of infectious agent. Fungal infection, for example, results in a strong induction of the antifungal peptide drosomycin, whereas the antibacterial peptides drosocin and diptericin are only weakly induced 11 . Conversely, challenge with Gram-negative bacteria strongly induces the antibacterial peptide genes, but has a less marked effect on drosomycin expression 11 . Drosophila can discriminate between various groups of microorganisms and mount a somewhat adaptive immune response 12 . The gene Spaetzle codes for a secreted protein of the cysteine-knot family of growth factors, which is activated by proteolytic cleavage 12 . The processed Spaetzle product is thought to bind to and activate the transmembrane receptor Toll, although direct interaction between the two proteins has not been reported to date. Toll activation is transduced through the adapter molecule Tube and the serine/threonine kinase Pelle, and leads to the phosphorylation and subsequent degradation of the inhibitor Cactus 12 . Cactus degradation frees Dif (a member of the Rel family of transcription factors), which translocates to the nucleus, where it is thought to bind to and activate the Drosomycin promoter 13 . The same genetic analysis revealed that expression of the antibacterial peptides drosocin and diptericin is independent of Toll 12 . The discovery of the key role played by Toll in the Drosophila host defense led to the description of the first mammalian Toll homolog, now referred to as the Toll-like receptor 4 (TLR4). Two such homologs, TLR2 and TLR4, were shown to play crucial roles in vertebrate innate immunity against bacteria 13 . TLR2 was shown to play a parallel role in response to peptidoglycan derived from the Gram-positive bacterial cell wall 12 . Eight additional Toll-related genes (Toll, Toll-3–Toll-8, as well as 18-wheeler), are present in the Drosophila genome. Two of these genes, Toll-3 and Toll-4, are expressed at low levels; by contrast, Toll-6, -7 and -8 are expressed at high levels during embryogenesis and molting, suggesting that Toll and 18w are involved in development 13 . As well as the Toll pathway, two other pathways more specific for bacterial infection have been demonstrated in Drosophila, namely, imd and 18w (Fig. 1), reflecting the diversity and specificity of responses to pathogens in insects. Epithelial immune responses Recent studies on antimicrobial peptides from Drosophila have shown that a variety of epithelial tissues in direct contact with the external environment can express the antifungal Drosophila peptide drosomycin, suggesting that a local response to infections is affecting these barrier tissues 12 . The imd gene in Drosophila plays a crucial role in the activation of this local response to infection. Drosomycin expression is regulated by the Toll pathway during the systemic response, but is regulated by imd in the respiratory tract, thus demonstrating the existence of distinct regulatory mechanisms for local and systemic induction of antimicrobial peptide Vertebrate innate immunity resembles a mosaic of invertebrate immune responses Michel Salzet