Drosophila establishing the framework of insect immunity

Genetic tractability established D. melanogaster as arguably the best-characterized model for dissecting the biology that underlies insect innate immunity, although recognition of the capacity of insects to respond to invaders was initiated with the discovery of the antimicrobial peptide (AMP) cecropin in the giant cecropia moth (Steiner et al., 1981). The microbicidal properties of the haemo-lymph and the identification of numerous inducible AMPs therein, pointed to an insect immune system able to recognize and respond to invading pathogens. Regulatory DNA sequence motifs, resembling those recognized by mammalian nuclear factor kB (NF-kB), were detected in AMP gene promoters, providing the first parallel with mammalian innate immunity (Sun et al, 1991). These discoveries set the course for applying the power of Drosophila genetics to the elucidation of upstream components of two key immune-signalling pathways, Toll and Imd (immune deficiency). Together these pathways permit differential recognition and response to invading micro-organisms through signal transduction, leading to nuclear translocation of specific NF-kBs and transcriptional activation of AMPs and other effectors. These immune responses, along with phagocytosis and the production of reactive oxygen species (ROS), are processes reminiscent of vertebrate innate immune systems. Other insect responses, such as encapsulation and melanization are also ancient, but only prominent in invertebrates.

Fruit fly genetics and molecular biology shaped our understanding of the machinery and processes that define insect innate immunity, while studies of other insect systems provided important complementary, supporting data. Discovery greatly accelerated with the sequencing of the D. melanogaster genome (Adams et al., 2000). This landmark placed the few immune proteins that were previously identified through intensive experimental investigations in the context of the full complement of related proteins. Genes that were genetically implicated in any of the characterized fruit fly immune responses led to screening of corresponding families of homologues identified in the genome, and thus facilitated generation of new hypotheses followed by targeted experimental testing. In a virtuous cycle, elucidation of innate immune components in Drosophila guided functional analysis of related factors in vertebrates, and vice versa (Leulier and Lemaitre, 2008).

Once the framework of innate immunity was established in both vertebrates and insects, it allowed classification of genes and families into broad functional categories: recognition, modulation, signal transduction, and effector components (Table 6.1). Recognition of foreign molecular features is the first step towards activating innate immune responses. Recognition is usually achieved through the binding of specialized pattern-recognition receptors (PRRs) of the immune system to cognate pathogen-associated molecular patterns (PAMPs), such as peptidoglycans, lipopolysaccharides, carbohydrates, and P-1,3-glucans (Lemaitre and Hoffmann, 2007). This recognition and binding to foreign bodies can result in direct and indirect outcomes, such as opsonization, phagocytosis, encapsulation, melanization, and lysis. These outcomes represent a coordinated immune system response to combat a recognized threat. The Toll, Imd, and Janus kinase/signal transduction and activators of transcription (JAK/STAT) signalling pathways are important for signal transduction events that link recognition of foreign bodies with initiation of effector responses. Modulation is important in controlling the balance between timely immune-signal amplification in response to a harmful pathogen, while preventing hyper-responsiveness to false or subcritical danger signals.

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