How insect immunity works

Broderick et al. (Chapter 2) first provide an overview of the best-understood insect immune system, that of D. melanogaster. They introduce the reader to one of the most important outputs of the fly's immune system: the powerful array of antimicrobial peptides and proteins (AMPs) that provide a broad-spectrum systemic defence against not only prokaryotic microbes, but also eukaryotic pathogens and parasites, such as fungi and protozoa. They then review the twin transcriptional control regulatory systems, named after crucial components of the signalling pathways Toll and Imd, which govern the production of AMPs. They also take into consideration the as yet rather incompletely understood Janus kinase/signal transduction and activators of transcription (JAK/STAT) cellular control system that links Toll- and Imd-regulated responses with others (e.g. the complement-like TEP proteins and a whole host of cellular defences). In the second part of their chapter, the authors turn to the much less well-studied set of local epithelial immune responses that are presumably deployed in most cases before the systemic response is activated. These epithelial responses include reactive oxygen species (ROS) and locally secreted AMPs. A key issue considered by the authors is how these responses are modulated to allow establishment of beneficial microbiota in the gut, and adjacent to other immune-reactive epithelia. They conclude that 'signalling between the local and systemic response, while not required in every interaction, may dictate whether microbial infection leads to tolerance, resolution, or host lethality'. We believe that immune tolerance will prove to be an important emerging theme of the next decade's research on insect immunity.

Ragan et al. (Chapter 3) provide an antidote to the fly-centred approach of the previous chapter by focusing on the immune roles of haemolymph proteins. These have mostly been studied by biochemical means using much larger insects such as Lepidoptera, especially the commercial silkmoth Bombyx mori and the tobacco hornworm Manduca sexta. The authors focus on microbial pattern-recognition proteins, and the complex interplay between proteinases, inactive homologues of pro-teinases, and proteinase inhibitors, all of which collaborate to regulate the proteolytic conversion of prophenoloxidase (proPO) to its active form, phe-noloxidase (PO). It is becoming ever clearer that the proPO system is among the most rapidly deployed immune defences in insects. Its value to the host is shown by the fact that pathogens and parasites are frequently distinguished by the presence of anti-PO counter-adaptations. It is also especially interesting that vertebrate animals don't have a homologue of this system. Why not? We don't know.

In Chapter 4, Imler and Eleftherianos return to Drosophila for an account of how this insect responds to the threat of viral infection. Although our understanding of insect antiviral responses is less advanced, it is already evident that the mechanisms involved are different to those used against bacteria and fungi. Responses to pathogenic viruses fall into two categories: those using RNA interference (RNAi) to attack the process of viral (RNA) genome replication, and those involving upregulation of a large set of, as yet, poorly defined viral infection-related genes. The importance of the RNAi pathway is extremely clear, since mutations in the RNAi system genes render flies more susceptible to viral infections. These genes evolve at exceedingly fast rates, as would be expected if they were under strong selection. Another smoking gun is the presence of anti-RNAi genes in viruses. There are many unsolved problems: for example, the extent to which known Drosophila immune-signalling pathways regulate antiviral immunity, and even the extent to which such upregulation is important, are not well understood.

To what extent do innate immune responses follow a pre-patterned disposition? Das et al. (Chapter 5) point out that it is becoming increasingly evident that insect immunity is much more complicated than this. Focusing on the immune system of the malaria mosquito Anopheles gambiae to give a detailed account of the extent to which recognition of microbial surfaces can give rise to highly specific immune responses, Das et al. consider the varied repertoire of pattern-recognition receptor (PRR) genes, which is further diversified by splicing at the mRNA level. Detailed accounts are given for the Gram-negative binding protein (GNBP) family, the peptidoglycan-recognition protein (PGRP) family, the immunoglobulin domain family, and the fibrinogen domain immuno-lectin (FBN) family. All these genes are present in multiple copies, so that invading microbes can potentially engender differential responses according to the nature of the detecting PRR. There is only a single gene for the Dscam (Down syndrome cell adhesion molecule) protein, but the ability for differential splicing of this gene's mRNA is particularly impressive, potentially generating literally thousands of different isoforms. It is already clear that at least some of this molecular diversity can generate immune responses that are differentially directed towards particular immune challenges. The extent to which different recognition is combined with unique antimicrobial action (as is the case with vertebrate immunoglobulins) remains unknown.

The advent of comparative genomics has shed light on the evolution of insect immune defences. Comparing the Drosophila group with mosquitoes and honey bees, in Chapter 6, Kafatos et al. disentangle common themes from specific components of immunity. Honey bees, for example, have a relatively small set of immune genes which demonstrate a high degree of conservatism. They are most intriguing when compared with non-social insects, as the differences between them are attributable to the evolution of sociality in bees and other Hymenoptera. The authors also highlight how the use of comparative genomics led to the unravelling of evolutionary novelties. Genes containing leucine-rich repeats are an example, which led to the discovery of a new complement-like mechanism in mosquitoes. This also mirrors some overlap with the mechanism of acquired immunity in lampreys and hagfish (see below), which in itself might be exciting.

To conclude the book's first part, Schneider (Chapter 7) also focuses on Drosophila, but from the very different standpoint of the integration of immune responses into the insect's general physiology. He points out that most studies of insect immune systems to date have regarded both immune challenges and responses as being stereotypic, whereas in fact both are highly idiosyncratic. To rectify this, Schneider focuses on the responsiveness of insect immune responses to the context in which they are elicited. Importantly, this context includes not only the nature and extent of the pathogenic or parasitic challenge, but also the state of the insect at the time of that challenge. For example, host nutritional state is known to be important in determining the outcome of infections. This is not only because immunity is expensive (and therefore competes with other physiological systems for resources), but also because immune responses themselves may alter food intake, food selection, and energy flow. Immune responses also vary in extent and quality according to the time of day (i.e. phase of circadian clock), and the insect's reproductive status and age (senescence). Even the quality and quantity of the insect's native gut microbiota is important, and it is becoming evident that we have to consider the microbial ecology of an infection in describing both the immune challenge and the consequences of the immune response. Schneider's important message is that as we have now identified so many important players in the immunological play, we need to read their parts more closely to see how their characters can develop according to the plot.

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