Elsevier

Molecular Immunology

Volume 44, Issue 13, July 2007, Pages 3338-3344
Molecular Immunology

How do invertebrates generate a highly specific innate immune response?

https://doi.org/10.1016/j.molimm.2007.02.019Get rights and content

Abstract

High immune specificity is usually considered an exclusive property of vertebrate adaptive immunity. Surprisingly, similar specificities were recently discovered in the invertebrates, which lack the adaptive system. Here, we propose alternative mechanisms for invertebrate specificity, including (i) high genetic diversity of receptors or effectors, (ii) synergistic interactions among immune components, and (iii) dosage effects. The latter two mechanisms act at the protein level, where they could mediate a much higher functional diversity than contained genetically. This may be essential considering the limited genetic diversity of invertebrate immunity genes. They may also contribute to immunological priming—an increased responsiveness of the invertebrate immune system after parasite challenge comparable to vertebrate immune memory. Similar processes are likely to act in the innate system of vertebrates and enhance the effectiveness of adaptive immunity.

Introduction

Evolutionary theory leaves no doubt: selection will favour the emergence of highly specific defences whenever their benefits in fighting parasites (sensu lato, including eukaryotes, bacteria, and viruses) outweigh their costs (e.g., Frank, 2000, Schmid-Hempel, 2005). Part of these costs are due to a genetic “burden”, which may result from the alteration of the genomic distribution of mutations, developmental processes, or cell signalling during evolution of the more specific response. They also entail a usage cost, which is due to the resources required for mounting an immune response and potential harmful side-effects such as autoimmunity (i.e., self molecules are misclassified as foreign). At the same time, this highly specific response may allow more effective elimination or containment of certain parasites. We here define high specificity as the ability of the host's immune system to respond differently towards at least some strains of the same parasite species. This level of specificity is much higher than usually considered in studies of invertebrate immunity and throughout the paper it will always be indicated by the attribute “high”. Such high specificity is especially advantageous when it is more likely to encounter only a subset of strains (or a single strain) of a certain parasite species, as under the following two conditions:

  • (i)

    Hosts are exposed to co-evolving parasite strains. Because of the close relationship with their hosts, such co-evolving parasites have the potential to adapt rapidly to general host defences. In turn, selection favours hosts with more specific responses.

  • (ii)

    Hosts co-exist with certain parasite strains at least temporarily, such that a first encounter with a parasite strain predicts subsequent encounters in the same or next host generation. In this case, selection should favour a host response which specifically targets the parasite strain encountered and which is then maintained throughout the same or until the next generation (single-generation or trans-generational immune priming). Such a fine-tuned highly specific response is particularly advantageous if it is more cost-efficient than a general defence, i.e., it ensures successful pathogen elimination through a lower dose of immune factors, resulting in reduced energetic expenses and reduced risk of immunopathology.

An extremely high degree of specificity can be found in the adaptive immune system of the higher vertebrates, where the combination of highly variable major histocompatibility complex (MHC) receptors and the enormous diversity of antibodies, B- and T cell receptors permits discrimination between self and non-self molecules (Janeway et al., 2001). Furthermore, specificity in the adaptive system is associated with immune memory, which significantly increases immunity during second infections with the same parasite strain (Kurtz, 2004). Invertebrates do not possess an adaptive immune system and have therefore been assumed to lack a highly specific immune defence. Two recent studies have provided convincing evidence that this assumption is wrong.

Individuals of the copepod Macrocyclops albidus increased immunity against a specific strain of its cestode parasite Schistocephalus solidus after they had been exposed to the parasite strain earlier in life (Kurtz and Franz, 2003). In the waterflea Daphnia magna, the offspring of animals exposed to a strain of its microparasite Pasteuria ramosa showed increased resistance against this specific strain but not against a second tested strain (Little et al., 2003). In addition, a certain degree of immune specificity was reported for the bumblebee Bombus terrestris, which developed a pathogen species-specific immune response against two closely related taxa of the genus Paenibacillus (Sadd and Schmid-Hempel, 2006).

The general importance of high immune specificity in the evolution of invertebrates has been emphasized in several recent reviews (e.g., Du Pasquier, 2006, Kurtz, 2004, Little et al., 2005, Schmid-Hempel, 2005). However, to date, the underlying molecular basis remains entirely unknown. Previous suggestions focused on the high genetic diversity of parasite recognition receptors and immune effectors. In the present article, we wish to draw attention to two additional mechanisms, namely the (i) synergistic interactions among and (ii) dosage effects of components of the immune system. The first of these additional alternatives was addressed by Du Pasquier (2006) and Schmid-Hempel (2005). We will here extend the discussion, taking into account the recent literature, which highlights the importance of these mechanisms in invertebrate immunity. We will only consider invertebrates outside of the chordata and focus on immunity against bacterial pathogens and eukaryotic parasites, ignoring viruses. For the latter, high immune specificity may be explained at least partially by RNA interference, which mediates virus resistance, e.g., in Drosophila (Cherry and Silverman, 2006) and which represents a mechanism with an inherently high level of specificity.

Section snippets

Specificity through genetic diversity

The most straightforward basis for high immune specificity relies on the genetic diversity of pathogen recognition receptors and/or immune effectors. Such diversity may permit efficient parasite recognition or elimination via a key-lock system, i.e., each receptor (or effector) matches one pathogen-associated molecule or molecular pattern. In general, receptor and effector genetic diversity may be generated by different processes: (i) high genomic diversity of the respective genes, e.g., within

Specificity through synergistic interactions

In the following, we would like to explore an alternative mechanism that does not rely on extreme genetic diversification but instead focuses on functional diversity generated at the protein level. It is based on the idea that two components of the immune system are able to generate a higher degree of specificity if they interact with each other than if they act separately. This can be illustrated by a simple calculation. If the host possesses 10 different receptor molecules, then these permit

Specificity through dosage effects

The specific recognition of pathogens could be greatly enhanced by increasing the presence of the relevant receptors (or combination of receptors). The underlying reason is that high dosage can enhance multimerization of the receptors or receptor combinations. Multimerization increases binding valency and avidity, and as such, the potential for specific recognition of parasite molecules—in analogy with the proposed mechanism for high specificity in T cell recognition (see above, Schamel et al.,

Outlook

Invertebrates are capable of highly specific immune responses. To date, the underlying mechanisms are entirely unknown. Our review explores several alternatives including genetic diversification, synergistic interactions within the immune system, and dosage effects. These mechanisms were presented as alternatives, although it is likely that they act together. For instance, genetic diversity of receptors and their dosage-dependent expression directly affects the diversity of synergistic effects

Acknowledgements

We thank Sylvia Cremer, Jonathan Ewbank, Dominique Ferrandon, Steven Frank, Michael Habig, Dan Hultmark, Joachim Kurtz, and Andrew Read for advice on this manuscript, the German Science Foundation for financial support (grant SCHU 1415/3), and the Wissenschaftskolleg zu Berlin, Germany, for a fellowship to HS.

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