Fitness costs associated with mounting a social immune response

Social immune systems comprise immune defences mounted by individuals for the benefit of others (sensu Cotter & Kilner 2010a). Just as with other forms of immunity, mounting a social immune response is expected to be costly but so far these fitness costs are unknown. We measured the costs of social immunity in a sub-social burying beetle, a species in which two or more adults defend a carrion breeding resource for their young by smearing the flesh with antibacterial anal exudates. Our experiments on widowed females reveal that a bacterial challenge to the breeding resource upregulates the antibacterial activity of a female's exudates, and this subsequently reduces her lifetime reproductive success. We suggest that the costliness of social immunity is a source of evolutionary conflict between breeding adults on a carcass, and that the phoretic communities that the beetles transport between carrion may assist the beetle by offsetting these costs.

Selection for cuticular melanism reveals immune function and life-history trade-offs in Spodoptera littoralis

Several insect species show an increase in cuticular melanism in response to high densities. In some species, there is evidence that this melanism is correlated with an up-regulation of certain immune system components, particularly phenoloxidase (PO) activity, and with the down-regulation of lysozyme activity, suggesting a trade-off between the two traits. As melanism has a genetic component, we selected both melanic and nonmelanic lines of the phase-polyphenic lepidopteran, Spodoptera littoralis, in order to test for a causative genetic link between melanism, PO activity and lysozyme activity, and to establish if there are any life-history costs associated with the melanic response. We found that, in fact, melanic lines had lower PO activity and higher lysozyme activity than nonmelanic lines, confirming a genetic trade-off between the two immune responses, but also indicating a genetic trade-off between melanism and PO activity. In addition, we found that lines with high PO activity had slower development rates suggesting that investment in PO, rather than in melanism, is costly.

Male morph predicts investment in larval immune function in the dung beetle, Onthophagus taurus

Investment in immunity is costly, so that resource-based trade-offs between immunity and sexually selected ornaments might be expected. The amount of resources that an individual can invest in each trait will be limited by the total resources available to them. It would therefore be informative to investigate how investment in immune function changes during growth or production of the sexual trait as resources are diverted to it. Using the dung beetle, Onthophagus taurus, which displays both sexual and male dimorphism in horn size, we examined changes in one measure of immune function, phenoloxidase (PO) activity, in the hemolymph of larvae prior to and during horn growth. We found that PO levels differed between small- and large-horned males throughout the final instar prior to the point where investment in horn growth was taking place. PO levels in females were intermediate to the 2 male morphs. These differences could not be accounted for by differences in condition, measured as hemolymph protein levels and weight. We suggest that the observed differences might be associated with sex- and morph-specific variation in juvenile hormone levels.

Density-dependent prophylaxis and condition-dependent immune function in Lepidopteran larvae: a multivariate approach

1. The risk of parasitism and infectious disease is expected to increase with population density as a consequence of positive density-dependent transmission rates. Therefore, species that encounter large fluctuations in population density are predicted to exhibit plasticity in their immune system, such that investment in costly immune defences is adjusted to match the probability of exposure to parasites and pathogens (i.e. density-dependent prophylaxis).

Costs of resistance: genetic correlations and potential trade-offs in an insect immune system

Theory predicts that natural selection will erode additive genetic variation in fitness-related traits. However, numerous studies have found considerable heritable variation in traits related to immune function, which should be closely linked to fitness. This could be due to trade-offs maintaining variation in these traits. We used the Egyptian cotton leafworm, Spodoptera littoralis, as a model system to examine the quantitative genetics of insect immune function. We estimated the heritabilities of several different measures of innate immunity and the genetic correlations between these immune traits and a number of life history traits. Our results provide the first evidence for a potential genetic trade-off within the insect immune system, with antibacterial activity (lysozyme-like) exhibiting a significant negative genetic correlation with haemocyte density, which itself is positively genetically correlated with both haemolymph phenoloxidase activity and cuticular melanization. We speculate on a potential trade-off between defence against parasites and predators, mediated by larval colour, and its role in maintaining genetic variation in traits under natural selection.

Heritability of immune function in the caterpillar Spodoptera littoralis

Phenoloxidase (PO) is believed to be a key mediator of immune function in insects and has been implicated both in non-self recognition and in resistance to a variety of parasites and pathogens, including baculoviruses and parasitoids. Using larvae of the Egyptian cotton leafworm, Spodoptera littoralis, we found that despite its apparent importance, haemolymph PO activity varied markedly between individuals, even amongst insects reared under apparently identical conditions. Sib-analysis methods were used to determine whether individuals varied genetically in their PO activity, and hence in one aspect of immune function. The heritability estimate of haemolymph PO activity was high (h 2 = 0.690 +/- 0.069), and PO activity in the haemolymph was strongly correlated with PO activity in both the cuticle and midgut; the sites of entry for most parasites and pathogens. Haemolymph PO activity was also strongly correlated with the degree to which a synthetic parasite (a small piece of nylon monofilament) was encapsulated and melanized (r = 0.622 +/- 0.142), suggesting that the encapsulation response is also heritable. The mechanism maintaining this genetic variation has yet to be elucidated.

Macronutrient balance mediates trade-offs between immune function and life history traits

1. Diet and health are intimately linked and recent studies have found that caloric restriction can affect immune function. However, when given a choice between diets that differ in their macronutrient composition, pathogen-infected individuals can select a diet that improves their survival, suggesting that the nutritional composition of the diet, as well as its calorie content, can play a role in defence against disease. Moreover, as individuals change their diet when infected, it suggests that a diet that is optimal for growth is not optimal for immunity, leading to trade-offs.
2. Currently, our knowledge of the effects of diet on immunity is limited because previous experiments have manipulated either single nutrients or the calorie content of the diet without considering their interactive effects. By simultaneously manipulating both the diet composition (quality) and its caloric density (quantity), in both naive and immune-challenged insects, we asked how do diet quality and quantity influence an individual's ability to mount an immune response? And to what extent are allocation trade-offs driven by quantity- versus quality-based constraints?
3. We restricted individuals to 20 diets varying in their protein and carbohydrate content and used 3D response surfaces to visualize dietary effects on larval growth and immune traits. Our results show that both constitutive and induced immune responses are not limited by the total quantity of nutrients consumed, but rather different traits respond differently to variation in the ratios of macronutrients (diet quality), and peak in different regions of macronutrient space. The preferred dietary composition therefore represents a compromise between the nutritional requirements of growth and immune responses. We also show that a non-pathogenic immune challenge does not affect diet choice, rather immune-challenged insects modify their allocation of nutrients to improve their immune response.
4. Our results indicate that immune traits are affected by the macronutrient content of the diet and that no diet can simultaneously optimize all components of the immune system. To date the emphasis has been on the effects of micronutrients in improving immunity, our findings indicate that this must be widened to include the neglected impact of macronutrients on defence against disease.

Kassorins: Novel innate immune system peptides from skin secretions of the African hyperoliid frogs, Kassina maculata and Kassina senegalensis

From defensive skin secretions acquired from two species of African hyperoliid frogs, Kassina maculata and Kassina senegalensis, we have isolated two structurally related, C-terminally amidated tridecapeptides of novel primary structure that exhibit a broad spectrum of biological activity. In reflection of their structural novelty and species of origin, we named the peptides kassorin M (FLEGLLNTVTGLLamide; 1387.8 Da) and kassorin S (FLGGILNTITGLLamide; 1329.8 Da), respectively. The primary structure and organisation of the biosynthetic precursors of kassorins M and S were deduced from cloned skin secretion-derived cDNA. Both open-reading frames encoded a single copy of kassorin M and S, respectively, located at the C-terminus. Kassorins display limited structural similarities to vespid chemotactic peptides (7/13 residues), temporin A (5/13 residues), the N-terminus of Lv-ranaspumin, a foam nest surfactant protein of the frog, Leptodactylus vastus, and an N-terminal domain of the equine sweat surfactant protein, latherin. Both peptides elicit histamine release from rat peritoneal mast cells. However, while kassorin S was found to possess antibacterial activity against Staphylococcus aureus, kassorin M was devoid of such activity. In contrast, kassorin M was found to contract the smooth muscle of guinea pig urinary bladder (EC50 = 4.66 nM) and kassorin S was devoid of this activity. Kassorins thus represent the prototypes of a novel family of peptides from the amphibian innate immune system as occurring in defensive skin secretions.

Genetic Evidence Implicates the Immune System and Cholesterol Metabolism in the Aetiology of Alzheimer's Disease

Background: Late Onset Alzheimer's disease (LOAD) is the leading cause of dementia. Recent large genome-wide association studies (GWAS) identified the first strongly supported LOAD susceptibility genes since the discovery of the involvement of APOE in the early 1990s. We have now exploited these GWAS datasets to uncover key LOAD pathophysiological processes. Methodology: We applied a recently developed tool for mining GWAS data for biologically meaningful information to a LOAD GWAS dataset. The principal findings were then tested in an independent GWAS dataset.

Llama antibody fragments have good potential for application as HIV-1 topical microbicides

There is an urgent global need for preventative strategies against HIV-1 infections. Llama heavy-chain antibody fragments (VHH) are a class of molecules recently described as potent cross-clade HIV-1 entry inhibitors. We studied the potential of a VHH-based microbicide in an application-oriented fashion. We show that VHH can be inexpensively produced in high amounts in the GRAS organism S. cerevisiae, resulting in very pure, and endotoxin free product. VHH are very stable under conditions they might encounter during transport, storage or use by women. We developed active formulations of VHH in aqueous gel and compressed and lyophilized tablets for controlled release from an intra vaginal device. The release profile of the VHH from e.g. a vaginal ring suggests sufficient bioavailability and protective concentration of the molecule at the mucosal site at the moment of the infection. The ex vivo penetration kinetics through human tissues show that the VHH diffuse into the mucosal layer and open the possibility to create a second defense layer either by blocking the HIV receptor binding sites or by blocking the receptors of immune cells in the mucosa. In conclusion, our data show that VHH have

PI3K beta Plays a Critical Role in Neutrophil Activation by Immune Complexes

Neutrophils are activated by immunoglobulin G (IgG)-containing immune complexes through receptors that recognize the Fc portion of IgG (Fc gamma Rs). Here, we used genetic and pharmacological approaches to define a selective role for the beta isoform of phosphoinositide 3-kinase (PI3K beta) in Fc gamma R-dependent activation of mouse neutrophils by immune complexes of IgG and antigen immobilized on a plate surface. At low concentrations of immune complexes, loss of PI3K beta alone substantially inhibited the production of reactive oxygen species (ROS) by neutrophils, whereas at higher doses, similar suppression of ROS production was achieved only by targeting both PI3K beta and PI3K delta, suggesting that this pathway displays stimulus strength-dependent redundancy. Activation of PI3K beta by immune complexes involved cooperation between Fc gamma Rs and BLT1, the receptor for the endogenous proinflammatory lipid leukotriene B-4. Coincident activation by a tyrosine kinase-coupled receptor (Fc gamma R) and a heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptor (BLT1) may provide a rationale for the preferential activation of the beta isoform of PI3K. PI3K beta-deficient mice were highly protected in an Fc gamma R-dependent model of autoantibody-induced skin blistering and were partially protected in an Fc gamma R-dependent model of inflammatory arthritis, whereas combined deficiency of PI3K beta and PI3K delta resulted in near-complete protection in the latter case. These results define PI3K beta as a potential therapeutic target in inflammatory disease.

Unconscious Vigilance: Worldview Defense without Adaptations for Terror, Coalition or Uncertainty Management

Individuals subtly reminded of death, coalitional challenges, or feelings of uncertainty display exaggerated preferences for affirmations and against criticisms of their cultural in-groups. Terror management, coalitional psychology, and uncertainty management theories postulate this “worldview defense” effectas the output of mechanisms evolved either to allay the fear of death, foster social support, or reduce anxiety by increasing adherence to cultural values. In 4 studies, we report evidence for an alternative perspective. We argue that worldview defense owes to unconscious vigilance, a state of accentuatedreactivity to affective targets (which need not relate to cultural worldviews) that follows detection of subtle alarm cues (which need not pertain to death, coalitional challenges, or uncertainty). In Studies 1 and 2, death-primed participants produced exaggerated ratings of worldview-neutral affective targets. In Studies 3 and 4, subliminal threat manipulations unrelated to death, coalitional challenges, or uncertaintyevoked worldview defense. These results are discussed as they inform evolutionary interpretations of worldview defense and future investigations of the influence of unconscious alarm on judgment.