Expression of VP7, a Bluetongue Virus Group Specific Antigen by Viral Vectors: Analysis of the Induced Immune Responses and Evaluation of Protective Potential in Sheep

Bluetongue virus (BTV) is an economically important Orbivirus transmitted by biting midges to domestic and wild ruminants. The need for new vaccines has been highlighted by the occurrence of repeated outbreaks caused by different BTV serotypes since 1998. The major group-reactive antigen of BTV, VP7, is conserved in the 26 serotypes described so far, and its role in the induction of protective immunity has been proposed. Viral-based vectors as antigen delivery systems display considerable promise as veterinary vaccine candidates. In this paper we have evaluated the capacity of the BTV-2 serotype VP7 core protein expressed by either a non-replicative canine adenovirus type 2 (Cav-VP7 R⁰) or a leporipoxvirus (SG33-VP7), to induce immune responses in sheep. Humoral responses were elicited against VP7 in almost all animals that received the recombinant vectors. Both Cav-VP7 R⁰ and SG33-VP7 stimulated an antigen-specific CD4⁺ response and Cav-VP7 R⁰ stimulated substantial proliferation of antigen-specific CD8⁺ lymphocytes. Encouraged by the results obtained with the Cav-VP7 R⁰ vaccine vector, immunized animals were challenged with either the homologous BTV-2 or the heterologous BTV-8 serotype and viral burden in plasma was followed by real-time RT-PCR. The immune responses triggered by Cav-VP7 R⁰ were insufficient to afford protective immunity against BTV infection, despite partial protection obtained against homologous challenge. This work underscores the need to further characterize the role of BTV proteins in cross-protective immunity.     

Urbanization,Trace Metal Pollution,and Malaria Prevalence in the House Sparrow

Anthropogenic pollution poses a threat for the environment and wildlife. Trace metals (TMs) are known to have negative effects on haematological status, oxidative balance, and reproductive success in birds. These pollutants particularly increase in concentration in industrialized, urbanized and intensive agricultural areas. Pollutants can also interfere with the normal functioning of the immune system and, as such, alter the dynamics of host-parasite interactions. Nevertheless, the impact of pollution on infectious diseases has been largely neglected in natural populations of vertebrates. Here, we used a large spatial scale monitoring of 16 house sparrow (Passer domesticus) populations to identify environmental variables likely to explain variation in TMs (lead, cadmium, zinc) concentrations in the feathers. In five of these populations, we also studied the potential link between TMs, prevalence of infection with one species of avian malaria, Plasmodium relictum, and body condition. Our results show that lead concentration is associated with heavily urbanized habitats and that areas with large woodland coverage have higher cadmium and zinc feather concentrations. Our results suggest that lead concentration in the feathers positively correlates with P. relictum prevalence, and that a complex relationship links TM concentrations, infection status, and body condition. This is one of the first studies showing that environmental pollutants are associated with prevalence of an infectious disease in wildlife. The mechanisms underlying this effect are still unknown even though it is tempting to suggest that lead could interfere with the normal functioning of the immune system, as shown in other species. We suggest that more effort should be devoted to elucidate the link between pollution and the dynamics of infectious diseases.     

Ketamine Decreases Resting State Functional Network Connectivity in Healthy Subjects: Implications for Antidepressant Drug Action

Increasing preclinical and clinical evidence underscores the strong and rapid antidepressant properties of the glutamate-modulating NMDA receptor antagonist ketamine. Targeting the glutamatergic system might thus provide a novel molecular strategy for antidepressant treatment. Since glutamate is the most abundant and major excitatory neurotransmitter in the brain, pathophysiological changes in glutamatergic signaling are likely to affect neurobehavioral plasticity, information processing and large-scale changes in functional brain connectivity underlying certain symptoms of major depressive disorder. Using resting state functional magnetic resonance imaging (rsfMRI), the „dorsal nexus “(DN) was recently identified as a bilateral dorsal medial prefrontal cortex region showing dramatically increased depression-associated functional connectivity with large portions of a cognitive control network (CCN), the default mode network (DMN), and a rostral affective network (AN). Hence, Sheline and colleagues (2010) proposed that reducing increased connectivity of the DN might play a critical role in reducing depression symptomatology and thus represent a potential therapy target for affective disorders. Here, using a randomized, placebo-controlled, double-blind, crossover rsfMRI challenge in healthy subjects we demonstrate that ketamine decreases functional connectivity of the DMN to the DN and to the pregenual anterior cingulate (PACC) and medioprefrontal cortex (MPFC) via its representative hub, the posterior cingulate cortex (PCC). These findings in healthy subjects may serve as a model to elucidate potential biomechanisms that are addressed by successful treatment of major depression. This notion is further supported by the temporal overlap of our observation of subacute functional network modulation after 24 hours with the peak of efficacy following an intravenous ketamine administration in treatment-resistant depression.     

Telomere length is repeatable,shortens with age and reproductive success,and predicts remaining lifespan in a long‐lived seabird

Telomeres are protective caps at the end of chromosomes, and their length is positively correlated with individual health and lifespan across taxa. Longitudinal studies have provided mixed results regarding the within‐individual repeatability of telomere length. While some studies suggest telomere length to be highly dynamic and sensitive to resource‐demanding or stressful conditions, others suggest that between‐individual differences are mostly present from birth and relatively little affected by the later environment. This dichotomy could arise from differences between species, but also from methodological issues. In our study, we used the highly reliable Terminal Restriction Fragment analysis method to measure telomeres over a 10‐year period in adults of a long‐lived seabird, the common tern (Sterna hirundo). Telomeres shortened with age within individuals. The individual repeatability of age‐dependent telomere length was high (>0.53), and independent of the measurement interval (i.e., one vs. six years). A small (R² = .01), but significant part of the between‐individual variation in telomere length was, however, explained by the number of fledglings produced in the previous year, while reproduction in years prior to the previous year had no effect. We confirmed that age‐dependent telomere length predicted an individual's remaining lifespan. Overall, our study suggests that the majority of between‐individual variation in adult telomere length is consistent across adult life, and that a smaller part of the variation can be explained by dynamic factors, such as reproduction.     

Food availability and competition do not modulate the costs of Plasmodium infection in dominant male canaries

Understanding the different factors that may influence parasite virulence is of fundamental interest to ecologists and evolutionary biologists. It has recently been demonstrated that parasite virulence may occur partly through manipulation of host competitive ability. Differences in competitive ability associated with the social status (dominant or subordinate) of a host may determine the extent of this competition-mediated parasite virulence. We proposed that differences between subordinate and dominant birds in the physiological costs of infection may change depending on the level of competition in social groups. We observed flocks of domestic canaries to determine dominant or subordinate birds, and modified competition by providing restricted (high competition) or ad libitum food (low competition). Entire flocks were then infected with either the avian malaria parasite, Plasmodium relictum or a control. Contrary to our predictions we found that the level of competition had no effect on the outcome of infection for dominant or subordinate birds. We found that dominant birds appeared to suffer greater infection mediated morbidity in both dietary treatments, with a higher and more sustained reduction in haematocrit, and higher parasitaemia, than subordinates. Our results show that dominance status in birds can certainly alter parasite virulence, though the links between food availability, competition, nutrition and virulence are likely to be complex and multifaceted.     

Multiple Avirulence Loci and Allele-Specific Effector Recognition Control the Pm3 Race-Specific Resistance of Wheat to Powdery Mildew

In cereals, several mildew resistance genes occur as large allelic series; for example, in wheat (Triticum aestivum and Triticum turgidum), 17 functional Pm3 alleles confer agronomically important race-specific resistance to powdery mildew (Blumeria graminis). The molecular basis of race specificity has been characterized in wheat, but little is known about the corresponding avirulence genes in powdery mildew. Here, we dissected the genetics of avirulence for six Pm3 alleles and found that three major Avr loci affect avirulence, with a common locus_1 involved in all AvrPm3-Pm3 interactions. We cloned the effector gene AvrPm3^a2/f2 from locus_2, which is recognized by the Pm3a and Pm3f alleles. Induction of a Pm3 allele-dependent hypersensitive response in transient assays in Nicotiana benthamiana and in wheat demonstrated specificity. Gene expression analysis of Bcg1 (encoded by locus_1) and AvrPm3 ^a2/f2 revealed significant differences between isolates, indicating that in addition to protein polymorphisms, expression levels play a role in avirulence. We propose a model for race specificity involving three components: an allele-specific avirulence effector, a resistance gene allele, and a pathogen-encoded suppressor of avirulence. Thus, whereas a genetically simple allelic series controls specificity in the plant host, recognition on the pathogen side is more complex, allowing flexible evolutionary responses and adaptation to resistance genes.     

Variations in immune parameters with age in a wild rodent population and links with survival

Recent findings suggest that immune functions do not unidirectionally deteriorate with age but that a potentially adaptive remodeling, where functions of the immune system get downregulated while others get upregulated with age could also occur. Scarce in wild populations, longitudinal studies are yet necessary to properly understand the patterns and consequences of age variations of the immune system in the wild. Meanwhile, it is challenging to understand if the observed variations in immune parameters with age are due to changes at the within‐individual level or to selective (dis)appearance of individuals with peculiar immune phenotypes. Thanks to a long‐term and longitudinal monitoring of a wild Alpine marmot population, we aimed to understand within‐ and between‐individual variation in the immune phenotype with age, in order to improve our knowledge about the occurrence and the evolutionary consequences of such age variations in the wild. To do so, we recorded the age‐specific leukocyte concentration and leukocyte profile in repeatedly sampled dominant individuals. We then tested whether the potential changes with age were attributable to within‐individual variations and/or selective (dis)appearance. Finally, we investigated if the leukocyte concentration and profiles were correlated to the probability of death at a given age. The leukocyte concentration was stable with age, but the relative number of lymphocytes decreased, while the relative number of neutrophils increased, over the course of an individual''s life. Moreover, between individuals of the same age, individuals with fewer lymphocytes but more neutrophils were more likely to die. Therefore, selective disappearance seems to play a role in the age variations of the immune parameters in this population. Further investigations linking age variations in immune phenotype to individual fitness are needed to understand whether remodeling of the immune system with age could or could not be adaptive.     

Thermally mediated body temperature, water content and aggregation behaviour in the intertidal gastropod Nerita atramentosa

Intertidal organisms are vulnerable to global warming as they already live at, or near to, the upper limit of their thermal tolerance window. The behaviour of ectotherms could, however, dampen their limited physiological abilities to respond to climate change (e.g. drier and warmer environmental conditions) which could substantially increase their survival rates. The behaviour of ectotherms is still mostly overlooked in climate change studies. Here, we investigate the potential of aggregation behaviour to compensate for climate change in an intertidal gastropod species (Nerita atramentosa) in South Australia. We used thermal imaging to investigate (1) the heterogeneity in individual snail water content and body temperature and surrounding substratum temperature on two topographically different habitats (i.e. rock platform and boulders) separated by 250 m at both day- and night-times, (2) the potential relationship between environment temperature (air and substratum) and snail water content and body temperature, and (3) the potential buffering effect of aggregation behaviour on snail water content and body temperature. Both substratum and snail temperature were more heterogeneous at small spatial scales (a few centimetres to a few metres) than between habitats. This reinforces the evidence that mobile intertidal ectotherms could survive locally under warmer conditions if they can locate and move behaviourally in local thermal refuges. N. atramentosa behaviour, water content and body temperature during emersion seem to be related to the thermal stability and local conditions of the habitat occupied. Aggregation behaviour reduces both desiccation and heat stresses but only on the boulder field. Further investigations are required to identify the different behavioural strategies used by ectothermic species to adapt to heat and dehydrating conditions at the habitat level. Ultimately, this information constitutes a fundamental prerequisite to implement conservation management plans for ectothermic species identified as vulnerable in the warming climate.     

Adjunct therapy of n-3 fatty acids to 5-ASA ameliorates inflammatory score and decreases NF-κB in rats with TNBS-induced colitis

5-aminosalicylic acid (5-ASA) is widely used for the treatment of inflammatory bowel disease (IBD). Recent studies have evaluated the potential of nutritional intervention as adjunct therapy to 5-ASA in IBD. N-3 polyunsaturated fatty acids (PUFA) have shown potent anti-inflammatory properties in gut inflammation. Therefore, we aimed to evaluate the efficacy of the dual therapy (n-3 PUFA plus 5-ASA) in rats with 2, 4, 6-trinitrobenzen sulfonic acid (TNBS)-induced colitis. Colitis was induced by intrarectal injection of TNBS while control rats received the vehicle. Rats received by gavage a fish oil-rich formula (n-3 groups) or an isocaloric and isolipidic oil formula supplemented with 5-ASA for 14 days. A dose response of 5-ASA (5–75 mg. suppression mg kg^? 1 d^? 1) was tested. Colitis was evaluated and several inflammatory markers were quantified in the colon. COX-2 expression (P<.05) and pro-inflammatory eicosanoids production of prostaglandin E₂ (P<.001) and leukotriene B₄ (P<.001) were significantly inhibited by n-3 PUFA or 5-ASA therapy. 5-ASA also reduces mRNA levels of tumor necrosis factor α (P<.05). n-3 PUFA or 5-ASA significantly inhibits nuclear factor κB (NF-κB) activation (P<.01 and P<.05, respectively). The dual therapy n-3 PUFA plus 5-ASA also inhibited inflammatory response by lowering NF-κB activation (P<.01) or inducing peroxisome proliferator-activated receptor-γ (PPARγ) expression (P<.05). These results indicate that 5-ASA plus n-3 PUFAs are more effective than a higher dose of 5-ASA alone to reduce NF-κB activation and to induce PPARγ. By contrast, the dual therapy did not improve the effects of individual treatments on eicosanoids or cytokine production. Use of n-3 PUFA in addition to 5-ASA may reduce dose of standard therapy.