The use of immunostimulants in fish larval aquaculture

The production of fish larvae is often hampered by high mortality rates, and it is believed that most of this economic loss due to infectious diseases is ca. 10% in Western European aquaculture sector. The development of strategies to control the pathogen load and immuno-prophylactic measures must be addressed further to realise the economic "potential" production of marine fish larvae and thus improve the overall production of adult fish. The innate defence includes both humoral and cellular defence mechanisms such as the complement system and the processes played by granulocytes and macrophages. A set of different substances such as beta-glucans, bacterial products, and plant constituents may directly initiate activation of the innate defence mechanisms acting on receptors and triggering intracellular gene activation that may result in production of anti-microbial molecules. These immunostimulants are often obtained from bacterial sources, brown or red algae and terrestrial fungi are also exploited as source of novel potentiating substances. The use of immunostimulants, as dietary supplements, can improve the innate defence of animals providing resistance to pathogens during periods of high stress, such as grading, reproduction, sea transfer and vaccination. The immunomodulation of larval fish has been proposed as a potential method for improving larval survival by increasing the innate responses of the developing animals until its adaptive immune response is sufficiently developed to mount an effective response to the pathogen. To this end it has been proposed that the delivery of immunostimulants as a dietary supplement to larval fish could be of considerable benefit in boosting the animals innate defences with little detriment to the developing animal. Conversely, there is a school of thought that raises the concern of immunomodulating a neotanous animal before its immune system is fully formed as this may adversely affect the development of a normal immune response.     

Infectious diseases of marine molluscs and host responses as revealed by genomic tools

More and more infectious diseases affect marine molluscs. Some diseases have impacted commercial species including MSX and Dermo of the eastern oyster, QPX of hard clams, withering syndrome of abalone and ostreid herpesvirus 1 (OsHV-1) infections of many molluscs. Although the exact transmission mechanisms are not well understood, human activities and associated environmental changes often correlate with increased disease prevalence. For instance, hatcheries and large-scale aquaculture create high host densities, which, along with increasing ocean temperature, might have contributed to OsHV-1 epizootics in scallops and oysters. A key to understanding linkages between the environment and disease is to understand how the environment affects the host immune system. Although we might be tempted to downplay the role of immunity in invertebrates, recent advances in genomics have provided insights into host and parasite genomes and revealed surprisingly sophisticated innate immune systems in molluscs. All major innate immune pathways are found in molluscs with many immune receptors, regulators and effectors expanded. The expanded gene families provide great diversity and complexity in innate immune response, which may be key to mollusc''s defence against diverse pathogens in the absence of adaptive immunity. Further advances in host and parasite genomics should improve our understanding of genetic variation in parasite virulence and host disease resistance.     

The innate immune response of finfish--a review of current knowledge

The decline in the fisheries of traditional marine species has been an incentive for the diversification of today's aquaculture sector into the intensive rearing of many finfish species. The increasing interest in commercial farming of different finfish species is expected to result in similar environmental and husbandry-related problems as have been experienced in the development of the salmonid farming industry. An understanding of the biology of the fish species being cultured, in particular the immune response is important for improved husbandry and health management of the species. The innate immune system of fish has generated increasing interest in recent years and is now thought to be of key importance in primary defence and in driving adaptive immunity. This review focuses on key components (cellular and humoral) of the innate immune responses of different fish species of commercial importance.     

Basal metabolic rate and the evolution of the adaptive immune system

Vertebrates have evolved an adaptive immune system in addition to the ancestral innate immune system. It is often assumed that a trade-off between costs and benefits of defence governs the evolution of immunological defence, but the costs and benefits specific to the adaptive immune system are poorly known. We used genetically engineered mice lacking lymphocytes (i.e. mice without adaptive, but with innate, immunity) as a model of the ancestral state in the evolution of the vertebrate immune system. To investigate if the magnitude of adaptive defence is constrained by the energetic costs of producing lymphocytes etc., we compared the basal metabolic rate of normal and lymphocyte-deficient mice. We found that lymphocyte-deficient mice had a higher basal metabolic rate than normal mice with both innate and adaptive immune defence. This suggests that the evolution of the adaptive immune system has not been constrained by energetic costs. Rather, it should have been favoured by the energy savings associated with a combination of innate and adaptive immune defence.     

A review on the interactions between gut microbiota and innate immunity of fish

Although fish immunology has progressed in the last few years, the contribution of the normal endogenous microbiota to the overall health status has been so far underestimated. In this context, the establishment of a normal or protective microbiota constitutes a key component to maintain good health, through competitive exclusion mechanisms, and has implications for the development and maturation of the immune system. The normal microbiota influences the innate immune system, which is of vital importance for the disease resistance of fish and is divided into physical barriers, humoral and cellular components. Innate humoral parameters include antimicrobial peptides, lysozyme, complement components, transferrin, pentraxins, lectins, antiproteases and natural antibodies, whereas nonspecific cytotoxic cells and phagocytes (monocytes/macrophages and neutrophils) constitute innate cellular immune effectors. Cytokines are an integral component of the adaptive and innate immune response, particularly IL-1 beta, interferon, tumor necrosis factor-alpha, transforming growth factor-beta and several chemokines regulate innate immunity. This review covers the innate immune mechanisms of protection against pathogens, in relation with the installation and composition of the normal endogenous microbiota in fish and its role on health. Knowledge of such interaction may offer novel and useful means designing adequate therapeutic strategies for disease prevention and treatment.     

Significance of the functional activity of toll-like receptors and other receptors of the innate immune system of the kidney physiology

The kidney needs to defend against microbial pathogens in order to maintain normal structure and function. This is achieved through innate and adaptive components of the immune system. For a long time, immunologists were concentrating on the adaptive immune system, which, as a result, was studied in detail; at the same time, the significance of the innate immune system was underestimated. This gap was partly filled in the recently, when the key role of the innate immune system in fighting microorganisms and in activating and regulating the adaptive immune system was convincingly established. In the first part of the present article, the sense apparatus of the innate immune system (the so-called pattern-recognition receptors) will be reviewed; particular attention will be paid to the toll-like receptors (TLRs), which bear the main burden of microorganism recognition. Signalling pathways that are activated by TLRs and result in the activation of effector mechanisms will also be reviewed. In the second part of the review, we will analyse available data on how these mechanisms of the innate immune system secure defence and normal functioning of the kidney.     

DNA vaccines as a tool for analysing the protective immune response against rhabdoviruses in rainbow trout

DNA vaccines based on the glycoprotein genes of the salmonid rhabdoviruses VHSV and IHNV have been demonstrated to be very efficient in inducing a protective immune response against the respective diseases in rainbow trout. Nanogram doses of plasmid DNA delivered by intramuscular injection are sufficient to induce high levels of immunity in fingerling-size fish, whereas larger fish require more vaccine for protection. The protection is long lasting and, more surprisingly, is partly established already 4 days post vaccination. The early protection involves cross-protective anti-viral defence mechanisms, while the long duration immunity is highly specific. The nature of these immune response mechanisms is discussed and it is suggested that the efficacy of the vaccines is related to their ability to activate the innate immune system as it is activated by live virus.     

Antagonism of miR-328 Increases the Antimicrobial Function of Macrophages and Neutrophils and Rapid Clearance of Non-typeable Haemophilus Influenzae (NTHi) from Infected Lung

Pathogenic bacterial infections of the lung are life threatening and underpin chronic lung diseases. Current treatments are often ineffective potentially due to increasing antibiotic resistance and impairment of innate immunity by disease processes and steroid therapy. Manipulation miRNA directly regulating anti-microbial machinery of the innate immune system may boost host defence responses. Here we demonstrate that miR-328 is a key element of the host response to pulmonary infection with non-typeable haemophilus influenzae and pharmacological inhibition in mouse and human macrophages augments phagocytosis, the production of reactive oxygen species, and microbicidal activity. Moreover, inhibition of miR-328 in respiratory models of infection, steroid-induced immunosuppression, and smoke-induced emphysema enhances bacterial clearance. Thus, miRNA pathways can be targeted in the lung to enhance host defence against a clinically relevant microbial infection and offer a potential new anti-microbial approach for the treatment of respiratory diseases.     

Immunomodulatory functions of type I interferons

Interferon-α (IFNα) and IFNβ, collectively known as type I IFNs, are the major effector cytokines of the host immune response against viral infections. However, the production of type I IFNs is also induced in response to bacterial ligands of innate immune receptors and/or bacterial infections, indicating a broader physiological role for these cytokines in host defence and homeostasis than was originally assumed. The main focus of this Review is the underappreciated immunomodulatory functions of type I IFNs in health and disease. We discuss their function in the regulation of innate and adaptive immune responses, the response to bacterial ligands, inflammasome activation, intestinal homeostasis and inflammatory and autoimmune diseases.     

Immunosenescence and age-related viral diseases

Immunosenescence is described as a decline in the normal functioning of the immune system associated with physiologic ageing.Immunosenescence contributes to reduced efficacy to vaccination and increased susceptibility to infectious diseases in the elderly.Extensive studies of laboratory animal models of ageing or donor lymphocyte analysis have identified changes in immunity caused by the ageing process.Most of these studies have identified phenotypic and functional changes in innate and adaptive immunity.However,it is unclear which of these defects are critical for impaired immune defense against infection.This review describes the changes that occur in innate and adaptive immunity with ageing and some age-related viral diseases where defects in a key component of immunity contribute to the high mortality rate in mouse models of ageing.     

Intracellular innate resistance to bacterial pathogens

Mammalian innate immunity stimulates antigen-specific immune responses and acts to control infection prior to the onset of adaptive immunity. Some bacterial pathogens replicate within the host cell and are therefore sheltered from some protective aspects of innate immunity such as complement. Here we focus on mechanisms of innate intracellular resistance encountered by bacterial pathogens and how some bacteria can evade destruction by the innate immune system. Major strategies of intracellular antibacterial defence include pathogen compartmentalization and iron limitation. Compartmentalization of pathogens within the host endocytic pathway is critical for generating high local concentrations of antimicrobial molecules, such as reactive oxygen species, and regulating concentrations of divalent cations that are essential for microbial growth. Cytosolic sensing, autophagy, sequestration of essential nutrients and membrane attack by antimicrobial peptides are also discussed.     

The effects of age and social interactions on innate immunity in a leaf-cutting ant

Both developmental and environmental factors shape investment in costly immune defences. Social insect workers have different selection pressures on their innate immune system compared to non-social insects because workers do not reproduce and their longevity affects the fitness of relatives. Furthermore, hygienic behavioural defences found in social insects can result in increased survival after fungal infection, although it is not known if there is modulation in physiological immune defence associated with group living vs. solitary living.Here we investigated whether physiological immune defence is affected by both age and the short-term presence or absence of nestmates in the leaf-cutting ant Acromyrmex octospinosus. We predicted that older ants would show immune senescence and that group living may result in prophylactic differences in immune defence compared to solitarily kept ants. We kept old and young workers alone or in nestmate groups for 48 h and assayed a key innate immune system enzyme, expressing phenoloxidase (PO) and its stored precursor (proPO), a defence that acts immediately, i.e. it is constitutive. Short-term solitary living did not affect PO or proPO levels relative to group living controls and we found no evidence for immunosenescence in proPO. However, we found a significant increase in active PO in older workers, which is consistent with two non-mutually exclusive explanations: it could be an adaptive response or indicative of immunosenescence. Our results suggest that future studies of immunosenescence should consider both active immune effectors in the body, such as PO, and the stored potential to express immune defences, such as proPO.     

动脉粥样硬化中适应性免疫应答的研究进展

动脉粥样硬化(atherosclerosis,AS)是导致心血管疾病的主要病理生理基础,现在被认为是一种慢性炎症性疾病.实验和临床证据表明适应性免疫应答可加速或抑制AS.适应性免疫细胞包括T细胞和B细胞,其通过分泌不同的细胞因子或抗体发挥促炎或抗炎作用,某些T细胞和B细胞亚型在AS进程中的作用仍存在争议,Th17和Treg细胞可根据微环境改变表型,提示T细胞可能具有可塑性.此外,脂质代谢和适应性免疫系统之间也存在复杂的相互作用.最近卡那单抗抗炎血栓形成结果研究为治疗AS的抗炎症策略提供了关键支持,针对免疫系统的免疫调节或疫苗接种也是治疗AS有希望的途径.本文就近年来适应性免疫应答在AS中的研究进展作一综述,并展望其作为诊断和防治心血管疾病靶点的未来前景.     

Response to vaccination of Atlantic cod (Gadus morhua L.) progenies from families with different estimated family breeding values for vibriosis resistance

The purpose of the study was to elucidate whether responses to vibriosis vaccination and gene expressions in parts of the innate immune system were different in families of Atlantic cod (Gadus morhua). The fish were progenies of families with differences in estimated breeding values (EBV) for vibriosis resistance. Families of coastal cod (CC) and northeast Arctic cod (AC) responded well to vaccination with a relative percent survival of 72–95. No correlation between response to vaccination and vibriosis resistance were found (p = 0.146). The AC family with medium low (M) resistance had significant (p ≤ 0.019) lowest mortality among all the unvaccinated fish but the CC-M family. Further, when comparing the vaccinated fish the AC family with very high (VH) resistance had significant (p ≤ 0.004) higher mortality than all except the CC-VL and CC-H families.Parts of the innate immune response were studied by measuring the gene expression of innate immune genes 2 and 4 days post dip vaccination. Vaccinated fish from two families had a weak but significant higher innate immune response compared to control fish of the same family. In vaccinated fish, the gene expression of interleukin (IL) 1b, IL-10, IL-12p40 and hepcidin were significant up-regulated. While, no measureable activations of interferon gamma (IFNγ), IL-8, cathelicidin, LBP/BPI and G-type lysozyme were found.     

Improved health and growth of fish fed mannan oligosaccharides: Potential mode of action

Nowadays, aquaculture industry still confronts several disease-related problems mainly caused by viruses, bacteria and parasites. In the last decade, the use of mannan oligosaccharides (MOS) in fish production has received increased attention due to its beneficial effects on fish performance and disease resistance. This review shows the MOS use in aquaculture with a specific emphasis on the effectiveness of the several MOS forms available in the market related to disease resistance, fish nutrition and the possible mechanisms involved. Among the main beneficial effects attributed to MOS dietary supplementation, enhanced fish performance, feed efficiency and pathogen protection by potentiation of the systemic and local immune system and the reinforcement of the epithelial barrier structure and functionality are some of the most commonly demonstrated benefits. These combined effects suggest that the reinforcement of the intestinal integrity and functionality, together with the stimulation of the innate immune system, are the primary mode of action of MOS in fish. However, the supplementation strategy related to the structure of the MOS added, the correct dose and duration, as well as fish species, size and culture conditions are determinant factors to achieve improvements in health status and growth performance.     

The complement system in teleosts

Complement, an important component of the innate immune system, is comprised of about 35 individual proteins. In mammals, activation of complement results in the generation of activated protein fragments that play a role in microbial killing, phagocytosis, inflammatory reactions, immune complex clearance, and antibody production. Fish appear to possess activation pathways similar to those in mammals, and the fish complement proteins identified thus far show many homologies to their mammalian counterparts. Because information about complement proteins, regulatory proteins, and complement receptors in fish is far from complete, it is unclear whether all the complement functions that have been identified in mammals also occur in fish. However, it has been clearly demonstrated that fish complement can lyse foreign cells and opsonise foreign organisms for destruction by phagocytes. There are also indications that complement fragments participate in inflammatory reactions. Fish possess multiple isoforms of several complement proteins, such as C3 and factor B. It has been hypothesised that the function of this diversity in complement proteins serves to expand their innate immune recognition capacity and response. Understanding the functions of complement in fish and the roles the individual proteins, including the various isoforms, play in host defence, is important not only for understanding the evolution of this system but also for the development of new strategies in fish health management.     

Toward general prophylactic cancer vaccination

It is well established that chronic infections can lead to cancer. Almost unknown is that, in contrast, acute brief viral and bacterial infections may have beneficial effects in cases of established neoplastic disease, while exposure to pathogenic products by infection, vaccination, and inhalation can cause prophylactic effects. In the following I will align evidence from case studies of spontaneous regression and from epidemiological studies with recent immunology to conclude that pathogenic substances belonging to the group of “pathogen‐associated molecular patterns” can trigger the innate immune system to establish anti‐neoplastic immune responses. A better understanding of the protective role of the innate immune system might leverage considerable prophylactic potential.     

Innate versus adaptive immunity in sticklebacks: evidence for trade-offs from a selection experiment

In vertebrates, the immune system consists of two arms of different characteristics: the innate and the acquired immune response. Parasites that are only shortly exposed to the immune system are most efficiently attacked by fast, constitutive innate immune mechanisms. Here, we experimentally selected within four fish families for high innate resistance versus susceptibility of three-spined sticklebacks (Gasterosteus aculeatus) against infection with the eye-fluke (Diplostomum pseudospathacaeum), a parasite whose metacercariae are protected from the immune system within the eye lens. We predicted that in families with high susceptibility, the adaptive immune system would be upregulated when challenged with infection. In accordance, we found that MHC class IIB expression is increased by approximately 50% in those lines selected for higher parasite load (i.e. low innate response). This suggests extensive genetic correlations between innate and adaptive immune system and/or crosstalk between both lines of defense. An efficient, specific innate immune response might reduce overall activation of the immune system and potentially alleviate associated effects of immunopathology.     

Regulation of innate immunity by the molecular machinery of macroautophagy

Innate immune responses are the first line of defence for an organism to restrict invading pathogens. They fulfil two main functions, namely detection of the pathogen to successively alarm the appropriate components of the immune system and early inhibition of the infection to prevent demise of the infected organism before a more tailored immune response, usually mediated by the adaptive immune system, can be mounted. Autophagy and phagocytosis, modified by the autophagic core machinery, contribute to these functions by regulating pathogen detection, influencing the production of innate immune mediators and directly restricting intracellular and extracellular pathogens as an effector mechanism of innate immunity. These aspects of the involvement of mainly macroautophagy in innate immune responses will be discussed in this review.