Toll-dependent and toll-independent innate antiviral immunity

Until recently, adaptive immunity and cytotoxic T cells were considered as the only essential components of the antiviral defence arsenal. Additional data that do not rule out the crucial role of these cells in the clearance of viral pathogens have, however, recently emerged. They indicate that innate immune cells such as macrophages, dendritic cells, gammadelta T cells as well as natural killer (NK) cells play a primordial role in this mechanism. It is now well established that innate immune cells can detect various pathogens (bacteria, viruses, fungi or parasites) very rapidly and respond to their presence through the activation of specific receptors. Once activated, these molecules trigger several signalling cascades that culminate in the establishment of very potent defence mechanisms. In addition, cytokines produced during this initial response are essential for the activation of the adaptive immune response which will add specificity and memory to the system. Among the innate immune receptors, attention has focused on the Toll-like receptors (TLR) and many reports indicate that some of the TLRs are clearly involved in defence against viral pathogens. However, new molecules, acting independently from any TLR, have recently been discovered. They define a second antiviral pathway which is presently the subject of intense research. In this article, we will review the role of the different molecules involved in each pathway within the framework of innate antiviral defence.     

Natural insect host-parasite systems show immune priming and specificity: puzzles to be solved

Study of the multiplicity of interactions between invertebrate hosts and their parasites helps to define the aspects of the host immune systems that have ecological and evolutionary significance. Such study, however, reveals how much is yet unknown. For instance, the costs of mounting an immune response, the nature of the long-lasting protection sometimes attained, and the high degree of specificity observed in certain hosts are phenomena that still await full explanation. An additional puzzle is the high degree of specificity achieved in light of the apparent low degree of specificity in the recognition and effector mechanisms of insect immune systems. Furthermore, while protective immunity is typically associated with vertebrate adaptive immune systems, invertebrates may have analogous capacities, whose nature is still largely unknown. This review will illustrate how the traditional host-centred view of immune defence can be usefully extended by taking account of parasite immune evasion strategies and the variation that such strategies create in the observed outcomes of infection.     

Maternal effects in disease resistance: poor maternal environment increases offspring resistance to an insect virus

Maternal effects can be adaptive and because of their intrinsic time delays may have important effects on population dynamics. In vertebrates, and increasingly invertebrates, it is well established that offspring defence is in part determined by maternal parasite exposure. It has also been suggested that there may be indirect maternal effects on immunity mediated by other components of the maternal environment, including density and resource availability. Here, we examine the effect maternal resource availability has on the immunity of offspring in an insect-virus system. We use five different maternal resource levels and examine immunity in the offspring both directly, by challenge with a virus, and by measuring a major component of the immune system, across three offspring environments. Both the direct infection assay and the measure of immunocompetence show clearly that offspring from mothers in poor environments are more resistant to parasites. This may result from life-history optimization of mothers in poor environments, or because the poor environment acts as a cue for higher disease risk in the next generation. This emphasizes the importance of maternal effects on disease resistance, mediated through indirect environmental factors that will have important implications to both the ecological and evolutionary dynamics of host-parasite interactions.     

Involvement of NK cells against tumors and parasites

Host resistance against pathogens depends on a complex interplay of innate and adaptive immune mechanisms. Acting as an early line of defence, the immune system includes activation of neutrophils, tissue macrophages, monocytes, dendritic cells, eosinophils and natural killer (NK) cells. NK cells are lymphoid cells that can be activated without previous stimulation and are therefore like macrophages in the first line of defence against tumor cells and a diverse range of pathogens. NK cells mediate significant activity and produce high levels of proinflammatory cytokines in response to infection. Their cytotoxicity production is induced principally by monocyte-, macrophage- and dendritic cell-derived cytokines, but their activation is also believed to be cytokine-mediated. Recognition of infection by NK cells is accomplished by numerous activating and inhibitory receptors on the NK cells' surface that selectively trigger the cytolytic activity in a major histocompability complex-independent manner. NK cells have trypanocidal activity of fibroblast cells and mediate direct destruction of extracellular epimastigote and trypomastigote forms of T. cruzi and T. lewisi in vitro; moreover, they kill plasmodia-infected erythrocytes directly through cell-cell interaction. This review provides a more detailed analysis of how NK cells recognize and respond to parasites and how they mediate cytotoxicity against tumor cells. Also the unique role of NK cells in innate immunity to infection and the relationship between parasites and carcinogenesis are discussed.     

Natural variation in priming of basal resistance: from evolutionary origin to agricultural exploitation

Biotic stress has a major impact on the process of natural selection in plants. As plants have evolved under variable environmental conditions, they have acquired a diverse spectrum of defensive strategies against pathogens and herbivores. Genetic variation in the expression of plant defence offers valuable insights into the evolution of these strategies. The 'zigzag' model, which describes an ongoing arms race between inducible plant defences and their suppression by pathogens, is now a commonly accepted model of plant defence evolution. This review explores additional strategies by which plants have evolved to cope with biotic stress under different selective circumstances. Apart from interactions with plant-beneficial micro-organisms that can antagonize pathogens directly, plants have the ability to prime their immune system in response to selected environmental signals. This defence priming offers disease protection that is effective against a broad spectrum of virulent pathogens, as long as the augmented defence reaction is expressed before the invading pathogen has the opportunity to suppress host defences. Furthermore, priming has been shown to be a cost-efficient defence strategy under relatively hostile environmental conditions. Accordingly, it is possible that selected plant varieties have evolved a constitutively primed immune system to adapt to levels of disease pressure. Here, we examine this hypothesis further by evaluating the evidence for natural variation in the responsiveness of basal defence mechanisms, and discuss how this genetic variation can be exploited in breeding programmes to provide sustainable crop protection against pests and diseases.     

生态免疫学研究进展

随着整合生物学思想的发展,生态学与免疫学的相互渗透与交叉,产生了生态免疫学这一崭新的学科,自从其诞生虽然只有短短的十几年时间,但发展迅速。生态免疫学主要从免疫代价的视角来解释生活史权衡、性选择和种群动态变化等生态学问题。动物的免疫功能对其抵抗疾病和最终的生存起至关重要的作用,影响动物免疫的因素具有多样性和复杂性的特点,而研究动物免疫功能变化的原因和结果一直是生态免疫学研究的重要内容。免疫防御是否具有能量或资源代价,这种代价是否昂贵是生态免疫学需要回答的基本问题之一,大量的实验已表明免疫防御的代价是昂贵的。由于能量或资源不是无限的,有限的能量或资源必须在多种经常相互竞争的生理功能间进行分配,这导致了免疫功能与动物的生长、繁殖等生活史组分之间的权衡,很多的研究表明增加一个过程的投资会降低对另一过程的投资。免疫同样在性选择特征进化以及维持雌性偏爱性修饰的雄性中发挥至关重要的作用,免疫功能障碍假说认为睾丸激素负责第二性征的产生并同时具有免疫抑制作用,表达性征的代价是降低了免疫功能,这使得宿主对病原体或寄生物攻击的易感性增加,因此只有高质量的雄性个体才能充分表达性征同时又不遭受大量寄生负荷。综述了生态免疫学的概念、研究内容以及未来研究需要关注的领域。     

Chemokines in host-protozoan-parasite interactions

Here, we review the interactions between parasites and chemokines and chemokine receptors in toxoplasmosis, trypanosomiasis, leishmaniasis, malaria and other diseases caused by protozoan parasites. The potential roles of chemokines after infection by these intracellular pathogens include host defence functions such as leukocyte recruitment, participation in cell-mediated immunity and antiprotozoal activity. However, these interactions can also help the parasite in, for example, the penetration of host cells.     

Beyond phytohaemagglutinin: assessing vertebrate immune function across ecological contexts

1. Over the past decade, there has been a substantial increase in interest in the immune system and the role it plays in the regulation of disease susceptibility, giving rise to the field of eco-immunology. 2. Eco-immunology aims to understand changes in host immune responses in the broader framework of an organism's evolutionary, ecological and life-history contexts. 3. The immune system, however, is complex and multifaceted and can be intimidating for the nonimmunologist interested in incorporating immunological questions into their research. Which immune responses should one measure and what is the biological significance of these measures? 4. The focus of this review is to describe a wide range of eco-immunology techniques, from the simple to the sophisticated, with the goal of providing researchers with a range of options to consider incorporating in their own research programs. 5. These techniques were chosen because they provide relatively straightforward, biologically meaningful assessments of immune function, many of which can be performed across a range of ecological contexts (i.e. field vs. laboratory) and in a wide range of vertebrate animals without relying on species-specific reagents. 6. By incorporating assessments of immune function into their specific research questions, animal ecologists will gain a more comprehensive understanding of organism-environment interactions.     

Predation on Multiple Trophic Levels Shapes the Evolution of Pathogen Virulence

The pathogen virulence is traditionally thought to co-evolve as a result of reciprocal selection with its host organism. In natural communities, pathogens and hosts are typically embedded within a web of interactions with other species, which could affect indirectly the pathogen virulence and host immunity through trade-offs. Here we show that selection by predation can affect both pathogen virulence and host immune defence. Exposing opportunistic bacterial pathogen Serratia marcescens to predation by protozoan Tetrahymena thermophila decreased its virulence when measured as host moth Parasemia plantaginis survival. This was probably because the bacterial anti-predatory traits were traded off with bacterial virulence factors, such as motility or resource use efficiency. However, the host survival depended also on its allocation to warning signal that is used against avian predation. When infected with most virulent ancestral bacterial strain, host larvae with a small warning signal survived better than those with an effective large signal. This suggests that larval immune defence could be traded off with effective defence against bird predators. However, the signal size had no effect on larval survival when less virulent control or evolved strains were used for infection suggesting that anti-predatory defence against avian predators, might be less constrained when the invading pathogen is rather low in virulence. Our results demonstrate that predation can be important indirect driver of the evolution of both pathogen virulence and host immunity in communities with multiple species interactions. Thus, the pathogen virulence should be viewed as a result of both past evolutionary history, and current ecological interactions.     

Pathogens pulling the strings: Effectors manipulating salicylic acid and phenylpropanoid biosynthesis in plants

During evolution, plants have developed sophisticated ways to cope with different biotic and abiotic stresses. Phytohormones and secondary metabolites are known to play pivotal roles in defence responses against invading pathogens. One of the key hormones involved in plant immunity is salicylic acid (SA), of which the role in plant defence is well established and documented. Plants produce an array of secondary metabolites categorized in different classes, with the phenylpropanoids as major players in plant immunity. Both SA and phenylpropanoids are needed for an effective immune response by the plant. To successfully infect the host, pathogens secrete proteins, called effectors, into the plant tissue to lower defence. Secreted effectors can interfere with several metabolic or signalling pathways in the host to facilitate infection. In this review, we will focus on the different strategies pathogens have developed to affect the levels of SA and phenylpropanoids to increase plant susceptibility.     

Recombinant viruses as tools to induce protective cellular immunity against infectious diseases.

Infections by intracellular pathogens such as viruses, some bacteria and many parasites, are cleared in most cases after activation of specific T cellular immune responses that recognize foreign antigens and eliminate infected cells. Vaccines against those infectious organisms have been traditionally developed by administration of whole live attenuated or inactivated microorganisms. Nowadays, research is focused on the development of subunit vaccines, containing the most immunogenic antigens from the particular pathogen. However, when purified subunit vaccines are administered using traditional immunization protocols, the levels of cellular immunity induced are mostly low and not capable of eliciting complete protection against diseases caused by intracellular microbes. In this review, we present a promising alternative to those traditional protocols, which is the use of recombinant viruses encoding subunit vaccines as immunization tools. Recombinant viruses have several interesting features that make them extremely efficient at inducing immune responses mediated by T-lymphocytes. This cellular immunity has recently been demonstrated to be of key importance for protection against malaria and AIDS, both of which are major targets of the World Health Organization for vaccine development. Thus, this review will focus in particular on the development of new vaccination protocols against these diseases.     

Vertebrate sickness behaviors: Adaptive and integrated neuroendocrine immune responses

Vertebrate sickness behaviors, which include lethargy, anorexia, and decreased libido, can facilitate defense against pathogens by conserving energy for use in other immune responses and by limiting parasites' access to nutrients. Such benefits come with considerable costs, however, as lethargy decreases the time available for other fitness-enhancing activities and dampened libido directly reduces reproductive prospects. While the degree of sickness behaviors expressed varies among individuals, populations, and species, the ecological and physiological factors driving this diversity remain unclear. Here, we consider how an organism's ecological context and life-history strategy may impact the ways in which it balances the costs and benefits of sickness behaviors to enable or suppress its expression. Striking an appropriate balance requires physiological assimilation of information about external ecological conditions as well as about the status of infection and host nutrition. This integration requires multi-directional communication among the endocrine, nervous, and immune systems, the purview of the field of psychoneuroimmunology. This discipline portrays cytokines, signaling molecules originally characterized solely by their roles within the immune system, as key mediators of a brain-immune network that ensures the adaptive expression of sickness behaviors. Study of these molecules and the behaviors they coordinate in an ecological context will greatly augment our understanding of the natural variation in immune function found among wild animals.     

Host-parasite dynamics and the evolution of host immunity and parasite fecundity strategies

We explore evolutionarily stable co-evolution of host-macroparasite interactions in a discrete-time two-species population dynamics model, in which the dynamics may be stable, cyclic or chaotic. The macroparasites are assumed to harm host individuals through decreased reproductive output. Hosts may develop costly immune responses to defend themselves against parasites. Parasites compete with conspecifics by adjusting their fecundities. Overall, the presence of both parasites and the immune response in hosts produces more stable dynamics and lower host population sizes than that observed in the absence of the parasites. In our evolutionary analyses, we show that maximum parasite fecundity is always an evolutionarily stable strategy (ESS), irrespective of the type of population interaction, and that maximum parasite fecundity generally induces a minimum parasite population size through over-exploitation of the host. Phenotypic polymorphisms with respect to immunity in the host species are common and expected in ESS host strategies: the benefits of immunication depend on the frequency of the immune hosts in the population. In particular, the steady-state proportions of immune hosts depend, in addition to all the parameters of the parasite dynamics only on the cost of immunity and on the virulence of parasites in susceptible hosts. The implicit ecological dynamics of the host-parasite interaction affect the proportion of immune host individuals in the population. Furthermore, when changes in certain population parameters cause the dynamics of the host-parasite interaction to move from stability to cyclicity and then to chaos, the proportion of immune hosts tends to decrease; however, we also detected counter-examples to this result. As a whole, incorporating immunological and genetic aspects, as well as life-history trade-offs, into host-macroparasite dynamics produces a rich extension to the patterns observed in the models of ecological interactions and epidemics, and deserves more attention than is currently the case.     

The role of ecological feedbacks in the evolution of host defence: what does theory tell us?

Hosts have evolved a diverse range of defence mechanisms in response to challenge by infectious organisms (parasites and pathogens). Whether defence is through avoidance of infection, control of the growth of the parasite once infected, clearance of the infection, tolerance to the disease caused by infection or innate and/or acquired immunity, it will have important implications for the population ecology (epidemiology) of the host-parasite interaction. As a consequence, it is important to understand the evolutionary dynamics of defence in the light of the ecological feedbacks that are intrinsic to the interaction. Here, we review the theoretical models that examine how these feedbacks influence the nature and extent of the defence that will evolve. We begin by briefly comparing different evolutionary modelling approaches and discuss in detail the modern game theoretical approach (adaptive dynamics) that allows ecological feedbacks to be taken into account. Next, we discuss a number of models of host defence in detail and, in particular, make a distinction between 'resistance' and 'tolerance'. Finally, we discuss coevolutionary models and the potential use of models that include genetic and game theoretical approaches. Our aim is to review theoretical approaches that investigate the evolution of defence and to explain how the type of defence and the costs associated with its acquisition are important in determining the level of defence that evolves.     

The skin as interface in the transmission of arthropod-borne pathogens

Animal skin separates the inner world of the body from the largely hostile outside world and is actively involved in the defence against microbes. However, the skin is no perfect defence barrier and many microorganisms have managed to live on or within the skin as harmless passengers or as disease-causing pathogens. Microbes have evolved numerous strategies that allow them to gain access to the layers underneath the epidermis where they either multiply within the dermis or move to distant destinations within the body for replication. A number of viruses, bacteria and parasites use arthropod vectors, like ticks or mosquitoes, to deliver them into the dermis while taking their blood meal. Within the dermis, successful pathogens subvert the function of a variety of skin resident cells or cells of the innate immune system that rush to the site of infection. In this review several interactions with cells of the skin by medically relevant vector-borne pathogens are discussed to highlight the different ways in which these pathogens have come to survive within the skin and to usurp the defence mechanisms of the host for their own ends.     

Predator avoidance and immune defence: costs and trade-offs in snails

Organisms are often confronted by both predators and pathogens. Defending against such widely divergent enemies requires more than one type of defence. Multiple defences, however, raise the possibility of trade-offs among defences. We tested for such trade-offs by manipulating the level of predator-avoidance behaviour and immune function in the freshwater snail Lymnaea stagnalis (Gastropoda: Pulmonata). Our results show that predator avoidance and immune function had clear costs in terms of reproduction and survival. Further, we show that increased levels of predator-avoidance behaviour reduced the snails' ability to defend against potential pathogens. Predator-avoidance behaviour may thus have the additional indirect cost of reduced immunocompetence and increased susceptibility to pathogens. Our results suggest that ecological factors (e.g. predator density) may considerably modify the expression and costs of immune defences.     

Characterisation of effector mechanisms at the host:parasite interface during the immune response to tissue-dwelling intestinal nematode parasites

The protective immune response that develops following infection with many tissue-dwelling intestinal nematode parasites is characterised by elevations in IL-4 and IL-13 and increased numbers of CD4+ T cells, granulocytes and macrophages. These cells accumulate at the site of infection and in many cases can mediate resistance to these large multicellular pathogens. Recent studies suggest novel potential mechanisms mediated by these immune cell populations through their differential activation and ability to stimulate production of novel effector molecules. These newly discovered protective mechanisms may provide novel strategies to develop immunotherapies and vaccines against this group of pathogens. In this review, we will examine recent studies elucidating mechanisms of host protection against three widely-used experimental murine models of tissue-dwelling intestinal nematode parasites: Heligmosomoides polygyrus, Trichuris muris and Trichinella spiralis.     

Innate immunity and adjuvants

Innate immunity was for a long time considered to be non-specific because the major function of this system is to digest pathogens and present antigens to the cells involved in acquired immunity. However, recent studies have shown that innate immunity is not non-specific, but is instead sufficiently specific to discriminate self from pathogens through evolutionarily conserved receptors, designated Toll-like receptors (TLRs). Indeed, innate immunity has a crucial role in early host defence against invading pathogens. Furthermore, TLRs were found to act as adjuvant receptors that create a bridge between innate and adaptive immunity, and to have important roles in the induction of adaptive immunity. This paradigm shift is now changing our thinking on the pathogenesis and treatment of infectious, immune and allergic diseases, as well as cancers. Besides TLRs, recent findings have revealed the presence of a cytosolic detector system for invading pathogens. I will review the mechanisms of pathogen recognition by TLRs and cytoplasmic receptors, and then discuss the roles of these receptors in the development of adaptive immunity in response to viral infection.     

Self-harm caused by an insect's innate immunity

It has been a long-held assumption that the innate immune system of insects causes self-harm when used to combat an immune insult. We show empirically that this assumption is correct. Invertebrate innate immunity relies heavily on effector systems which, on activation, produce cytotoxins that kill pathogens. Reliance on these robust, fast-acting, generic killing mechanisms ensures a potent and rapid response to pathogen invasion, but has the potential disadvantage of causing self-damage. We show that the innate immune response against an immune insult produces measurable phenotypic and functional damage to self-tissue in the beetle Tenebrio molitor. This type of self-harm (autoreactivity) and the life-history implications that arise from it are important to understand evolutionary phenomena such as the dynamics between hosts and parasites as well as the nature of immune system costs.