昆虫天然免疫相关基因研究进展

在长期进化过程中,昆虫形成了强大的天然免疫防御系统,即体液免疫和细胞免疫。体液免疫主要包括Toll、IMD和JAK/STAT 3条信号通路,通过信号转导及免疫途径调控免疫相关基因的表达,诱导产生抗菌肽和其他效应分子。细胞免疫由血细胞介导,主要完成对病原物的包裹、吞噬和集结等。近年来,昆虫基因组学快速发展,通过生物信息学等方法从昆虫基因组数据中已鉴定到大量免疫相关基因,对这些基因的研究加深了人们对昆虫天然免疫分子机制的认识和理解。根据基因功能,免疫相关基因分为识别、信号转导、调制器、效应分子、黑化反应、RNA干扰和其他基因等7类,这些基因通过互作来调控体液免疫和细胞免疫。本文对昆虫免疫相关基因的分类、功能及家族进化等方面的研究成果进行总结,并对今后昆虫免疫的研究重点进行了展望,以期为昆虫免疫分子机制的研究及开发新的害虫防治策略提供依据。     

Vitally important – does early innate immunity predict recruitment and adult innate immunity?

The immune system is one of the most important adaptations that has evolved to protect animals from a wide range of pathogens they encounter from early life onwards. During the early developmental period this is particularly true for the innate immunity, as other components of the immune system are, as yet, poorly developed. But innate immunity may not only be crucial for early life survival, but may also have long‐lasting effects, for example if early life immunity reflects the functioning of the immune system as a whole. For this reason, we investigated the importance of four constitutive innate immune parameters (natural antibodies, complement activity, concentrations of haptoglobin, and concentrations of nitric oxide) for recruitment in free‐living great tits. We compared nestling immunity of recruits with nestling immunity of their nonrecruited siblings. We also investigated within individual consistency of these innate immune parameters for those individuals that recruited, which may be taken as a measure of immune capacity. In accordance with previous studies, we found a clear effect of tarsus length and a trend for body mass on the likelihood to recruit. Nevertheless, we found no evidence that higher levels of constitutive innate immunity as a nestling facilitated local recruitment. Furthermore, individual innate immunity was not consistent across life stages, that is to say, nestling immune parameters did not determine, or respectively, reflect adult innate immune parameters. This plasticity in innate immune components may explain why we did not find long‐lasting survival benefits.     

Arsenic ecotoxicology and innate immunity

Understanding the ecotoxicological effects of arsenic in theenvironment is paramount to mitigating its deleterious effectson ecological and human health, particularly on the immune response.Toxicological and long-term health effects of arsenic exposurehave been well studied. Its specific effects on immune function,however, are less well understood. Eukaryotic immune functionoften includes both general (innate) as well as specific (adaptive)responses to pathogens. Innate immunity is thought to be theprimary defense during early embryonic development, subsequentlypotentiating adaptive immunity in jawed vertebrates, whereasall other eukaryotes must rely solely on the innate immune responsethroughout their life cycle. Here, we review the known ecotoxicologicaleffects of arsenic on general health, including immune function,and propose the adoption of zebrafish as a vertebrate modelfor studying such effects on innate immunity.     

Mitochondria in innate immune responses

The innate immune system has a key role in the mammalian immune response. Recent research has demonstrated that mitochondria participate in a broad range of innate immune pathways, functioning as signalling platforms and contributing to effector responses. In addition to regulating antiviral signalling, mounting evidence suggests that mitochondria facilitate antibacterial immunity by generating reactive oxygen species and contribute to innate immune activation following cellular damage and stress. Therefore, in addition to their well-appreciated roles in cellular metabolism and programmed cell death, mitochondria appear to function as centrally positioned hubs in the innate immune system. Here, we review the emerging knowledge about the roles of mitochondria in innate immunity.     

SOCS proteins, cytokine signalling and immune regulation

Suppressor of cytokine signalling (SOCS) proteins are inhibitors of cytokine signalling pathways. Studies have shown that SOCS proteins are key physiological regulators of both innate and adaptive immunity. These molecules positively and negatively regulate macrophage and dendritic-cell activation and are essential for T-cell development and differentiation. Evidence is also emerging of the involvement of SOCS proteins in diseases of the immune system. In this Review we bring together data from recent studies on SOCS proteins and their role in immunity, and propose a cohesive model of how cytokine signalling regulates immune-cell function.     

Cellular stress response and pulmonary inflammation

Innate immunity as the first line of the immune system, provides initial protection against various pathogens and infections. Recent studies suggest a link between cell stress response and immune response upon exogenous insults in the lung. The key proteins in cellular stress responses were demonstrated to be involved in the activation and regulation of the immune signaling pathways. Further research on the function of these stress proteins in innate immunity defenses, particularly in pulmonary diseases and inflammation may help to clarify the disease pathogenesis and provide potential therapeutic treatments for various infectious and inflammatory lung diseases.     

Seeing strangers or announcing "danger": galectin-3 in two models of innate immunity

Recent investigations on the molecular mechanisms by which our immune system recognizes infections and initiates defense against those infections have led to the proposition of two models explaining the way our innate immunity system functions; the self-nonself model and the Danger model. In this review, the roles of galectin-3 in innate immunity against infections--host-pathogen interactions--will be discussed. We will shed light on the potential contribution of a beta-galactoside binding mammalian lectin, galectin-3 as a molecule implicated in innate immunity from the angle of both the self-nonself model and the Danger model.     

Mathematical and Computational Modeling for Tumor Virotherapy with Mediated Immunity

We propose a new mathematical modeling framework based on partial differential equations to study tumor virotherapy with mediated immunity. The model incorporates both innate and adaptive immune responses and represents the complex interaction among tumor cells, oncolytic viruses, and immune systems on a domain with a moving boundary. Using carefully designed computational methods, we conduct extensive numerical simulation to the model. The results allow us to examine tumor development under a wide range of settings and provide insight into several important aspects of the virotherapy, including the dependence of the efficacy on a few key parameters and the delay in the adaptive immunity. Our findings also suggest possible ways to improve the virotherapy for tumor treatment.     

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.     

Double-stranded RNA induces sequence-specific antiviral silencing in addition to nonspecific immunity in a marine shrimp: convergence of RNA interference and innate immunity in the invertebrate antiviral response?

Double-stranded RNA (dsRNA) is a common by-product of viral infections and a potent inducer of innate antiviral immune responses in vertebrates. In the marine shrimp Litopenaeus vannamei, innate antiviral immunity is also induced by dsRNA in a sequence-independent manner. In this study, the hypothesis that dsRNA can evoke not only innate antiviral immunity but also a sequence-specific antiviral response in shrimp was tested. It was found that viral sequence-specific dsRNA affords potent antiviral immunity in vivo, implying the involvement of RNA interference (RNAi)-like mechanisms in the antiviral response of the shrimp. Consistent with the activation of RNAi by virus-specific dsRNA, endogenous shrimp genes could be silenced in a systemic fashion by the administration of cognate long dsRNA. While innate antiviral immunity, sequence-dependent antiviral protection, and gene silencing could all be induced by injection of long dsRNA molecules, injection of short interfering RNAs failed to induce similar responses, suggesting a size requirement for extracellular dsRNA to engage antiviral mechanisms and gene silencing. We propose a model of antiviral immunity in shrimp by which viral dsRNA engages not only innate immune pathways but also an RNAi-like mechanism to induce potent antiviral responses in vivo.     

Specificity and complexity of the Caenorhabditis elegans innate immune response

In response to infection, Caenorhabditis elegans produces an array of antimicrobial proteins. To understand the C. elegans immune response, we have investigated the regulation of a large, representative sample of candidate antimicrobial genes. We found that all these putative antimicrobial genes are expressed in tissues exposed to the environment, a position from which they can ward off infection. Using RNA interference to inhibit the function of immune signaling pathways in C. elegans, we found that different immune response pathways regulate expression of distinct but overlapping sets of antimicrobial genes. We also show that different bacterial pathogens regulate distinct but overlapping sets of antimicrobial genes. The patterns of genes induced by pathogens do not coincide with any single immune signaling pathway. Thus, even in this simple model system for innate immunity, striking specificity and complexity exist in the immune response. The unique patterns of antimicrobial gene expression observed when C. elegans is exposed to different pathogens or when different immune signaling pathways are perturbed suggest that a large set of yet to be identified pathogen recognition receptors (PRRs) exist in the nematode. These PRRs must interact in a complicated fashion to induce a unique set of antimicrobial genes. We also propose the existence of an "antimicrobial fingerprint," which will aid in assigning newly identified C. elegans innate immunity genes to known immune signaling pathways.     

Seeing strangers or announcing “danger”: Galectin-3 in two models of innate immunity

Recent investigations on the molecular mechanisms by which our immune system recognizes infections and initiates defense against those infections have led to the proposition of two models explaining the way our innate immunity system functions; the self-nonself model and the Danger model. In this review, the roles of galectin-3 in innate immunity against infections—host-pathogen interactions—will be discussed. We will shed light on the potential contribution of a β-galactoside binding mammalian lectin, galectin-3 as a molecule implicated in innate immunity from the angle of both the self-nonself model and the Danger model. Published in 2004.     

Regulators and signalling in insect antimicrobial innate immunity: Functional molecules and cellular pathways

Insects possess an immune system that protects them from attacks by various pathogenic microorganisms that would otherwise threaten their survival. Immune mechanisms may deal directly with the pathogens by eliminating them from the host organism or disarm them by suppressing the synthesis of toxins and virulence factors that promote the invasion and destructive action of the intruder within the host. Insects have been established as outstanding models for studying immune system regulation because innate immunity can be explored as an integrated system at the level of the whole organism. Innate immunity in insects consists of basal immunity that controls the constitutive synthesis of effector molecules such as antimicrobial peptides, and inducible immunity that is activated after detection of a microbe or its product(s). Activation and coordination of innate immune defenses in insects involve evolutionary conserved immune factors. Previous research in insects has led to the identification and characterization of distinct immune signalling pathways that modulate the response to microbial infections. This work has not only advanced the field of insect immunology, but it has also rekindled interest in the innate immune system of mammals. Here we review the current knowledge on key molecular components of insect immunity and discuss the opportunities they present for confronting infectious diseases in humans.     

Comparative Genomics RNAi Screen Identifies Eftud2 as a Novel Regulator of Innate Immunity

The extent of the innate immune response is regulated by many positively and negatively acting signaling proteins. This allows for proper activation of innate immunity to fight infection while ensuring that the response is limited to prevent unwanted complications. Thus mutations in innate immune regulators can lead to immune dysfunction or to inflammatory diseases such as arthritis or atherosclerosis. To identify novel innate immune regulators that could affect infectious or inflammatory disease, we have taken a comparative genomics RNAi screening approach in which we inhibit orthologous genes in the nematode Caenorhabditis elegans and murine macrophages, expecting that genes with evolutionarily conserved function also will regulate innate immunity in humans. Here we report the results of an RNAi screen of approximately half of the C. elegans genome, which led to the identification of many candidate genes that regulate innate immunity in C. elegans and mouse macrophages. One of these novel conserved regulators of innate immunity is the mRNA splicing regulator Eftud2, which we show controls the alternate splicing of the MyD88 innate immunity signaling adaptor to modulate the extent of the innate immune response.     

Sepsis: molecular mechanisms underlying lipopolysaccharide recognition

Sepsis is an often-fatal response of the immune system against microbial pathogens. The molecular mechanisms that have been designed to protect the host from invading pathogens are responsible for the damage and injury. It is now widely known that this crucial response of the immune system is mediated by innate immunity, which employs a plethora of pattern recognition receptors that recognise motifs expressed by pathogens. A lack of knowledge of the mediators involved in innate recognition has led to unsuccessful attempts at designing effective therapeutic interventions for sepsis. However, in recent years, great leaps forward have been achieved in our knowledge of these mediators. In this review we attempt to unravel the molecular mechanisms underlying bacterial recognition, particularly recognition of bacterial lipopolysaccharide, and we propose future potential therapeutic targets for septic shock.     

Innate recognition of malarial parasites by mammalian hosts

Innate immunity plays a central role in combating infections. However, the importance of innate immune sensors in detecting intracellular parasites, such as Plasmodium spp., has only recently emerged as a central topic in the field of host-pathogen interactions. Genetic dissection of innate immune pathways has uncovered a complex relationship between the host innate immune system and Plasmodium blood-stage parasites. In fact, recognition molecules of the innate immune system, such as toll-like receptors, might not only be implicated in host defense but also in the pathogenesis of the disease. Whether Plasmodium liver stage parasites are recognised and controlled by the host innate immune system remains to be discovered. In this review we discuss recent findings on how the host innate immune system may sense and fight the different forms of Plasmodium and how the latter may have evolved mechanisms to escape host detection and/or to manipulate the defensive reaction of the host.     

Phagosome as the organelle linking innate and adaptive immunity

The means by which phagocytosis and antimicrobial defense mechanisms are linked have expanded greatly in recent years. It is now clear that the process of phagocytosis does more than just degrade internalized microbes, but also helps coordinate the actions of the innate and adaptive immune system. This review will discuss the means by which Toll-like receptor signaling pathways are coordinated around the processes of phagocytosis, phagosome trafficking and autophagy and how these signaling pathways influence T-cell-mediated immunity. In this regard, we propose that at the subcellular level, phagosomes represent the smallest definable unit that links innate and adaptive immunity.     

Life is a huge compromise: Is the complexity of the vertebrate immune-neuroendocrine system an advantage or the price to pay?

Recent advances in comparative immunology have established that invertebrates produce hypervariable molecules probably related to immunity, suggesting the possibility of raising a specific immune response. “Priming” and “tailoring” are terms now often associated with the invertebrate innate immunity. Comparative immunologists contributed to eliminate the idea of a static immune system in invertebrates, making necessary to re-consider the evolutive meaning of immunological memory of vertebrates. If the anticipatory immune system represents a maximally efficient immune system, why can it be observed only in vertebrates, especially in consideration that molecular hypervariability exists also in invertebrates? Using well-established theories concerning the evolution of the vertebrate immunity as theoretical basis we analyze from an Eco-immunology-based perspective why a memory-based immune system may have represented an evolutive advantage for jawed vertebrates. We hypothesize that for cold-blooded vertebrates memory represents a complimentary component that flanks the robust and fundamental innate immunity. Conversely, immunological memory has become indispensable and fully exploited in warm-blooded vertebrates, due to their stable inner environment and high metabolic rate, respectively.     

The Plasmodium parasite--a 'new' challenge for insect innate immunity

Though lacking adaptive immunity, insects possess a powerful innate immune system, a genome-encoded defence machinery used to confront infections. Studies in the fruit fly Drosophila melanogaster revealed a remarkable capacity of the innate immune system to differentiate between and subsequently respond to different bacteria and fungi. However, hematophagous compared to non-hematophagous insects encounter additional blood-borne infectious agents, such as parasites and viruses, during their lifetime. Anopheles mosquitoes become infected with the malaria parasite Plasmodium during feeding on infected human hosts and may then transmit the parasite to new hosts during subsequent bites. Whether Anopheles has developed mechanisms to confront these infections is the subject of this review. Initially, we review our current understanding of innate immune reactions and give an overview of the Anopheles immune system as revealed through comparative genomic analyses. Then, we examine and discuss the capacity of mosquitoes to recognize and respond to infections, especially to Plasmodium, and finally, we explore approaches to investigate and potentially utilize the vector immune competence to prevent pathogen transmission. Such approaches constitute a new challenge for insect immunity research, a challenge for global health.     

Invariant NKT cells amplify the innate immune response to lipopolysaccharide

NKT cells are thought of as a bridge between innate and adaptive immunity. In this study, we demonstrate that mouse NKT cells are activated in response to Escherichia coli LPS, and produce IFN-gamma, but not IL-4, although activation through their TCR typically induces both IL-4 and IFN-gamma production. IFN-gamma production by NKT cells is dependent on LPS-induced IL-12 and IL-18 from APC. LPS induced IFN-gamma production by NKT cells does not require CD1d-mediated presentation of an endogenous Ag and exposure to a combination of IL-12 and IL-18 is sufficient to activate them. In mice that are deficient for NKT cells, innate immune cells are activated less efficiently in response to LPS, resulting in the reduced production of TNF and IFN-gamma. We propose that in addition to acting as a bridge to adaptive immunity, NKT cells act as an early amplification step in the innate immune response and that the rapid and complete initiation of this innate response depends on the early production of IFN-gamma by NKT cells.