Linking immune defenses and life history at the levels of the individual and the species

Immune defenses have been suggested to play an important rolein mediating life history trade-offs. Detecting and understandingsuch trade-offs, however, is complicated by the complexity ofthe immune system. The measurement of multiple immune indicesin studies of "eco-immunology" has only recently become morecommon, but has great potential for furthering an understandingof the ecological and evolutionary forces driving immunologicalvariation. Building on previous proposals, I create a frameworkintegrating immunological and life history axes that can beused to formulate predictions and interpret variation in multipletypes of immune defense at both the individual and species levelsin vertebrates. In particular, this framework predicts that"fast-living" species (those with high reproductive and lowsurvival rates) should rely more heavily on nonspecific andinflammatory immune defenses, while "slow-living" species shouldexhibit stronger specific and especially antibody-mediated immunity.At the level of individuals within species, nonspecific andinflammatory responses should be downregulated, and specificdefenses upregulated (1) in individuals experiencing the greatestdemands on their resources (for example, undertaking large reproductiveefforts); (2) in the sex investing more in a particular activity(for example, females during reproduction); and (3) during themost demanding periods of the year (for example, the breedingseason). A review of the literature reveals that incorporatingmultiple facets of the immune system into a model of the relationshipbetween immune defense and life histories brings disparate questionsand systems into a common context, and helps explain empiricalresults that are sometimes counterintuitive.     

The Complex Contributions of Genetics and Nutrition to Immunity in Drosophila melanogaster

Both malnutrition and undernutrition can lead to compromised immune defense in a diversity of animals, and “nutritional immunology” has been suggested as a means of understanding immunity and determining strategies for fighting infection. The genetic basis for the effects of diet on immunity, however, has been largely unknown. In the present study, we have conducted genome-wide association mapping in Drosophila melanogaster to identify the genetic basis for individual variation in resistance, and for variation in immunological sensitivity to diet (genotype-by-environment interaction, or GxE). D. melanogaster were reared for several generations on either high-glucose or low-glucose diets and then infected with Providencia rettgeri, a natural bacterial pathogen of D. melanogaster. Systemic pathogen load was measured at the peak of infection intensity, and several indicators of nutritional status were taken from uninfected flies reared on each diet. We find that dietary glucose level significantly alters the quality of immune defense, with elevated dietary glucose resulting in higher pathogen loads. The quality of immune defense is genetically variable within the sampled population, and we find genetic variation for immunological sensitivity to dietary glucose (genotype-by-diet interaction). Immune defense was genetically correlated with indicators of metabolic status in flies reared on the high-glucose diet, and we identified multiple genes that explain variation in immune defense, including several that have not been previously implicated in immune response but which are confirmed to alter pathogen load after RNAi knockdown. Our findings emphasize the importance of dietary composition to immune defense and reveal genes outside the conventional “immune system” that can be important in determining susceptibility to infection. Functional variation in these genes is segregating in a natural population, providing the substrate for evolutionary response to pathogen pressure in the context of nutritional environment.     

Models of T cell deficiency in listeriosis: the effects of cortisone and cyclosporin A on normal and nude BALB/c mice

It is often difficult to test the role of T lymphocytes in resistance to infection because most models of T cell deficiency are associated with altered nonspecific resistance. In an attempt to address this problem, we compared the effects of cyclosporin A (CyA), cortisone (CA), and the athymic state on the course of murine listeriosis. We chose listeriosis because resistance to Listeria monocytogenes occurs in two phases. Bacterial multiplication is controlled by nonspecific defense mechanisms in the early phase and by acquired T cell-dependent immunity in the second phase. Mice treated with CA died during the early phase, probably because of inhibition of the antimicrobial activity of nonimmune macrophages. Accordingly, the immunosuppressive effect of CA was similar in athymic and normal mice. Untreated nude mice developed chronic low grade infection, probably because of heightened activity of nonimmune macrophages. In contrast, immunosuppression with CyA did not affect early resistance but induced overwhelming, fatal disease in the later phase when control mice began to acquire resistance. CyA did not change the course of listeriosis in nude mice, confirming its specificity for T cell-dependent immunity. Thus, this study shows that CyA is a potent and specific inhibitor of T cell-mediated immunity and that T cell-dependent resistance is essential for survival from listeriosis, a conclusion that could not have been established by studies of the nude mouse or immunosuppression by CA.     

Contribution of the Argonaute-1 Isoforms to Invertebrate Antiviral Defense

Argonaute (Ago) protein, the central component of the RNA interference (RNAi) pathway, plays important roles in host innate antiviral immunity. Most organisms harbor a large number of different Ago proteins and isoforms; however, the roles of Ago isoforms in immune defense against pathogens remain unclear. In the present study, three Argonaute-1 (Ago1) isoforms, termed Ago1A, Ago1B, and Ago1C, were found in Marsupenaeus japonicus shrimp. Quantitative real-time PCR (polymerase chain reaction) revealed that isoforms Ago1A and Ago1B containing an insertion sequence in the PIWI domain, were significantly up-regulated in lymphoid organ and hemolymph, and also upon white spot syndrome virus (WSSV) challenge, indicating the involvement of Ago1A and Ago1B in antiviral immunity. The results showed that silencing of Ago1A with a sequence-specific siRNA led to a significant increase of WSSV loads. It was revealed that knockdown of Ago1B mRNA by 37–70% resulted in higher virus loads in shrimp. However, upon silencing Ago1B by more than 85%, a two-fold increase in Ago1A mRNA was observed but viral load was the same as untreated controls challenged with WSSV, suggesting that the simultaneous up-regulation of Ago1A might compensate for the loss of Ago1B. These data indicated that Ago1A played more important roles in the antiviral immune response than Ago1B. The simultaneous inhibition of Ago1A and Ago1B resulted in a greater increase in viral loads than Ago1A or Ago1B alone, indicating that Ago1A and Ago1B isoforms were involved in shrimp antiviral immunity. It was revealed that Ago1C had no effect on virus infection. Therefore, the current study presented the first report on the contribution of Ago isoforms in the invertebrate defense against virus infection.     

Fungal Pathogens: The Battle for Plant Infection

The attempted infection of a plant by a pathogen, such as a fungus or an Oomycete, may be regarded as a battle whose major weapons are proteins and smaller chemical compounds produced by both organisms. Indeed, plants produce an astonishing plethora of defense compounds that are still being discovered at a rapid pace. This pattern arose from a multi-million year, ping-pong?type co-evolution, in which plant and pathogen successively added new chemical weapons in this perpetual battle. As each defensive innovation was established in the host, new ways to circumvent it evolved in the pathogen. This complex co-evolution process probably explains not only the exquisite specificity observed between many pathogens and their hosts, but also the ineffectiveness or redundancy of some defensive genes which often encode enzymes with overlapping activities. Plants evolved a complex, multi-level series of structural and chemical barriers that are both constitutive or preformed and inducible. These defenses may involve strengthening of the cell wall, hypersensitive response (HR), oxidative burst, phytoalexins and pathogenesis-related (PR) proteins. The pathogen must successfully overcome these obstacles before it succeeds in causing disease. In some cases, it needs to modulate or modify plant cell metabolism to its own benefit and/or to abolish defense reactions. Central to the activation of plant responses is timely perception of the pathogen by the plant. A crucial role is played by elicitors which, depending on their mode of action, are broadly classified into nonspecific elicitors and highly specific elicitors or virulence effector/avirulence factors. A protein battle for penetration is then initiated, marking the pathogen attempted transition from extracellular to invasive growth before parasitism and disease can be established. Three major types of defense responses may be observed in plants: non-host resistance, host resistance, and host pathogenesis. Plant innate immunity may comprise a continuum from non-host resistance involving the detection of general elicitors to host-specific resistance involving detection of specific elicitors by R proteins. It was generally assumed that non-host resistance was based on passive mechanisms and that nonspecific rejection usually arose as a consequence of the non-host pathogen failure to breach the first lines of plant defense. However, recent evidence has blurred the clear-cut distinction among non-host resistance, host-specific resistance and disease. The same obstacles are also serious challenges for host pathogens, reducing their success rate significantly in causing disease. Indeed, even susceptible plants mount a (insufficient) defense response upon recognition of pathogen elicited molecular signals. Recent evidence suggests the occurrence of significant overlaps between the protein components and signalling pathways of these types of resistance, suggesting the existence of both shared and unique features for the three branches of plant innate immunity.     

Concept of inducing of rapid immunological protection against pathogens

Concept of construction of new type of vaccines for inducing rapid nonspecific immunological protection against pathogens by activation of innate immunity mechanisms has been formulated. Materials about formula of the concept, theses of theory of innate immunity, and experimental and clinical data, which confirm the concept, are presented. Results of studies with recombinant proinflammatorycytokines and synthetic ligands for Toll-like receptors as well as with polycomponent vaccine containing antigens of opportunistic bacteria (Immunovac VP-4) are also presented. Obtained data allowed to assume that activation of innate immunity mechanisms by preparations carrying pathogen-associated and molecular structures of microorganisms can result in formation of rapid and nonspecific protection against any pathogen.     

唾液和泪液中主要黏蛋白MUC5B和MUC7协同互补功能

黏蛋白家族中MUC5B和MUC7是人体唾液和泪液中的两种主要黏蛋白成分,早期被认为在非特异性免疫应答、黏液构成以及组织功能的维护等方面发挥作用。近年来,它们的一些新功能如抗HIV、协助非黏蛋白功能的发挥等作用逐渐被发现,故其生理和病理意义也因传统观念的修正而得到扩充。由于MUC5B和MUC7在唾液和泪液中的存在方式并不完全相同,对它们在不同环境条件下功能的相似性、差异性和互补性的研究,具有重要的现实意义。     

Helminthic host defense peptides: using the parasite to defend the host

Parasitic helminths are destined to share niches with a variety of microbiota that inevitably influence their interaction with the host. To modulate the microbiome for their benefit and defend against pathogenic isolates, helminths have developed host defense peptides (HDPs) and proteins as integral elements of their immunity. These often exert a relatively nonspecific membranolytic activity toward bacteria, sometimes with limited or no toxicity toward host cells. With a few exceptions, such as nematode cecropin-like peptides and antibacterial factors (ABFs), helminthic HDPs are largely underexplored. This review scrutinizes current knowledge on the repertoire of such peptides in helminths and promotes their research as potential leads for an anti-infective solution to the burgeoning problem of antibiotic resistance.     

Mechanism of the nonspecific protective action of Shigella antigens

The mechanism promoting the nonspecific action of antigens obtained from S. flexneri and S. sonnei by a sparing method has been studied. These antigens stimulate the T- and B- systems of immunity, that is followed by activation of myelopoiesis and the humoral protective factors of the body, which seems to underlie the formation of resistance to infection caused by nonspecific microorganisms.     

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。     

The immunocorrective effect of laser reflexotherapy in experimental influenza infection

The influence of two schemes of laser acupuncture on some cell-mediated and humoral immunity characteristics of mice, as well as on their nonspecific antiviral resistance, in acute experimental influenza infection has been studied. The use of both schemes has been found to considerably decrease the severity of infection, enhancing the activity of lymphocytes of infected mice in the graft versus host reaction, the O2-producing activity of alveolar macrophages and modulating the ratio of antihemagglutinins and nonspecific antiviral inhibitors in the blood serum.     

Cutting edge: Role of C-C chemokine receptor 5 in organ-specific and innate immunity to Cryptococcus neoformans.

After intratracheal inoculation of the AIDS-associated pathogen Cryptococcus neoformans, 12-wk survival was >90% for CCR5+/+ mice but <25% for CCR5-/- mice. There were no defects in lung leukocyte recruitment (wk 5), pulmonary clearance, or delayed-type hypersensitivity in CCR5-/- mice. However, CCR5-/- mice had defects in leukocyte recruitment into the brain and, strikingly, in elimination of cryptococcal polysaccharide from the brain. In nonimmune CCR5-/- mice, there was a significant defect in macrophage recruitment after challenge with shed cryptococcal products (C. neoformans filtrate Ag) but not other nonspecific stimuli. Thus, CCR5 plays specific roles in innate immunity and organ-specific leukocyte trafficking during host defense against C. neoformans.     

Complex surveillance of streptococcus pyogenes. VI. Relationship between hypersensitivity to zymosan and indicators of immunity against group A streptococci

A prospective study involving 20 volunteers was designed to test relationships between the sensitivity to zymosan and the indicators of nonspecific immunity against streptococci (inhibitory activity of blood and production of mediators). The immunization with Mannozym produced a conversion of zymosan-induced MIF with a subsequent improvement of immunity indicators in 4 out of 7 primovaccinated and 2 revaccinated subjects. This effect was detectable in some vaccines within 2-4 days after immunization and persisted for up to 5 months. Initially detected changes, their kinetics in the vaccinated subjects as well as time-related variations in the pattern of indicators during a one-year period of observation seem to suggest that there was a relationship between the natural and induced cellular sensitivity to zymosan and the inhibitory activity of blood. The inhibitory activity of blood was effectuated through enhanced mediator-induced phagocytic activity and nonspecific opsonin mechanisms. The mediators fluctuated in their values with time and were demonstrable in immunized subjects. There were observed interlinked reactions of cellular immunity with zymosan, peptidoglycan and streptococci. The mechanisms found are believed to constitute a fundamental, relatively easy-to-stimulate means of human immunity which may explain the experimental and epidemiological inconsistencies in the strictly type-specific interpretation of the M - anti-M system. Under in vitro conditions the effect of nonspecific immunization was bacteriostatic, but the role of these nonspecific mechanisms under conditions in vivo remains unclear. It is recommended that effectiveness of nonspecific immunization be verified under conditions of natural infection in man.     

益气补肾方药对化疗荷瘤小鼠免疫功能的影响

目的　探讨益气补肾方药 (由金匮肾气方加味人参、黄芪组成 ,以下均称方药 ,TS)对环磷酰胺 (CY)处理的荷H2 2 瘤小鼠非特异免疫功能的影响。方法　用CY处理荷H2 2 瘤小鼠 ,建立免疫力低下动物模型。用乳酸脱氢酶 (LDH)释放法分别检测NK细胞、巨噬细胞 (M)的活性 ,用RT PCR法检测白细胞介素 12 (IL 12 )mRNA在脾脏细胞中的表达。结果　TS CY组小鼠吸光度A值为 1 332± 0 5 10 ,明显高于CY组小鼠 (P <0 0 1)。TS CY组小鼠A值为 1 12 9± 0 2 80 ,明显高于CY组小鼠 (P <0 0 1)。此方药能明显提高CY所致免疫力低下小鼠NK细胞、M的活性 ,增加IL 12在脾细胞中的表达。结论　该方药可以明显提高环磷酰胺所致免疫力低下荷瘤小鼠的非特异免疫功能。     

Serum progranulin levels are elevated in patients with chronic hepatitis B virus infection,reflecting viral load

Progranulin (PGRN) is implicated in infection, immunity and host defense, but its role in the pathogenesis of HBV infection remains unknown. Here we investigated whether there is dysregulated production and the clinical significance of circulating PGRN in patients with chronic HBV infection. Serum concentrations of PGRN were analyzed by enzyme-linked immunosorbent assay. Serum PGRN levels were significantly higher in patients with chronic HBV infection than healthy subjects. PGRN levels were significantly associated with HBV-DNA levels, but did not correlate with the concentrations of alanine aminotransferase and aspartate aminotransferase. This study demonstrates increased circulating PGRN production and association between PGRN levels and viral loads in patients with chronic HBV infection, suggesting a functional role of PGRN in the pathogenesis of HBV infection.     

植物与病原微生物互作分子基础的研究进展

植物在与病原微生物共同进化过程中形成了复杂的免疫防卫体系。植物的先天免疫系统可大致分为两个层面。第一个层面的免疫基于细胞表面的模式识别受体对病原物相关分子模式的识别,该免疫过程被称为病原物相关分子模式触发的免疫(PAMP-triggered immunity,PTI),能帮助植物抵抗大部分病原微生物;第二个层面的免疫起始于细胞内部,主要依靠抗病基因编码的蛋白产物直接或间接识别病原微生物分泌的效应子并且激发防卫反应,来抵抗那些能够利用效应子抑制第一层面免疫的病原微生物,这一过程被称为效应子触发的免疫(Effector-triggered immunity,ETI)。这两个层面的免疫都是基于植物对"自我"及"非我"的识别,依靠MAPK级联等信号网络,将识别结果传递到细胞核内,调控相应基因的表达,做出适当的免疫应答。本文着重阐述了植物与病原微生物互作过程中不同层面的免疫反应所发生主要事件的分子基础及研究进展。     

植物与病原微生物互作分子基础的研究进展

植物在与病原微生物共同进化过程中形成了复杂的免疫防卫体系。植物的先天免疫系统可大致分为两个层面。第一个层面的免疫基于细胞表面的模式识别受体对病原物相关分子模式的识别, 该免疫过程被称为病原物相关分子模式触发的免疫(PAMP-triggered immunity, PTI), 能帮助植物抵抗大部分病原微生物; 第二个层面的免疫起始于细胞内部, 主要依靠抗病基因编码的蛋白产物直接或间接识别病原微生物分泌的效应子并且激发防卫反应, 来抵抗那些能够利用效应子抑制第一层面免疫的病原微生物, 这一过程被称为效应子触发的免疫(Effector-triggered immunity, ETI)。这两个层面的免疫都是基于植物对“自我”及“非我”的识别, 依靠MAPK级联等信号网络, 将识别结果传递到细胞核内, 调控相应基因的表达, 做出适当的免疫应答。本文着重阐述了植物与病原微生物互作过程中不同层面的免疫反应所发生主要事件的分子基础及研究进展。