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.     

Natural killer activity against human K562 tumour cells during Plasmodium cynomolgi malarial infection of rhesus monkeys

Abstract This study assessed the natural killer (NK) cell activity profile during Plasmodium cynomologi infection in rhesus monkeys. There was a significant decrease in the NK cell activity in the peripheral blood leukocytes of infected monkeys during the early, asending phase of infection. However, as the parasite load decreased, NK cell activity returned to normal levels. This could be correlated with the peak increase in lymphocyte counts. This indicated that a decrease in NK cell activity observed at an earlier stage during an active P. vivax malarial infection was a temporary phenomenon.     

Genetic analysis of innate immunity: TIR adapter proteins in innate and adaptive immune responses

The innate immune system senses pathogens largely through signals initiated by a collection of phylogenetically related proteins known as "Toll-like receptors" (TLRs), of which 10 representatives are encoded in the human genome. Our understanding of the sensing role played by the TLRs began with the positional cloning of a spontaneous mutation (Lps(d)) in the gene encoding the mammalian lipopolysaccharide (LPS) receptor. Other key innate immunity proteins have been disclosed by germline mutagenesis, and are discussed in the present review.     

Control of pathogens and microbiota by innate lymphoid cells

Innate lymphoid cells (ILCs) are the innate counterpart of T cells. Upon infection or injury, ILCs react promptly to direct the developing immune response to the one most adapted to the threat facing the organism. Therefore, ILCs play an important role early in resistance to infection, but also to maintain homeostasis with the symbiotic microbiota following perturbations induced by diet and pathogens. Such roles of ILCs have been best characterized in the intestine and lung, mucosal sites that are exposed to the environment and are therefore colonized with diverse but specific types of microbes. Understanding the dialogue between pathogens, microbiota and ILCs may lead to new strategies to re-inforce immunity for prevention, vaccination and therapy.     

抗病毒感染固有免疫应答的信号转导

入侵病毒的探知和适应性免疫应答启动均依靠固有免疫系统。三种模式识别受体(PRRs)在宿主防御系统第一线占据极其重要地位:Toll样受体、维甲酸诱导基因I样受体、核苷酸结合寡聚化结构域样受体。PRRs识别病原相关分子模式(PAMP)或危险信号分子模式(DAMPs)启动和调节固有免疫和适应性免疫应答。每种PRR都有单独的识别配体和细胞定位。激活的PRRs将信号分子传递给其配体分子(MyD88,TRIF,IRAK,IPS-1),配体活化后作为信使激活信号途径下游激酶(IKK复合物,MAPKs,TBK1,RIP-1)和转录因子(NF-κB,AP-1,IRF3),最终产生细胞因子、趋化因子、促炎细胞因子和I型干扰素。本文重点讨论PRRs信号通路及该领域取得的成果,以期为人类健康和免疫疾病防治提供策略。     

Hidden talents of natural killers: NK cells in innate and adaptive immunity

Natural killer (NK) cells are innate immune lymphocytes capable of killing target cells and producing immunoregulatory cytokines. Herein, we discuss recent studies that indicate that NK cells span the conventional boundaries between innate and adaptive immunity. For example, it was recently discovered that NK cells have the capacity for memory‐like responses, a property that was previously thought to be limited to adaptive immunity. NK cells have also been identified in multiple tissues, and a subset of cells that specialize in the production of the T_H17 cytokine IL‐22, NK‐22s, was recently described in mucosal‐associated lymphoid tissue. Finally, we review work that shows that NK cells develop at sites that were traditionally thought to be occupied only by adaptive immune cells, including the thymus and lymph nodes.     

Adaptation of macrophages to exercise training improves innate immunity

The effects of 3-week exercise training on the functions of peritoneal macrophages from BALB/c mice were investigated. Lipopolysaccharide (LPS)-stimulated nitric oxide (NO) and proinflammatory cytokine production in macrophages from trained mice was markedly higher than those from control mice. Meanwhile, exercise training decreased the steady state level of β₂-adrenergic receptor (β₂AR) mRNA in macrophages. Overexpression of β₂AR in the macrophage cell line RAW264 by transfecting with β₂AR cDNA suppressed NO synthase (NOS) II expression but dose not influenced proinflammatory cytokine expression. When expression of transfected β₂AR in RAWar cells was downregulated by a tetracycline repressor-regulated mammalian expression system, NOS II mRNA expression was significantly increased; this suggested that the changes in the β₂AR expression level in macrophages associated with exercise training play a role in the regulation of NO production following LPS stimulation. These findings indicate that exercise training improves macrophage innate immune function in a β₂AR-dependent and -independent manner.     

Cytokine synergy: An underappreciated contributor to innate anti-viral immunity

Inflammatory cytokines, such as tumor necrosis factor and the members of the interferon family, are potent mediators of the innate anti-viral immune response. The intracellular anti-viral states resulting from treatment of cultured cells with each of these molecules independently has been well studied; but, within complex tissues, the early inflammatory response is likely mediated by simultaneously expressed mixtures of these, and other, protective anti-viral cytokines. Such cytokine mixtures have been shown to induce potently synergistic anti-viral responses in vitro which are more complex than the simple summation of the individual cytokine response profiles. The physiological role of this ‘cytokine synergy’, however, remains largely unappreciated in vivo. This brief commentary will attempt to summarize the potential effects and mechanisms of anti-viral cytokine synergy as well as present several ‘real-world’ applications where this phenomenon might play an important role.     

Toll-like receptors and innate immunity

Toll-like receptors (TLRs) are evolutionarily conserved innate receptors expressed in various immune and non-immune cells of the mammalian host. TLRs play a crucial role in defending against pathogenic microbial infection through the induction of inflammatory cytokines and type I interferons. Furthermore, TLRs also play roles in shaping pathogen-specific humoral and cellular adaptive immune responses. In this review, we describe the recent advances in pathogen recognition by TLRs and TLR signaling.     

Styrax japonica supplementation diet enhances the innate immune response in Epinephelus bruneus against bacterial and protozoan infections

Kelp grouper, Epinephelus bruneus, fed for 30 days with 0% (control), 0.1%, 1.0%, and 2.0% of Styrax japonica supplementation diets, led to reductions in mortality after being challenged with a bacterium (Vibrio harveyi) and a ciliate protozoan (Uronema marinum). The enriched diets significantly increased the survival rate as compared to the controls. The phagocytic and respiratory activities were significantly increased in kelp groupers given 1.0% and 2.0% enriched diets. The complement activity, lysozyme activity, serum bactericidal activity, and total protein level significantly increased with any enriched diet against the pathogens; however antiprotease activity and myeloperoxidase levels significantly increased only with 1.0% and 2.0% enriched diets while the α2-macroglobulin level was significantly enhanced with 1.0% enriched diet. The study suggests that incorporation of S. japonica at 1.0% and 2.0% level in the diet significantly enhances the immune responses in the kelp grouper E. bruneus against V. harveyi and U. marinum.     

Human myeloperoxidase in innate and acquired immunity

Polymorphonuclear leukocytes (PMNs) are important players in innate and acquired immunity. These cells accumulate at inflammatory sites and contribute to host defence, regulation of the inflammatory process, and also to tissue injury. One of the key components of PMNs is the heme-containing enzyme myeloperoxidase (MPO) that is stored in large amount in azurophilic granules of resting cells. Here we review the (patho)physiological role of MPO from the viewpoint of participation of PMNs in immune reactions. Myeloperoxidase is able to catalyse a wide range of one- and two-electron substrate oxidations. With special products, MPO contributes to apoptosis induction in PMNs and other cells, and, thus, to termination of inflammatory response. On the other hand, MPO released from necrotic cells promotes an inflammation by further recruitment of PMNs, and chemical modification of proteins and other tissue constituents. Myeloperoxidase is a fascinating, multifunctional, and challenging enzyme that hasn’t yet revealed all its secrets.     

Gene expression in Plasmodium: from gametocytes to sporozoites

Completion of the complex developmental program of Plasmodium in the mosquito is essential for parasite transmission, yet this part of its life cycle is still poorly understood. In recent years, considerable progress has been made in the identification and characterization of genes expressed during parasite development in the mosquito. This line of investigation was greatly facilitated by the availability of the genome sequence of several Plasmodium, and by the application of approaches such as proteomics, microarrays, gene disruption by homologous recombination (gene knockout) and by use of subtraction libraries. Here, we review what is presently known about genes expressed in gametocytes and during the Plasmodium life cycle in the mosquito.     

Rapid recruitment of innate immunity regulates variation of intracellular pathogen resistance in Drosophila

Genetic variation in susceptibility to pathogens is a central concern both to medicine and agriculture and to the evolution of animals. Here, we have investigated the link between such natural genetic variation and the immune response in wild-type Drosophila melanogaster, a major model organism for immunological research. We found that within nine wild-type strains, different Drosophila genotypes show wide-ranging variation in their ability to survive infection from the pathogenic bacteria Listeria monocytogenes. Canton-S, a resistant strain, showed increased capacity to induce stronger innate immune activities (antimicrobial peptides (AMPs), phenol oxidase activity, and phagocytosis) compared to the susceptible strain (white) at early time points during bacterial infection. Moreover, PGRP-LE-induced innate immune activation immediately after infection greatly improves survival of the susceptible strain strongly suggesting a mechanism behind the natural genetic variation of these two strains. Taken together we provide the first experimental evidence to suggest that differences in innate immune activity at early time points during infection likely mediates infection susceptibility in Drosophila.     

Injection of xenogeneic cells into teleost fish elicits systemic and local cellular innate immune responses

The early innate immune response of the teleost gilthead seabream (Sparus aurata L.) against xenogeneic cells was studied. Fish received a single intraperitoneal injection of xenogeneic cells (tumour cell line), following which leucocyte mobilization, degranulation, peroxidase content, respiratory burst and phagocytic and cytotoxic activities were determined in both peritoneal exudate leucocytes (PELs) and head-kidney leucocytes (HKLs). The total number of PELs increased from 4 h post-injection until the end of the experiment (3 days). Interestingly, flow cytometric analysis of PEL and HKL suspensions revealed variations in the proportion of cell types. The percentage of HK acidophilic granulocytes significantly increased after 72 h, whereas PE acidophils increased after 4 h. Moreover, numbers of PE lymphocytes and monocyte-macrophages significantly increased during the experiment. The peroxidase content of the leucocytes was unaffected, although PEL degranulation was largely enhanced. This liberation of peroxidases correlated well with the enhancement of the oxidative respiratory burst activity in PELs, reflecting leucocyte activation. However, phagocytosis only increased in PELs 4 h after intraperitoneal injection, whereas the cytotoxic activity of HKLs increased 1 and 2 days post-injection but, in general, decreased in the PELs. Our data thus demonstrate that the appearance of xenogeneic cells involves leucocyte mobilization and innate immune-response activation at the site of invasion and in the head-kidney. Involvement of the various leucocyte types and potential modes of activation are discussed.This work was partially funded by the European Commission (QLRT-2001-00722). A. Cuesta and I. Salinas are fellows of Fundación CajaMurcia and Fundación Séneca, respectively.     

自然杀伤T细胞抗胞内菌感染的研究进展

自然杀伤T细胞(NKT细胞)是免疫细胞中一类具有特定标记的T细胞亚群,能特异性识别南抗原呈递细胞表面CD1d分子所呈递的糖脂类抗原.活化后的NKT细胞能分泌多种细胞因子,参与机体的天然免疫和获得性免疫反应,还能直接杀伤靶细胞,具有效应细胞的功能.研究发现,NKT细胞在抗胞内菌感染中发挥着重要作用.     

Chemokines provide the sustained inflammatory bridge between innate and acquired immunity

In this review we focus on the role of chemokines in discreet areas of innate immunity and demonstrate that chemokines are key participants to not only the early inflammatory response to a foreign agent, but important to the sustained immune reaction. Our studies support the concept that a concerted and interactive innate and acquired immune reaction is key for an automatic, dynamic, sustained, and regulated response toward clearing foreign stimuli. It is imperative that the in vivo concept of innate and acquired immunity be considered a continuum of a global assault on a foreign agent and not as modes, which are independent of one another.     

Alternative pathways driven by STING: From innate immunity to lipid metabolism

The Stimulator of Interferon Genes (STING) is a major adaptor protein that is central to the initiation of type I interferon responses and proinflammatory signalling. STING-dependent signalling is triggered by the presence of cytosolic nucleic acids that are generated following pathogen infection or cellular stress. Beyond this central role in controlling immune responses through the production of cytokines and chemokines, recent reports have uncovered inflammation-independent STING functions. Amongst these, a rapidly growing body of evidence demonstrates a key role of STING in controlling metabolic pathways at several levels. Since immunity and metabolic homeostasis are tightly interconnected, these findings deepen our understanding of the involvement of STING in human pathologies. Here, we discuss these findings and reflect on their impact on our current understanding of how nucleic acid immunity controls homeostasis and promotes pathological outcomes.     

肠道病毒71型与天然免疫系统相互作用的研究进展

肠道病毒71型(enterovirus 71,EV71)为小RNA病毒科肠道病毒属成员,是引起手足口病的主要病原体之一。EV71流行广泛,其感染可引发中枢神经系统疾病,并造成重症手足口病,给公共卫生安全带来极大挑战。EV71的致病机制与病毒和宿主天然免疫系统的相互作用关系密切,涉及病毒逃逸干扰素反应、病毒抑制核因子κB(nuclear factorκB,NF-κB)信号通路及病毒与天然免疫细胞相互作用等多个环节。本文就近年来EV71与宿主天然免疫系统相互作用的研究进展进行综述。     

Natural killer cell exhaustion in SARS-CoV-2 infection

At the end of 2019, an outbreak of a severe respiratory disease occurred in Wuhan China, and an increase in cases of unknown pneumonia was alerted. In January 2020, a new coronavirus named SARS-CoV-2 was identified as the cause. The virus spreads primarily through the respiratory tract, and lymphopenia and cytokine storms have been observed in severely ill patients. This suggests the existence of an immune dysregulation as an accompanying event during a serious illness caused by this virus. Natural killer (NK) cells are innate immune responders, critical for virus shedding and immunomodulation. Despite its importance in viral infections, the contribution of NK cells in the fight against SARS-CoV-2 has yet to be deciphered. Different studies in patients with COVID-19 suggest a significant reduction in the number and function of NK cells due to their exhaustion. In this review, we summarize the current understanding of how NK cells respond to SARS-CoV-2 infection.