IL-12 and Viral Infections

Interleukin-12 activates natural killer cells and promotes the differentiation of Th1 CD4+ cells; it is a critical factor in viral immunity. IL-12 is secreted by antigen presenting cells including dendritic cells, macrophages and astrocytes, both in tissues and in secondary lymphoid organs. Experimental studies have shown that administration of the cytokine rapidly activates both innate and specific immune responses; this results in enhanced host cellular responses and generally, promotes clearance of virus and host recovery from infection. The observations of many laboratories, studying viral immunity to both RNA and DNA based pathogens, are summarized.     

Differences in signalling by directly and indirectly binding ligands in bacterial chemotaxis

In chemotaxis of Escherichia coli and other bacteria, extracellular stimuli are perceived by transmembrane receptors that bind their ligands either directly, or indirectly through periplasmic‐binding proteins (BPs). As BPs are also involved in ligand uptake, they provide a link between chemotaxis and nutrient utilization by cells. However, signalling by indirectly binding ligands remains much less understood than signalling by directly binding ligands. Here, we compared intracellular responses mediated by both types of ligands and developed a new mathematical model for signalling by indirectly binding ligands. We show that indirect binding allows cells to better control sensitivity to specific ligands in response to their nutrient environment and to coordinate chemotaxis with ligand transport, but at the cost of the dynamic range being much narrower than for directly binding ligands. We further demonstrate that signal integration by the chemosensory complexes does not depend on the type of ligand. Overall, our data suggest that the distinction between signalling by directly and indirectly binding ligands is more physiologically important than the traditional distinction between high‐ and low‐abundance receptors.     

Importance of extra- and intracellular domains of TLR1 and TLR2 in NFkappa B signaling

Recognition of ligands by toll-like receptor (TLR) 2 requires interactions with other TLRs. TLRs form a combinatorial repertoire to discriminate between the diverse microbial ligands. Diversity results from extracellular and intracellular interactions of different TLRs. This paper demonstrates that TLR1 and TLR2 are required for ara-lipoarabinomannan- and tripalmitoyl cysteinyl lipopeptide-stimulated cytokine secretion from mononuclear cells. Confocal microscopy revealed that TLR1 and TLR2 cotranslationally form heterodimeric complexes on the cell surface and in the cytosol. Simultaneous cross-linking of both receptors resulted in ligand-independent signal transduction. Using chimeric TLRs, we found that expression of the extracellular domains along with simultaneous expression of the intracellular domains of both TLRs was necessary to achieve functional signaling. The domains from each receptor did not need to be contained within a single contiguous protein. Chimeric TLR analysis further defined the toll/IL-1R domains as the area of crucial intracellular TLR1-TLR2 interaction.     

A dual role for proline iminopeptidase in the regulation of bacterial motility and host immunity

During plant–pathogen interactions, pathogenic bacteria have evolved multiple strategies to cope with the sophisticated defence systems of host plants. Proline iminopeptidase (PIP) is essential to Xanthomonas campestris pv. campestris (Xcc) virulence, and is conserved in many plant‐associated bacteria, but its pathogenic mechanism remains unclear. In this study, we found that disruption of pip in Xcc enhanced its flagella‐mediated bacterial motility by decreasing intracellular bis‐(3′,5′)‐cyclic dimeric guanosine monophosphate (c‐di‐GMP) levels, whereas overexpression of pip in Xcc restricted its bacterial motility by elevating c‐di‐GMP levels. We also found that PIP is a type III secretion system‐dependent effector capable of eliciting a hypersensitive response in non‐host, but not host plants. When we transformed pip into the host plant Arabidopsis, higher bacterial titres were observed in pip‐overexpressing plants relative to wild‐type plants after Xcc inoculation. The repressive function of PIP on plant immunity was dependent on PIP's enzymatic activity and acted through interference with the salicylic acid (SA) biosynthetic and regulatory genes. Thus, PIP simultaneously regulates two distinct regulatory networks during plant–microbe interactions, i.e. it affects intracellular c‐di‐GMP levels to coordinate bacterial behaviour, such as motility, and functions as a type III effector translocated into plant cells to suppress plant immunity. Both processes provide bacteria with the regulatory potential to rapidly adapt to complex environments, to utilize limited resources for growth and survival in a cost‐efficient manner and to improve the chances of bacterial survival by helping pathogens to inhabit the internal tissues of host plants.     

The reactive oxygen species network pathways: an essential prerequisite for perception of pathogen attack and the acquired disease resistance in plants

Availability of complete Arabidopsis(Arabidopsis thaliana) and rice(Oryza sativa) genome sequences, together with molecular recourses of functional genomics and proteomics have revolutionized our understanding of reactive oxygen species (ROS) signalling network mediating disease resistance in plants. So far, ROS have been associated with aging, cellular and molecular alteration in animal and plant cells. Recently, concluding evidences suggest that ROS network is essential to induce disease resistance and even to mediate resistance to multiple stresses in plants. ROS are obligatory by-products emerging as a result of normal metabolic reactions. They have the potential to be both beneficial and harmful to cellular metabolism. Their dual effects on metabolic reactions are dosage specific. In this review we focus our attention on cellular ROS level to trigger beneficial effects on plant cells responding to pathogen attack. By exploring the research related contributions coupled with data of targeted gene disruption, and RNA interference approaches, we show here that ROS are ubiquitous molecules of redox-pathways that play a crucial role in plant defence mechanism. The molecular prerequisites of ROS network to activate plant defence system in response to pathogen infections are here underlined. Bioinformatic tools are now available to scientists for high throughput analysis of cellular metabolisms. These tools are used to illustrate crucial ROS-related genes that are involved in the defence mechanism of plants. The review describes also the emerging findings of ROS network pathways to modulate multiple stress resistance in plants.     

Mycobacteria and innate cells: critical encounter for immunogenicity

Protective immunity against mycobacterial infections such as Mycobacterium tuberculosis is mediated by interactions between specific T cells and activated macrophages.To date,many aspects of mycobacterial immunity have shown that innate cells are the key elements that substantially influence the subsequent adaptive host response.During the early phases of infection,phagocytic cells and innate lymphocyte subsets play a pivotal role.Here we summarize the findings of recent investigations on macrophages,dendritic cells and gammadelta T lymphocytes in the response to mycobacteria.     

植物的蓝光受体及其信号转导

近年来,对拟南芥及其它植物的分子遗传研究,在隐花色素和向光素的分子、基因和蓝光信号转导方面取得了显著进展。本文就这两种蓝光受体的基本结构及蓝光信号转导进行介绍。     

Hantavirus infections in fluctuating host populations: the role of maternal antibodies

Infected females may transfer maternal antibodies (MatAbs) to their offspring, which may then be transiently protected against infections the mother has encountered. However, the role of maternal protection in infectious disease dynamics in wildlife has largely been neglected. Here, we investigate the effects of Puumala hantavirus (PUUV)-specific MatAbs on PUUV dynamics, using 7 years'' data from a cyclic bank vole population in Finland. For the first time to our knowledge, we partition seropositivity data from a natural population into separate dynamic patterns for MatAbs and infection. The likelihood of young of the year carrying PUUV-specific MatAbs during the breeding season correlated positively with infection prevalence in the overwintered parent population in the preceding spring. The probability of PUUV infection varied between seasons (highest in spring, lowest in late summer) and depended on population structure, but was also, in late autumn, notably, negatively related to summer MatAb prevalence, as well as to infection prevalence earlier in the breeding season. Hence, our results suggest that high infection prevalence in the early breeding season leads to a high proportion of transiently immune young individuals, which causes delays in transmission. This suggests, in turn, that MatAb protection has the potential to affect infection dynamics in natural populations.     

Association and dissociation kinetics for CheY interacting with the P2 domain of CheA

The chemotaxis system of Escherichia coli makes use of an extended two-component sensory response pathway in which CheA, an autophosphorylating protein histidine kinase (PHK) rapidly passes its phosphoryl group to CheY, a phospho-accepting response regulator protein (RR). The CheA-->CheY phospho-transfer reaction is 100-1000 times faster than the His-->Asp phospho-relays that operate in other (non-chemotaxis) two-component regulatory systems, suggesting that CheA and CheY have unique features that enhance His-->Asp phospho-transfer kinetics. One such feature could be the P2 domain of CheA. P2 encompasses a binding site for CheY, but an analogous RR-binding domain is not found in other PHKs. In previous work, we removed P2 from CheA, and this decreased the catalytic efficiency of CheA-->CheY phospho-transfer by a factor of 50-100. Here we examined the kinetics of the binding interactions between CheY and P2. The rapid association reaction (k(assn) approximately 10(8)M(-1)s(-1) at 25 degrees C and micro=0.03 M) exhibited a simple first-order dependence on P2 concentration and appeared to be largely diffusion-limited. Ionic strength (micro) had a moderate effect on k(assn) in a manner predictable based on the calculated electrostatic interaction energy of the protein binding surfaces and the expected Debye-Hückel shielding. The speed of binding reflects, in part, electrostatic interactions, but there is also an important contribution from the inherent plasticity of the complex and the resulting flexibility that this allows during the process of complex formation. Our results support the idea that the P2 domain of CheA contributes to the overall speed of phospho-transfer by promoting rapid association between CheY and CheA. However, this alone does not account for the ability of the chemotaxis system to operate much more rapidly than other two-component systems: k(cat) differences indicate that CheA and CheY also achieve the chemical events of phospho-transfer more rapidly than do PHK-RR pairs of slower systems.     

Role of the JAK/STAT signal transduction pathway in the regulation of gene expression in CNS

Over the last 20 years the JAK/STAT signal transduction pathway has been extensively studied. An enormous amount of data on different cell signal transduction pathways is now available. The JAK/STAT signal transduction pathway is one of the intracellular signaling pathways activated by cytokines and growth factors that was first studied in the hematopoietic system, but recent data demonstrate that this signal transduction is also greatly utilized by other systems. The JAK/STAT pathway is a signaling cascade that links the activation of specific cell membrane receptors to nuclear gene expression. This review is focused on the role of JAK/STAT signal transduction pathway activation in the central nervous system (CNS).     

A new genetic model for calcium induced autophagy and ER-stress in Drosophila photoreceptor cells

Cytoplasmic Ca²⁺ overload is known to trigger autophagy and ER-stress. Furthermore, ER-stress and autophagy are commonly associated with degenerative pathologies, but their role in disease progression is still a matter of debate, in part, owing to limitations of existing animal model systems. The Drosophila eye is a widely used model system for studying neurodegenerative pathologies. Recently, we characterized the Drosophila protein, Calphotin, as a cytosolic immobile Ca²⁺ buffer, which participates in Ca²⁺ homeostasis in Drosophila photoreceptor cells. Exposure of calphotin hypomorph flies to continuous illumination, which induces Ca²⁺ influx into photoreceptor cells, resulted in severe Ca²⁺-dependent degeneration. Here we show that this degeneration is autophagy and ER-stress related. Our studies thus provide a new model in which genetic manipulations trigger changes in cellular Ca²⁺ distribution. This model constitutes a framework for further investigations into the link between cytosolic Ca²⁺, ER-stress and autophagy in human disorders and diseases.     

Cardiac RNA Induces Inflammatory Responses in Cardiomyocytes and Immune Cells via Toll-like Receptor 7 Signaling

We have recently reported that extracellular RNA (exRNA) released from necrotic cells induces cytokine production in cardiomyocytes and immune cells and contributes to myocardial ischemia/reperfusion injury. However, the signaling mechanism by which exRNA exhibits its pro-inflammatory effect is unknown. Here we hypothesize that exRNA directly induces inflammation through specific Toll-like receptors (TLRs). To test the hypothesis, we treated rat neonatal cardiomyocytes, mouse bone marrow-derived macrophages (BMDM), or mouse neutrophils with RNA (2.5–10 μg/ml) isolated from rat cardiomyocytes or the hearts from mouse, rat, and human. We found that cellular RNA induced production of several cytokines such as macrophage inflammatory protein-2 (MIP-2), ILs, TNFα, and the effect was completely diminished by RNase, but not DNase. The RNA-induced cytokine production was partially inhibited in cells treated with TLR7 antagonist or genetically deficient in TLR7. Deletion of myeloid differentiation primary response protein 88 (MyD88), a downstream adapter of TLRs including TLR7, abolished the RNA-induced MIP-2 production. Surprisingly, genetic deletion of TLR3 had no impact on the RNA-induced MIP-2 response. Importantly, extracellular RNA released from damaged cardiomyocytes also induced cytokine production. Finally, mice treated with 50 μg of RNA intraperitoneal injection exhibited acute peritonitis as evidenced by marked neutrophil and monocyte migration into the peritoneal space. Together, these data demonstrate that exRNA of cardiac origin exhibits a potent pro-inflammatory property in vitro and in vivo and that exRNA induces cytokine production through TLR7-MyD88 signaling.