Nutrient sensing and metabolic stress pathways in innate immunity

Cells monitor nutrient availability through several highly conserved pathways that include the mTOR signalling axis regulated by AKT/PI3K, HIF and AMPK, as well as the GCN2/eIF2α integrated stress response pathway that provides cellular adaptation to amino acid starvation. Recent evidence has identified a critical interplay between these nutrient sensing pathways and innate immunity to bacterial pathogens, viruses and parasites. These observations suggest that, in addition to the well‐characterized pro‐inflammatory signalling mediated by pattern recognition molecules, a metabolic stress programme contributes to shape the global response to pathogens.     

Enzyme activity demonstrates multiple pathways of innate immunity in Indo-Pacific anthozoans

Coral reefs are threatened by increasing levels of coral disease and the functional loss of obligate algal symbionts (bleaching). Levels of immunity relate directly to susceptibility to these threats; however, our understanding of fundamental aspects of coral immunology is lacking. We show that three melanin-synthesis pathway components (mono-phenoloxidase, ortho-diphenoloxidase (tyrosinase-type pathway) and para-diphenoloxidase (laccase-type pathway)) are present in both their active (phenoloxidase, PO) and inactive (prophenoloxidase, PPO) forms across a diverse range of 22 species of healthy Indo-Pacific anthozoans. We also demonstrate transglutaminase activity of the coagulation cascade for, to our knowledge, the first time in a coral. Melanin-synthesis enzyme activities varied among taxa, although they were generally lowest in the coral family Acroporidae and highest in the Poritidae and Oculinidae. Inactive tyrosinase-type activity (PPO) and active laccase-type activity (PO) correlate with taxonomic patterns in disease resistance, whereas the converse pattern in activity levels correlates with bleaching resistance. Overall, we demonstrate the presence of several melanin-synthesis pathways in Indo-Pacific corals, co-regulation among some pathway components, and highlight their potential roles in coral health.     

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.     

Endocytic pathways regulate Toll-like receptor 4 signaling and link innate and adaptive immunity

Immune responses are initiated when molecules of microbial origin are sensed by the Toll-like receptors (TLRs). We now report the identification of essential molecular components for the trafficking of the lipopolysaccharide (LPS) receptor complex. LPS was endocytosed by a receptor-mediated mechanism dependent on dynamin and clathrin and colocalized with TLR4 on early/sorting endosomes. TLR4 was ubiquitinated and associated with the ubiquitin-binding endosomal sorting protein hepatocyte growth factor-regulated tyrosine kinase substrate, Hrs. Inhibition of endocytosis and endosomal sorting increased LPS signaling. Finally, the LPS receptor complex was sorted to late endosomes/lysosomes for degradation and loading of associated antigens onto HLA class II molecules for presentation to CD4+ T cells. Our results show that endosomal trafficking of the LPS receptor complex is essential for signal termination and LPS-associated antigen presentation, thus controlling both innate and adaptive immunity through TLR4.     

Anopheles gambiae innate immunity

The successful development of Plasmodium in Anopheles mosquitoes is governed by complex molecular and cellular interactions that we are just beginning to understand. Anopheles immune system has received particular attention as genetic evidence points clearly to its critical role in eliminating the majority of parasites invading the midgut epithelium. Several factors regulating Plasmodium development have been identified and tentatively assigned to the individual steps leading to mosquito immune reactions; non-self-recognition, signal modulation, signal transduction and effector mechanisms. Detailed knowledge of these steps and their underlying molecular mechanisms may offer novel perspectives to abort Plasmodium development in the vector. Here, we summarize our current knowledge of mosquito innate immunity highlighting both, recent advances and areas where additional research is required.     

Physiology of innate immunity

The mechanisms of innate immunity functioning--the first row of counteraction (resistance) to infectious agents are reviewed. A concept of pathogen associated molecular patterns--the unique prokaryotic conservative structures--as well as a concept of pattern-recognizing receptors of innate immunity cell recognizing the given bacterial patterns, are discussed. The data on molecular and genetic structures of both Toll-like- and NOD-receptors: the important compounds of pattern-recognizing receptors, the main signaling pathways from receptor to cell genome activation as well as the principles of immune cell activation by pathogen associated molecular patterns are submitted.     

Mitochondria in innate immunity

Mitochondria are cellular organelles involved in host-cell metabolic processes and the control of programmed cell death. A direct link between mitochondria and innate immune signalling was first highlighted with the identification of MAVS-a crucial adaptor for RIGI-like receptor signalling-as a mitochondria-anchored protein. Recently, other innate immune molecules, such as NLRX1, TRAF6, NLRP3 and IRGM have been functionally associated with mitochondria. Furthermore, mitochondrial alarmins-such as mitochondrial DNA and formyl peptides-can be released by damaged mitochondria and trigger inflammation. Therefore, mitochondria emerge as a fundamental hub for innate immune signalling.     

Defensins in innate immunity

The innate immune system is the first line of defense against many common microorganisms, which can initiate adaptive immune responses to provide increased protection against subsequent re-infection by the same pathogen. As a major family of antimicrobial peptides, defensins are widely expressed in a variety of epithelial cells and sometimes in leukocytes, playing an important role in the innate immune system due to their antimicrobial, chemotactic and regulatory activities. This review introduces their structure, classification, distribution, synthesis, and focuses on their biological activities and mechanisms, as well as clinical relevance. These studies of defensins in the innate immune system have implications for the prevention and treatment of a variety of infectious diseases, including bacterial ocular disease.     

线粒体与固有免疫应答

线粒体是真核细胞至关重要的细胞器,在细胞生命周期中参与了很多关键进程,如ATP的供给、Ca2+动态平衡的维持、活性氧簇(Reactive oxygen species,ROS)的产生与清除、细胞凋亡等[1]。因此,不难想象,线粒体能够通过自身参与的各种生理     

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.     

Meeting report: a symposium on the evolution of common molecular pathways underlying innate immunity

The University of California, Davis hosted a symposium on innate immunity in January 2012. Professors Bruce Beutler, Jules Hoffmann, Luke O'Neill and Pamela Ronald discussed their research on mechanisms that multicellular organisms use to recognize microbes.     

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.