Toll receptors in innate immunity.

Innate immunity is the first-line host defense of multicellular organisms that rapidly operates to limit infection upon exposure to infectious agents. In addition, the cells and molecules operating during this early stage of the immune response in vertebrates have a decisive impact on the shaping of the subsequent adaptive response. Genetic studies initially performed in the fruitfly Drosophila and later in mice have revealed the importance of proteins of the Toll family in the innate immune response. We present here our current understanding of the role of this evolutionary ancient family of proteins that are thought to function as cytokine receptors (Toll in Drosophila) or pattern-recognition receptors (TLRs in mammals) and activate similar, albeit non-identical, signal-transduction pathways in flies and mammals.     

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     

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.     

Mitochondria and antiviral innate immunity

Mitochondria, dynamic organelles that undergo continuous cycles of fusion and fission, are the powerhouses of eukaryotic cells. Recent research indicates that mitochondria also act as platforms for antiviral immunity in vertebrates. Mitochondrial-mediated antiviral immunity depends on activation of the retinoic acid-inducible gene I (RIG-I)-like receptors signal transduction pathway and the participation of the mitochondrial outer membrane adaptor protein “mitochondrial antiviral signaling (MAVS)”. Here we discuss recent findings that suggest how mitochondria contribute to antiviral innate immunity.     

Pathogen recognition and innate immunity

Microorganisms that invade a vertebrate host are initially recognized by the innate immune system through germline-encoded pattern-recognition receptors (PRRs). Several classes of PRRs, including Toll-like receptors and cytoplasmic receptors, recognize distinct microbial components and directly activate immune cells. Exposure of immune cells to the ligands of these receptors activates intracellular signaling cascades that rapidly induce the expression of a variety of overlapping and unique genes involved in the inflammatory and immune responses. New insights into innate immunity are changing the way we think about pathogenesis and the treatment of infectious diseases, allergy, and autoimmunity.     

Nods and 'intracellular' innate immunity

Innate immunity relies on the detection of microbial invaders by two distinct systems. One system comprises a family of membrane-bound receptors, termed the Toll-like receptors, while the other family, termed the nucleotide-binding site/leucine-rich repeat (NBS/LRR) proteins, consists of molecules that are found in the cytoplasmic compartment. These two detection systems recognize conserved molecular components of microbes including such structural motifs as lipopolysaccharide from the Gram-negative bacterial cell wall and peptidoglycan (PGN) found in the cell wall of both Gram-negative and Gram-positive bacteria. This review focuses on two members of the NBS/LRR family of proteins, Nod1 and Nod2. Recently, the microbial motifs sensed by these two molecules have been characterized. Both Nod1 and Nod2 recognize PGN, however, each requires distinct molecular motifs to attain sensing. Nod1 recognizes a naturally occurring muropeptide of PGN that presents a unique amino acid at its terminus called diaminopilemic acid (DAP). This amino acid is found mainly in the PGN of Gram-negative bacteria designating Nodl as a sensor of Gram-negative bacteria. In contrast, Nod2 can detect the minimal bioactive fragment of PGN, called muramyl dipeptide. Thus Nod2 is a general sensor of bacterial PGN. Since mutations in the gene encoding Nod2 were recently shown to be associated with the chronic inflammatory disease, Crohn's disease, these results are discussed in the context of how disrupting the interplay between host detection and bacterial aggression may lead to inflammatory diseases.     

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.     

Bridging innate and adaptive immunity

The Nobel Prize in Physiology or Medicine for 2011 to Jules Hoffmann, Bruce Beutler, and the late Ralph Steinman recognizes accomplishments in understanding and unifying the two strands of immunology, the evolutionarily ancient innate immune response and modern adaptive immunity.     

Connecting mitochondria and innate immunity

Viral infection results in the activation of multiple signaling pathways, but how these pathways are coordinated remains a mystery. Two studies, one published in this issue of Cell (Seth et al., 2005) and the other in Molecular Cell (Xu et al., 2005), identify a new intracellular signaling protein that is required for activating type I interferon expression in response to viral infection. In addition,Seth et al. (2005) show that the function of this protein, which they call MAVS, requires that it be localized to the mitochondria. This observation establishes an unexpected link between innate immunity and an organelle with evolutionary origins in aerobic bacteria.     

Toll-like receptors and innate immunity

Toll-like receptors have a crucial role in the detection of microbial infection in mammals and insects. In mammals, these receptors have evolved to recognize conserved products unique to microbial metabolism. This specificity allows the Toll proteins to detect the presence of infection and to induce activation of inflammatory and antimicrobial innate immune responses. Recognition of microbial products by Toll-like receptors expressed on dendritic cells triggers functional maturation of dendritic cells and leads to initiation of antigen-specific adaptive immune responses.     

Sugars and plant innate immunity

Sugars are involved in many metabolic and signalling pathways in plants. Sugar signals may also contribute to immune responses against pathogens and probably function as priming molecules leading to pathogen-associated molecular patterns (PAMP)-triggered immunity and effector-triggered immunity in plants. These putative roles also depend greatly on coordinated relationships with hormones and the light status in an intricate network. Although evidence in favour of sugar-mediated plant immunity is accumulating, more in-depth fundamental research is required to unravel the sugar signalling pathways involved. This might pave the way for the use of biodegradable sugar-(like) compounds to counteract plant diseases as cheaper and safer alternatives for toxic agrochemicals.     

Autophagy and plant innate immunity

Plant innate immunity is often associated with specialized programmed cell death at or near the site of pathogen infection. Despite the isolation of several lesion mimic mutants, the molecular mechanisms that regulate cell death during an immune response remain obscure. Recently, autophagy, an evolutionarily conserved process of bulk protein and organelle turnover, was shown to play an important role in limiting cell death initiated during plant innate immune responses. Consistent with its role in plants, several studies in animals also demonstrate that the autophagic machinery is involved in innate as well as adaptive immunities. Here, we review the role of autophagy in plant innate immunity. Because autophagy is observed in healthy and dying plant cells, we will also examine whether autophagy plays a protective or a destructive role during an immune response.     

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.     

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.