MITA/STING: A central and multifaceted mediator in innate immune response

The recognition of nucleic acids is a general strategy used by the host to detect invading pathogens. Many studies have established that MITA/STING is a central component in the innate immune response to cytosolic DNA and RNA derived from pathogens. MITA can act both as a direct sensor of cyclic dinucleotides (CDNs) and as an adaptor for the recruitment of downstream signaling components. In both roles, MITA is part of signaling cascades that orchestrate innate immune defenses against various pathogens, including viruses, bacteria and parasites. Here, we highlight recent studies that have uncovered the molecular mechanisms of MITA-mediated signal transduction and regulation, and discuss some notable issues that remain elusive.     

Systems biology of virus-host signaling network interactions

Viruses have evolved to manipulate the host cell machinery for virus propagation, in part by interfering with the host cellular signaling network. Molecular studies of individual pathways have uncovered many viral host-protein targets; however, it is difficult to predict how viral perturbations will affect the signaling network as a whole. Systems biology approaches rely on multivariate, context-dependent measurements and computational analysis to elucidate how viral infection alters host cell signaling at a network level. Here we describe recent advances in systems analyses of signaling networks in both viral and non-viral biological contexts. These approaches have the potential to uncover virus- mediated changes to host signaling networks, suggest new therapeutic strategies, and assess how cell-to-cell variability affects host responses to infection. We argue that systems approaches will both improve understanding of how individual virus-host protein interactions fit into the progression of viral pathogenesis and help to identify novel therapeutic targets.     

Membrane rafts: a potential gateway for bacterial entry into host cells

Pathogenic bacteria have developed various mechanisms to evade host immune defense systems. Invasion of pathogenic bacteria requires interaction of the pathogen with host receptors, followed by activation of signal transduction pathways and rearrangement of the cytoskeleton to facilitate bacterial entry. Numerous bacteria exploit specialized plasma membrane microdomains, commonly called membrane rafts, which are rich in cholesterol, sphingolipids and a special set of signaling molecules which allow entry to host cells and establishment of a protected niche within the host. This review focuses on the current understanding of the raft hypothesis and the means by which pathogenic bacteria subvert membrane microdomains to promote infection.     

Pseudorabies virus tegument protein UL13 recruits RNF5 to inhibit STING-mediated antiviral immunity

Pseudorabies virus (PRV) has evolved various immune evasion mechanisms that target host antiviral immune responses. However, it is unclear whether and how PRV encoded proteins modulate the cGAS-STING axis for immune evasion. Here, we show that PRV tegument protein UL13 inhibits STING-mediated antiviral signaling via regulation of STING stability. Mechanistically, UL13 interacts with the CDN domain of STING and recruits the E3 ligase RING-finger protein 5 (RNF5) to promote K27-/K29-linked ubiquitination and degradation of STING. Consequently, deficiency of RNF5 enhances host antiviral immune responses triggered by PRV infection. In addition, mutant PRV lacking UL13 impaired in antagonism of STING-mediated production of type I IFNs and shows attenuated pathogenicity in mice. Our findings suggest that PRV UL13 functions as an antagonist of IFN signaling via a novel mechanism by targeting STING to persistently evade host antiviral responses.     

Adhesive proteins of the malaria parasite

Malaria infection of the host cells requires host-parasite recognition events mediated by adhesion and signaling molecules. Recent development of systems for stable transformation and targeted integration of exogenous DNA in malaria parasites provides a powerful tool to study the structure and function of Plasmodium attachment motifs, and their role in infection and disease.     

Interplay of signaling pathways in plant disease resistance

Plants are under constant threat of infection by pathogens armed with a diverse array of effector molecules to colonize their host. Plants have, in turn, evolved sophisticated detection and response systems that decipher pathogen signals and induce appropriate defenses. Genetic analysis of plant mutants impaired in mounting a resistance response to invading pathogens has uncovered a number of distinct, but interconnecting, signaling networks that are under both positive and negative control. These pathways operate, at least partly, through the action of small signaling molecules such as salicylate, jasmonate and ethylene. The interplay of signals probably allows the plant to fine-tune defense responses in both local and systemic tissue.     

Mechanisms of inhibition of the host interferon alpha/beta-mediated antiviral responses by viruses

Complex multicellular organisms have evolved sophisticated mechanisms to prevent and control infection by pathogens. Among these mechanisms, the type I interferon or interferon alpha/beta system represents one of the first lines of defense against viral infections. Typically, viral infection induces the synthesis and secretion of interferon alpha/beta by the infected cell, which in turn activates signaling pathways leading to an antiviral state. As a counter measure, many viruses have developed intriguing mechanisms to evade the interferon alpha/beta system of the host. In this review, we will summarize recent research developments in this interesting field of virus-host cell interactions.     

Host immune response to intracellular bacteria: A role for MHC-linked class-Ib antigen-presenting molecules

MHC-linked class-Ib molecules are a subfamily of class-I molecules that display limited genetic polymorphism. At one time these molecules were considered to have an enigmatic function. However, recent studies have shown that MHC-linked class-Ib molecules can function as antigen presentation structures that bind bacteria-derived epitopes for recognition by CD8+ effector T cells. This role for class-Ib molecules has been demonstrated across broad classes of intracellular bacteria including Listeria moncytogenes, Salmonella typhimurium, and Mycobacterium tuberculosis. Additionally, evidence is emerging that MHC-linked class-Ib molecules also serve an integral role as recognition elements for NK cells as well as several TCR alpha/beta and TCR gamma/delta T-cell subsets. Thus, MHC-linked class-Ib molecules contribute to the host immune response by serving as antigen presentation molecules and recognition ligands in both the innate and adaptive immune response to infection. In this review, we will attempt to summarize the work that supports a role for MHC-linked class-Ib molecules in the host response to infection with intracellular bacteria.     

Molecular crosstalk in host-parasite relationships: schistosome- and leech-host interactions

The host-parasite relationship is based on subtle interplay between parasite survival strategies and host defense mechanisms. In this context, parasites often use the same or similar immune signaling molecules and/or molecular mimicry to escape host immunosurveillance. Both processes represent an adaptive strategy to ensure host immunocompatibility. This bidirectional communication between parasites and their hosts includes the renin-angiotensin, opioid and opiate systems. Here, Michel Salzet, André Capron and George Stefano review recent work on the interaction of common signaling mechanisms in schistosomes, leeches and their host.     

Role of mTOR Downstream Effector Signaling Molecules in Francisella Tularensis Internalization by Murine Macrophages

Francisella tularensis is an infectious, gram-negative, intracellular microorganism, and the cause of tularemia. Invasion of host cells by intracellular pathogens like Francisella is initiated by their interaction with different host cell membrane receptors and the rapid phosphorylation of different downstream signaling molecules. PI3K and Syk have been shown to be involved in F. tularensis host cell entry, and both of these signaling molecules are associated with the master regulator serine/threonine kinase mTOR; yet the involvement of mTOR in F. tularensis invasion of host cells has not been assessed. Here, we report that infection of macrophages with F. tularensis triggers the phosphorylation of mTOR downstream effector molecules, and that signaling via TLR2 is necessary for these events. Inhibition of mTOR or of PI3K, ERK, or p38, but not Akt signaling, downregulates the levels of phosphorylation of mTOR downstream targets, and significantly reduces the number of F. tularensis cells invading macrophages. Moreover, while phosphorylation of mTOR downstream effectors occurs via the PI3K pathway, it also involves PLCγ1 and Ca²⁺ signaling. Furthermore, abrogation of PLC or Ca²⁺ signaling revealed their important role in the ability of F. tularensis to invade host cells. Together, these findings suggest that F. tularensis invasion of primary macrophages utilize a myriad of host signaling pathways to ensure effective cell entry.     

Implications of molecular contacts and signaling initiated by Neisseria gonorrhoeae

Neisseria gonorrhoeae employs diverse strategies with which to adhere to and invade host cells during the course of infection. These primary encounters provide means by which biologically active molecules can be efficiently targeted to disrupt or exploit normal host cell metabolism and immune response elements, which in turn leads to the pathological responses characteristic of gonococcal disease. Current studies have begun to elucidate in detail the molecular interactions orchestrating these processes and the signaling events that they provoke.     

The role of innate immune receptors in the control of Brucella abortus infection: toll-like receptors and beyond

Research into intracellular sensing of microbial products is an up and coming field in innate immunity. Toll-like receptors (TLRs) recognize Brucella spp. and bacterial components and initiate mononuclear phagocyte responses that influence both innate and adaptive immunity. Recent studies have revealed the intracellular signaling cascades involved in the TLR-initiated immune response to Brucella infection. TLR2, TLR4 and TLR9 have been implicated in host interactions with Brucella; however, TLR9 has the most prominent role. Further, the relationship between specific Brucella molecules and various signal transduction pathways needs to be better understood. MyD88-dependent and TRIF-independent signaling pathways are involved in Brucella activation of innate immune cells through TLRs. We have recently reported the critical role of MyD88 molecule in dendritic cell maturation and interleukin-12 production during B. abortus infection. This article discusses recent studies on TLR signaling and also highlights the contribution of NOD and type I IFN receptors during Brucella infection. The better understanding of the role by such innate immune receptors in bacterial infection is critical in host-pathogen interactions.     

Invertebrate cytokines: the phylogenetic emergence of interleukin-1

Cytokines are polypeptides released by activated vertebrate blood cells which have profound effects on other blood cells and which have hormone-like properties affecting other organ systems as well. In recent years a wide variety of these mediators has been isolated and characterized. Many of these molecules have subsequently been cloned and expressed in E. coli. The tremendous importance of these proteins to host immune and non-specific defense systems along with the striking similarities of their properties among different species suggested to us that cytokines may have been proteins that have been conserved through evolution. Investigations of the evolution of cytokines will help us decipher the complex cellular, humoral and molecular interactions that regulate host defenses. Studies of the invertebrates will shed light on the phylogenetic emergence of these molecules as well.     

肠出血性大肠杆菌Ⅲ型分泌系统效应因子与宿主细胞相互作用研究进展

肠出血性大肠杆菌(Enterohemorrhagic Escherichia coli,EHEC)通过其Ⅲ型分泌系统将效应因子注入到宿主细胞内,破坏宿主细胞内的多种信号通路从而有利于细菌的感染及定植。近年来对于EHEC Ⅲ型分泌系统效应因子与宿主细胞相互作用研究成为EHEC致病机制研究新的热点,研究表明,除了经典的效应因子外,一些新发现的效应因子在细菌的致病过程中也发挥着重要作用,有些效应因子能够抑制宿主细胞内正常的信号通路,有些效应因子还具有抑制细胞凋亡,干扰炎症信号通路和抑制吞噬的作用。这些发现揭示了EHEC效应因子具有多种功能,它们通过与宿主细胞间的相互作用,在细菌的感染过程中发挥着重要作用。     

Macrophage signaling by glycosylphosphatidylinositol-anchored mucin-like glycoproteins derived from Trypanosoma cruzi trypomastigotes

Activation of cells from the innate immune system has an important role in host resistance to early infection with the intracellular protozoan parasite, Trypanosoma cruzi. Here we review the studies that have identified and structurally characterized the glycosylphosphatidylinositol (GPI) anchors, as parasite molecules responsible for the activation of cells from the macrophage lineage. We also cover the studies that have identified the receptor, signaling pathways as well as the array of genes expressed in macrophages that are activated by these glycoconjugates. We discuss the possible implications of such response on the host resistance to T. cruzi infection and the pathogenesis of Chagas disease.     

G protein-linked effector and second messenger systems involved in melatonin signal transduction

The isolation and characterization of multiple melatonin receptors in a wide range of tissues and cells signifies the functional diversity of melatonin. In different cellular environments, melatonin can regulate distinct second messengers or even positively or negatively regulate the same signal transduction pathway. The capacity by which melatonin receptors modulate the activities of various effector molecules is determined by the complement of signaling components present in any particular cell type. The specific interactions between many signaling molecules have been discerned in an increasing number of cellular systems and this information is being used to explain the physiological actions of melatonin. This review will attempt to summarize recent research by many groups that has revealed numerous subtleties of the melatonin-coupled signaling pathways.