Regulation of Salmonella-host cell interactions via the ubiquitin system

Salmonella infections cause acute intestinal inflammatory responses through the action of bacterial effector proteins secreted into the host cytosol. These proteins promote Salmonella survival, amongst others, by deregulating the host innate immune system and interfering with host cell ubiquitylation signaling. This review describes the recent findings of dynamic changes of the host ubiquitinome during pathogen infection, how bacterial effector proteins modulate the host ubiquitin system and how the host innate immune system counteracts Salmonella invasion by using these pathogens as signaling platforms to initiate immune responses.     

Innate immune signaling in defense against intestinal microbes

The gastrointestinal system is a common entry point for pathogenic microbes to access the inner environment of the body. Anti-microbial factors produced by the intestinal mucosa limit the translocation of both commensal and pathogenic microbes across the intestinal epithelial cell barrier. The regulation of these host defense mechanisms largely depends on the activation of innate immune receptors by microbial molecules. Under steady-state conditions, the microbiota provides constitutive signals to the innate immune system, which helps to maintain a healthy inflammatory tone within the intestinal mucosa and, thus, enhances resistance to infection with enteric pathogens. During an acute infection, the intestinal epithelial cell barrier is breached, and the detection of microbial molecules in the intestinal lamina propria rapidly stimulates innate immune signaling pathways that coordinate early defense mechanisms. Herein, we review how microbial molecules shed by both commensal and pathogenic microbes direct host defenses at the intestinal mucosa. We highlight the signaling pathways, effector molecules, and cell populations that are activated by microbial molecule recognition and, thereby, are involved in the maintenance of homeostatic levels of host defense and in the early response to acute enteric infection. Finally, we discuss how manipulation of these host defense pathways by stimulating innate immune receptors is a potential therapeutic strategy to prevent or alleviate intestinal disease.     

Metabolic reprogramming & inflammation: Fuelling the host response to pathogens

Successful immune responses to pathogens rely on efficient host innate processes to contain and limit bacterial growth, induce inflammatory response and promote antigen presentation for the development of adaptive immunity. This energy intensive process is regulated through multiple mechanisms including receptor-mediated signaling, control of phago-lysomal fusion events and promotion of bactericidal activities. Inherent macrophage activities therefore are dynamic and are modulated by signals and changes in the environment during infection. So too does the way these cells obtain their energy to adapt to altered homeostasis. It has emerged recently that the pathways employed by immune cells to derive energy from available or preferred nutrients underline the dynamic changes associated with immune activation. In particular, key breakpoints have been identified in the metabolism of glucose and lipids which direct not just how cells derive energy in the form of ATP, but also cellular phenotype and activation status. Much of this comes about through altered flux and accumulation of intermediate metabolites. How these changes in metabolism directly impact on the key processes required for anti-microbial immunity however, is less obvious. Here, we examine the 2 key nutrient utilization pathways employed by innate cells to fuel central energy metabolism and examine how these are altered in response to activation during infection, emphasising how certain metabolic switches or ‘reprogramming’ impacts anti-microbial processes. By examining carbohydrate and lipid pathways and how the flux of key intermediates intersects with innate immune signaling and the induction of bactericidal activities, we hope to illustrate the importance of these metabolic switches for protective immunity and provide a potential mechanism for how altered metabolic conditions in humans such as diabetes and hyperlipidemia alter the host response to infection.     

泛素系统在结核分枝杆菌与宿主相互作用中的调控机制研究进展

结核分枝杆菌(Mycobacterium tuberculosis,Mtb)是一种极其成功的胞内病原菌,可通过多种策略实现免疫逃逸,从而在宿主巨噬细胞中长期存活。在对抗病原菌的防御过程中,泛素系统(Ubiquitin system)在激活宿主炎症免疫反应、细胞自噬、吞噬体成熟和细胞死亡等天然免疫功能及相关信号通路中发挥了重要的调控作用。而另一方面,近年的研究表明Mtb 等胞内病原菌可通过分泌效应蛋白(Effector proteins)挟持并利用宿主泛素系统进而抑制宿主的免疫功能,这些病原-宿主互作的界面有望成为抗结核药物研发的新靶点。     

Crosstalk of signalling processes of innate immunity with Yersinia Yop effector functions

The interaction of microbial pathogens with host cells critically determines the genesis of infectious diseases. Gram-negative, pathogenic bacteria from the genus Yersinia deliver a set of virulence proteins, the so-called Yersinia outer proteins (Yops), inside the eukaryotic cell where the Yops perturb key cellular functions of innate immunity. In our past work, we used Yersinia enterocolitica as a tool to explore the crosstalk between the bacterial pathogen and its host cell. Yersiniae counteract phagocytosis, suppress proinflammatory signalling and trigger apoptosis in macrophages. Macrophage cell death results from the deregulation of Toll-like receptors-dependent conserved signalling pathways by Yersinia infection. We summarize our current understanding about the signals and reactions elicited on both the bacterial and host cell sides that determine the fate of the infected cell along with the innate immune response.     

Type I interferon response to extracellular bacteria in the airway epithelium

The airway epithelium possesses many mechanisms to prevent bacterial infection. Not only does it provide a physical barrier, but it also acts as an extension of the immune system through the expression of innate immune receptors and corresponding effectors. One outcome of innate signaling by the epithelium is the production of type I interferons (IFNs), which have traditionally been associated with activation via viral and intracellular organisms. We discuss how three extracellular bacterial pathogens of the airway activate this intracellular signaling cascade through both surface components as well as via secretion systems, and the differing effects of type I IFN signaling on host defense of the respiratory tract.     

Innate immunity turned inside-out: antimicrobial defense by phagocyte extracellular traps

The formation of extracellular traps (ETs) by phagocytic cells has been recognized as a novel and important mechanism of the host innate immune response against infections. ETs are formed by different host immune cells such as neutrophils, mast cells, and eosinophils after stimulation with mitogens, cytokines, or pathogens themselves, in a process dependent upon induction of a reactive-oxygen-species-mediated signaling cascade. ETs consist of nuclear or mitochondrial DNA as a backbone with embedded antimicrobial peptides, histones, and cell-specific proteases and thereby provide a matrix to entrap and kill microbes and to induce the contact system. This review summarizes the latest research on ETs and their role in innate immunity and host innate defense. Attention is also given to mechanisms by which certain leading bacterial pathogens have evolved to avoid entrapment and killing in these specialized structures.     

Innate immune inflammatory cell death: PANoptosis and PANoptosomes in host defense and disease

Regulated cell death (RCD) triggered by innate immune activation is an important strategy for host survival during pathogen invasion and perturbations of cellular homeostasis. There are two main categories of RCD, including nonlytic and lytic pathways. Apoptosis is the most well-characterized nonlytic RCD, and the inflammatory pyroptosis and necroptosis pathways are among the best known lytic forms. While these were historically viewed as independent RCD pathways, extensive evidence of cross-talk among their molecular components created a knowledge gap in our mechanistic understanding of RCD and innate immune pathway components, which led to the identification of PANoptosis. PANoptosis is a unique innate immune inflammatory RCD pathway that is regulated by PANoptosome complexes upon sensing pathogens, pathogen-associated molecular patterns (PAMPs), damage-associated molecular patterns (DAMPs) or the cytokines produced downstream. Cytosolic innate immune sensors and regulators, such as ZBP1, AIM2 and RIPK1, promote the assembly of PANoptosomes to drive PANoptosis. In this review, we discuss the molecular components of the known PANoptosomes and highlight the mechanisms of PANoptosome assembly, activation and regulation identified to date. We also discuss how PANoptosomes and mutations in PANoptosome components are linked to diseases. Given the impact of RCD, and PANoptosis specifically, across the disease spectrum, improved understanding of PANoptosomes and their regulation will be critical for identifying new therapeutic targets and strategies.     

PRR-signaling pathways: Learning from microbial tactics

Recognition of bacterial pathogens by the mammalian host relies on the induction of early innate immune responses initiated by the activation of pattern-recognition receptors (PRRs) upon sensing of their cognate microbe-associated-patterns (MAMPs). Successful pathogens have evolved to intercept PRR activation and signaling at multiple steps. The molecular dissection of the underlying mechanisms revealed many of the basic mechanisms used by the immune system.Here we provide an overview of the different strategies used by bacterial pathogens and commensals to subvert and reprogram PPR-mediated innate immune responses. A particular attention is given to recent discoveries highlighting novel molecular details of the host inflammatory response in mammalian cells and current advances in our understanding of the interaction of commensals with PRR-mediated responses.     

Toll-like receptors in innate immunity

Functional characterization of Toll-like receptors (TLRs) has established that innate immunity is a skillful system that detects invasion of microbial pathogens. Recognition of microbial components by TLRs initiates signal transduction pathways, which triggers expression of genes. These gene products control innate immune responses and further instruct development of antigen-specific acquired immunity. TLR signaling pathways are finely regulated by TIR domain-containing adaptors, such as MyD88, TIRAP/Mal, TRIF and TRAM. Differential utilization of these TIR domain-containing adaptors provides specificity of individual TLR-mediated signaling pathways. Several mechanisms have been elucidated that negatively control TLR signaling pathways, and thereby prevent overactivation of innate immunity leading to fatal immune disorders. The involvement of TLR-mediated pathways in autoimmune and inflammatory diseases has been proposed. Thus, TLR-mediated activation of innate immunity controls not only host defense against pathogens but also immune disorders.     

自噬与固有免疫应答相互调节研究进展

自噬在细胞分化、肿瘤、炎症、免疫等多方面发挥关键作用.近年来,随着分子生物学、细胞生物学、免疫学等学科的发展,研究发现细胞自噬与固有免疫应答有着重要的相互调控作用.自噬是固有免疫的重要组成成分,可以通过溶酶体直接降解被自噬体包裹的病原体.自噬参与众多固有免疫信号的调控.固有免疫信号也诱导或抑制自噬.自噬在抗胞内病原体感染中发挥重要作用.     

Expanding the Universe of Cytokines and Pattern Recognition Receptors: Galectins and Glycans in Innate Immunity

Effective immunity relies on the recognition of pathogens and tumors by innate immune cells through diverse pattern recognition receptors (PRRs) that lead to initiation of signaling processes and secretion of pro- and anti-inflammatory cytokines. Galectins, a family of endogenous lectins widely expressed in infected and neoplastic tissues have emerged as part of the portfolio of soluble mediators and pattern recognition receptors responsible for eliciting and controlling innate immunity. These highly conserved glycan-binding proteins can control immune cell processes through binding to specific glycan structures on pathogens and tumors or by acting intracellularly via modulation of selective signaling pathways. Recent findings demonstrate that various galectin family members influence the fate and physiology of different innate immune cells including polymorphonuclear neutrophils, mast cells, macrophages, and dendritic cells. Moreover, several pathogens may actually utilize galectins as a mechanism of host invasion. In this review, we aim to highlight and integrate recent discoveries that have led to our current understanding of the role of galectins in host–pathogen interactions and innate immunity. Challenges for the future will embrace the rational manipulation of galectin–glycan interactions to instruct and shape innate immunity during microbial infections, inflammation, and cancer.     

Efferocytosis of dying cells differentially modulate immunological outcomes in tumor microenvironment

Programmed cell death (apoptosis) is an integral part of tissue homeostasis in complex organisms, allowing for tissue turnover, repair, and renewal while simultaneously inhibiting the release of self antigens and danger signals from apoptotic cell-derived constituents that can result in immune activation, inflammation, and autoimmunity. Unlike cells in culture, the physiological fate of cells that die by apoptosis in vivo is their rapid recognition and engulfment by phagocytic cells (a process called efferocytosis). To this end, apoptotic cells express specific eat-me signals, such as externalized phosphatidylserine (PS), that are recognized in a specific context by receptors to initiate signaling pathways for engulfment. The importance of carefully regulated recognition and clearance pathways is evident in the spectrum of inflammatory and autoimmune disorders caused by defects in PS receptors and signaling molecules. However, in recent years, several additional cell death pathways have emerged, including immunogenic cell death, necroptosis, pyroptosis, and netosis that interweave different cell death pathways with distinct innate and adaptive responses from classical apoptosis that can shape long-term host immunity. In this review, we discuss the role of different cell death pathways in terms of their immune potential outcomes specifically resulting in specific cell corpse/phagocyte interactions (phagocytic synapses) that impinge on host immunity, with a main emphasis on tolerance and cancer immunotherapy.     

NOX enzymes and Toll-like receptor signaling

Invading microorganisms are recognized by the host innate immune system through pattern recognition receptors. Among these receptors, Toll-like receptors (TLRs) are able to sense the molecular signatures of microbial pathogens, protozoa, fungi, and virus and activate proinflammatory signaling cascades. In addition to their role in bacterial killing by phagocytes, reactive oxygen species generated by NADPH oxidase (NOX) homologues also play key roles in signaling and host defense in a variety of cell types. Recent studies have demonstrated a link between TLR activation and NOX homologues following microbial recognition highlighting their important role in the innate immune response and host defense.     

The role of mitochondria in cellular defense against microbial infection

Mitochondria have been long recognized for their key role in the modulation of cell death pathways. Thus, it is therefore not surprising that this organelle represents a recurrent target for pathogenic microbes, aiming to manipulate the fate of the infected host cell. More recently, mitochondria have been shown to serve as a crucial platform for innate immune signaling, as illustrated by the identification of MAVS (also known as IPS-1, VISA and Cardif), NLRX1 and STING as mitochondrial proteins. This review discusses the tight interplay between microbial infection, innate immune signaling and mitochondria.     

Vaccine adjuvants: putting innate immunity to work

Adjuvants enhance immunity to vaccines and experimental antigens by a variety of mechanisms. In the past decade, many receptors and signaling pathways in the innate immune system have been defined and these innate responses strongly influence the adaptive immune response. The focus of this review is to delineate the innate mechanisms by which adjuvants mediate their effects. We highlight how adjuvants can be used to influence the magnitude and alter the quality of the adaptive response in order to provide maximum protection against specific pathogens. Despite the impressive success of currently approved adjuvants for generating immunity to viral and bacterial infections, there remains a need for improved adjuvants that enhance protective antibody responses, especially in populations that respond poorly to current vaccines. However, the larger challenge is to develop vaccines that generate strong T cell immunity with purified or recombinant vaccine antigens.     

Insight into bacterial virulence mechanisms against host immune response via the Yersinia pestis-human protein-protein interaction network

A Yersinia pestis-human protein interaction network is reported here to improve our understanding of its pathogenesis. Up to 204 interactions between 66 Y. pestis bait proteins and 109 human proteins were identified by yeast two-hybrid assay and then combined with 23 previously published interactions to construct a protein-protein interaction network. Topological analysis of the interaction network revealed that human proteins targeted by Y. pestis were significantly enriched in the proteins that are central in the human protein-protein interaction network. Analysis of this network showed that signaling pathways important for host immune responses were preferentially targeted by Y. pestis, including the pathways involved in focal adhesion, regulation of cytoskeleton, leukocyte transendoepithelial migration, and Toll-like receptor (TLR) and mitogen-activated protein kinase (MAPK) signaling. Cellular pathways targeted by Y. pestis are highly relevant to its pathogenesis. Interactions with host proteins involved in focal adhesion and cytoskeketon regulation pathways could account for resistance of Y. pestis to phagocytosis. Interference with TLR and MAPK signaling pathways by Y. pestis reflects common characteristics of pathogen-host interaction that bacterial pathogens have evolved to evade host innate immune response by interacting with proteins in those signaling pathways. Interestingly, a large portion of human proteins interacting with Y. pestis (16/109) also interacted with viral proteins (Epstein-Barr virus [EBV] and hepatitis C virus [HCV]), suggesting that viral and bacterial pathogens attack common cellular functions to facilitate infections. In addition, we identified vasodilator-stimulated phosphoprotein (VASP) as a novel interaction partner of YpkA and showed that YpkA could inhibit in vitro actin assembly mediated by VASP.