Remodeling of host glycoproteins during bacterial infection

Protein glycosylation is a common post-translational modification found in all living organisms. This modification in bacterial pathogens plays a pivotal role in their infectious processes including pathogenicity, immune evasion, and host-pathogen interactions. Importantly, many key proteins of host immune systems are also glycosylated and bacterial pathogens can notably modulate glycosylation of these host proteins to facilitate pathogenesis through the induction of abnormal host protein activity and abundance. In recent years, interest in studying the regulation of host protein glycosylation caused by bacterial pathogens is increasing to fully understand bacterial pathogenesis. In this review, we focus on how bacterial pathogens regulate remodeling of host glycoproteins during infections to promote the pathogenesis.     

Parasite immune evasion: a momentous molecular war

Current research in immunology shows that parasite evasion of host immunity is ubiquitous and involves a wide range of molecular mechanisms. Furthermore, immune evasion appears to generate a large spectrum of pathogenic effects, such as cytokine storms and inflammation. Understanding the relationships between the beneficial effects of immune evasion and its pathogenic consequences therefore provides a new framework to reassess many of the core questions of the evolutionary ecology of host-parasite interactions, such as the evolution of virulence, immune defence strategies, infective dose and host specificity, and to address questions that thus far could not be satisfactorily analysed.     

Interaction of human, rat, and mouse immunoglobulin A (IgA) with Staphylococcal superantigen-like 7 (SSL7) decoy protein and leukocyte IgA receptor

Host survival depends on an effective immune system and pathogen survival on the effectiveness of immune evasion mechanisms. Staphylococcus aureus utilizes a number of molecules to modulate host immunity, including the SSL family of which SSL7 binds IgA and inhibits Fcα receptor I (FcαRI)-mediated function. Other Gram-positive bacterial pathogens produce IgA binding proteins, which, similar to SSL7, also bind the Fc at the CH2/CH3 interface (the junction between constant domains 2 and 3 of the heavy chain). The opposing activities of the host FcαRI-IgA receptor ligand pair and the pathogen decoy proteins select for host and pathogen variants, which exert stronger protection or evasion, respectively. Curiously, mouse but not rat IgA contains a putative N-linked glycosylation site in the center of this host receptor and pathogen-binding site. Here, we demonstrate that this site is glycosylated and that the effect of amino acid changes and glycosylation of the CH2/CH3 interface inhibits interaction with the pathogen IgA binding protein SSL7, while maintaining binding of pIgR, essential to the biosynthesis and transport of SIgA.     

Innate immunity gone awry: linking microbial infections to chronic inflammation and cancer

Clinical and epidemiologic studies have suggested an association between infectious agents and chronic inflammatory disorders and cancer. Better understanding of microbial pattern-recognition receptors and innate immune signaling pathways of the host is helping to elucidate the connection between microbial infection and chronic disease. We propose that a key aspect of pathogenesis is an aberrant epithelial barrier that can be instigated by microbial toxins, environmental insults, or the genetic predisposition of the host. Loss of epithelial integrity results in activation of resident inflammatory cells by microbial invaders or endogenous ligands. When coupled with a failure of normal control mechanisms that limit leukocyte activation, a cascade is established that induces chronic inflammation and its consequences. Here, we outline this mechanistic framework and briefly review how alteration of innate immune response genes in murine models can provide insights into the potential microbial origins of diverse conditions including Crohn's disease, psoriasis, atherosclerosis, diabetes, and liver cancer.     

Structural basis of the herpesvirus M3-chemokine interaction

Viruses have been fighting the immune systems of their hosts for millions of years and have evolved evasion strategies to ensure their survival. Viruses can teach us efficient mechanisms to control the immune system, and this information can be used to design new strategies of immune modulation that we might apply to diminish immunopathological responses that cause human diseases. Large DNA viruses, such as poxviruses and herpesviruses, encode proteins that are secreted from infected cells, bind cytokines and neutralize their activity. A subgroup of these viral proteins binds chemokines, a complex family of cytokines that control the recruitment of cells to sites of infection and inflammation. One of the major unresolved questions in the field was to understand how these viral secreted proteins bind chemokines with high affinity, despite having no amino acid sequence similarity to the host chemokine receptors, which are seven-transmembrane-domain proteins that cannot be engineered as soluble proteins.     

The dynamics of gut‐associated microbial communities during inflammation

Our intestine is host to a large microbial community (microbiota) that educates the immune system and confers niche protection. Profiling of the gut‐associated microbial community reveals a dominance of obligate anaerobic bacteria in healthy individuals. However, intestinal inflammation is associated with a disturbance of the microbiota—known as dysbiosis—that often includes an increased prevalence of facultative anaerobic bacteria. This group contains potentially harmful bacterial species, the bloom of which can further exacerbate inflammation. Here, we review the mechanisms that generate changes in the microbial community structure during inflammation. One emerging concept is that electron acceptors generated as by‐products of the host inflammatory response feed facultative anaerobic bacteria selectively, thereby increasing their prevalence within the community. This new paradigm has broad implications for understanding dysbiosis during gut inflammation and identifies potential targets for intervention strategies.     

Removal of N-linked glycosylation sites in the V1 region of simian immunodeficiency virus gp120 results in redirection of B-cell responses to V3

One mechanism of immune evasion utilized by human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) envelope glycoproteins is the presence of a dense carbohydrate shield. Accumulating evidence from in vitro and in vivo experiments suggests that alterations in N-linked glycosylation of SIV gp120 can enhance host humoral immune responses that may be involved in immune control. The present study was designed to determine the ability of glycosylation mutant viruses to redirect antibody responses to shielded envelope epitopes. The influence of glycosylation on the maturation and specificity of antibody responses elicited by glycosylation mutant viruses containing mutations of specific N-linked sites in and near the V1 and V2 regions of SIVmac239 gp120 was determined. Results from these studies demonstrated a remarkably similar maturation of antibody responses to native, fully glycosylated envelope proteins. However, analyses of antibodies to defined envelope domains revealed that mutation of glycosylation sites in V1 resulted in increased antibody recognition to epitopes in V1. In addition, we demonstrated for the first time that mutation of glycosylation sites in V1 resulted in a redirection of antibody responses to the V3 loop. Taken together, these results demonstrate that N-linked glycosylation is a determinant of SIV envelope B-cell immunogenicity in addition to in vitro antigenicity. In addition, our results demonstrate that the absence of N-linked carbohydrates at specific sites can influence the exposure of epitopes quite distant in the linear sequence.     

Protein glycosylation in infectious disease pathobiology and treatment

A host of bacteria and viruses are dependent on O-linked and N-linked glycosylation to perform vital biological functions. Pathogens often have integral proteins that participate in host-cell interactions such as receptor binding and fusion with host membrane. Fusion proteins from a broad range of disparate viruses, such as paramyxovirus, HIV, ebola, and the influenza viruses share a variety of common features that are augmented by glycosylation. Each of these viruses contain multiple glycosylation sites that must be processed and modified by the host post-translational machinery to be fusogenically active. In most viruses, glycosylation plays a role in biogenesis, stability, antigenicity and infectivity. In bacteria, glycosylation events play an important role in the formation of flagellin and pili and are vitally important to adherence, attachment, infectivity and immune evasion. With the importance of glycosylation to pathogen survival, it is clear that a better understanding of the processes is needed to understand the pathogen requirement for glycosylation and to capitalize on this requirement for the development of novel therapeutics.     

Improving Statistical Certainty of Glycosylation Similarity between Influenza A Virus Variants Using Data-Independent Acquisition Mass Spectrometry

Amino acid sequences of immunodominant domains of hemagglutinin (HA) on the surface of influenza A virus (IAV) evolve rapidly, producing viral variants. HA mediates receptor recognition, binding and cell entry, and serves as the target for IAV vaccines. Glycosylation, a post-translational modification that places large branched polysaccharide molecules on proteins, can modulate the function of HA and shield antigenic regions allowing for viral evasion from immune responses. Our previous work showed that subtle changes in the HA protein sequence can have a measurable change in glycosylation. Thus, being able to quantitatively measure glycosylation changes in variants is critical for understanding how HA function may change throughout viral evolution. Moreover, understanding quantitatively how the choice of viral expression systems affects glycosylation can help in the process of vaccine design and manufacture. Although IAV vaccines are most commonly expressed in chicken eggs, cell-based vaccines have many advantages, and the adoption of more cell-based vaccines would be an important step in mitigating seasonal influenza and protecting against future pandemics. Here, we have investigated the use of data-independent acquisition (DIA) mass spectrometry for quantitative glycoproteomics. We found that DIA improved the sensitivity of glycopeptide detection for four variants of A/Switzerland/9715293/2013 (H3N2): WT and mutant, each expressed in embryonated chicken eggs and Madin–Darby canine kidney cells. We used the Tanimoto similarity metric to quantify changes in glycosylation between WT and mutant and between egg-expressed and cell-expressed virus. Our DIA site-specific glycosylation similarity comparison of WT and mutant expressed in eggs confirmed our previous analysis while achieving greater depth of coverage. We found that sequence variations and changing viral expression systems affected distinct glycosylation sites of HA. Our methods can be applied to track glycosylation changes in circulating IAV variants to bolster genomic surveillance already being done, for a more complete understanding of IAV evolution.     

Co‐opting oxylipin signals in microbial disease

Oxylipins, or oxygenated lipids, are universal signalling molecules across all kingdoms of life. These molecules, either produced by microbial pathogens or their mammalian host, regulate inflammation during microbial infection. In this review, we summarise current literature on the biosynthesis pathways of microbial oxylipins and their biological activity towards mammalian cells. Collectively, these studies have illustrated how microbial pathogens can modulate immune rsponse and disease outcome via oxylipin‐mediated mechanisms.     

Disruption of immune regulation by microbial pathogens and resulting chronic inflammation

Activation of the immune response is a tightly regulated, coordinated effort that functions to control and eradicate exogenous microorganisms, while also responding to endogenous ligands. Determining the proper balance of inflammation is essential, as chronic inflammation leads to a wide array of host pathologies. Bacterial pathogens can instigate chronic inflammation via an extensive repertoire of evolved evasion strategies that perturb immune regulation. In this review, we discuss two model pathogens, Mycobacterium tuberculosis and Porphyromonas gingivalis, which efficiently escape various aspects of the immune system within professional and non‐professional immune cell types to establish chronic inflammation. J. Cell. Physiol. 228: 1413–1422, 2013. © 2012 Wiley Periodicals, Inc.     

Current status of immune mechanisms of killing of intracellular microorganisms

The interaction between intracellular pathogens and the mammalian host follows different pathways that reflect evolved survival mechanisms of both the pathogen and the host to assure each one's own survival. From the host's perspective, different immune mechanisms predominate at different stages of infection. Both phagocytic and non-phagocytic target cells participate in microbial uptake and, in some cases, intracellular destruction. In addition, the development of specific immunity ensures sustained activation of intracellular microbicidal mechanisms in the target cells, and induction of apoptotic or lytic target cell death by cytotoxic T lymphocytes. From the pathogen's perspective, different evasion strategies are employed to counteract host defenses. Understanding microbial survival strategies and the immune mechanisms that result in killing of intracellular pathogens will deepen our insight into the pathogenesis of infection that could be applied towards the development of effective vaccination and immunotherapy.     

Macrophage cell death in microbial infections

Macrophages can respond to microbial infections with programmed cell death. The major cell death pathways of apoptosis, pyroptosis and necroptosis are tightly regulated to ensure adequate immune reactions to virulent and persistent invaders. Macrophage death eliminates the replicative niche of intracellular pathogens and induces immune attack. Not surprisingly, successful pathogens have evolved strategies to modulate macrophage cell death pathways to enable microbial survival and replication. Uncontrolled macrophage death can also lead to tissue damage, which may augment bacterial dissemination and pathology. In this review, we highlight how pathogens hijack macrophage cell death signals to promote microbial survival and immune evasion.     

Virus glycosylation: role in virulence and immune interactions

The study of N-linked glycosylation as it relates to virus biology has become an area of intense interest in recent years due to its ability to impart various advantages to virus survival and virulence. HIV and influenza, two clear threats to human health, have been shown to rely on expression of specific oligosaccharides to evade detection by the host immune system. Additionally, other viruses such as Hendra, SARS-CoV, influenza, hepatitis and West Nile rely on N-linked glycosylation for crucial functions such as entry into host cells, proteolytic processing and protein trafficking. This review focuses on recent findings on the importance of glycosylation to viral virulence and immune evasion for several prominent human pathogens.     

肠道菌群功能与影响因素研究进展

人体肠道作为一种营养丰富的天然环境有多达100兆个微生物,其中绝大多数存于结肠内,密度接近1011~1012/m L。人类肠道内的微生物多样性是微生物菌落和宿主共同进化的结果,自然选择和进化使肠道菌群与宿主处于一种动态平衡且稳定的关系。文章综述了肠道菌群对宿主可能产生的影响以及引起肠道菌群发生改变的某些因素,肠道微生物影响宿主的代谢、营养吸收、免疫功能以及神经功能调节,而饮食及其他条件又能引起肠道菌群的改变。深入分析肠道菌群的具体结构、探索不同微生物在宿主体内究竟发挥着怎样的作用以及如何充分利用微生物的不同特性改善人类健康应成为今后研究的重点方向。     

Defining dysbiosis and its influence on host immunity and disease

Mammalian immune system development depends on instruction from resident commensal microorganisms. Diseases associated with abnormal immune responses towards environmental and self antigens have been rapidly increasing over the last 50 years. These diseases include inflammatory bowel disease (IBD), multiple sclerosis (MS), type I diabetes (T1D), allergies and asthma. The observation that people with immune mediated diseases house a different microbial community when compared to healthy individuals suggests that pathogenesis arises from improper training of the immune system by the microbiota. However, with hundreds of different microorganisms on our bodies it is hard to know which of these contribute to health and more importantly how? Microbiologists studying pathogenic organisms have long adhered to Koch's postulates to directly relate a certain disease to a specific microbe, raising the question of whether this might be true of commensal–host relationships as well. Emerging evidence supports that rather than one or two dominant organisms inducing host health, the composition of the entire community of microbial residents influences a balanced immune response. Thus, perturbations to the structure of complex commensal communities (referred to as dysbiosis) can lead to deficient education of the host immune system and subsequent development of immune mediated diseases. Here we will overview the literature that describes the causes of dysbiosis and the mechanisms evolved by the host to prevent these changes to community structure. Building off these studies, we will categorize the different types of dysbiosis and define how collections of microorganisms can influence the host response. This research has broad implications for future therapies that go beyond the introduction of a single organism to induce health. We propose that identifying mechanisms to re‐establish a healthy complex microbiota after dysbiosis has occurred, a process we will refer to as rebiosis, will be fundamental to treating complex immune diseases.     

Can some microbes promote host stress and benefit evolutionarily from this strategy?

Microbes can influence host physiology and behavior in many ways. Here we review evidence suggesting that some microbes can contribute to host stress (and other microbes can contribute to increased resilience to stress). We explain how certain microbes, which we call “stress microbes,” can potentially benefit evolutionarily from inducing stress in a host, gaining access to host resources that can help fuel rapid microbial replication by increasing glucose levels in the blood, increasing intestinal permeability, and suppressing the immune system. Other microbes, which we term “resilience microbes,” can potentially benefit from making hosts more resilient to stress. We hypothesize that “stress microbes” use a fast life history strategy involving greater host exploitation while “resilience microbes” use a slow life history strategy characterized by more aligned evolutionary interests with the host. In this paper, we review the evidence that microbes affect host stress and explain the evolutionary pressures that could lead microbes to manipulate host stress, discuss the physiological mechanisms that are known to be involved in both stress and microbial activity, and provide some testable predictions that follow from this hypothesis.     

The role of the commensal microbiota in adaptive and maladaptive stressor-induced immunomodulation

Over the past decade, it has become increasingly evident that there are extensive bidirectional interactions between the body and its microbiota. These interactions are evident during stressful periods, where it is recognized that commensal microbiota community structure is significantly changed. Many different stressors, ranging from early life stressors to stressors administered during adulthood, lead to significant, community-wide differences in the microbiota. The mechanisms through which this occurs are not yet known, but it is known that commensal microbes can recognize, and respond to, mammalian hormones and neurotransmitters, including those that are involved with the physiological response to stressful stimuli. In addition, the physiological stress response also changes many aspects of gastrointestinal physiology that can impact microbial community composition. Thus, there are many routes through which microbial community composition might be disrupted during stressful periods. The implications of these disruptions in commensal microbial communities for host health are still not well understood, but the commensal microbiota have been linked to stressor-induced immunopotentiation. The role of the microbiota in stressor-induced immunopotentiation can be adaptive, such as when these microbes stimulate innate defenses against bacterial infection. However, the commensal microbiota can also lead to maladaptive immune responses during stressor-exposure. This is evident in animal models of colonic inflammation where stressor exposure increases the inflammation through mechanisms involving the microbiota. It is likely that during stressor exposure, immune cell functioning is regulated by combined effects of both neurotransmitters/hormones and commensal microbes. Defining this regulation should be a focus of future studies.