Bacterial glycans: key mediators of diverse host immune responses

Recent studies have shown that the synthesis of various polysaccharides by bacteria can induce immune responses that are beneficial to the bacterium, the host, or both. Here, we discuss the diverse interactions between bacterial glycans and the host immune system.     

Modulation of host immune responses by nematode cystatins

Parasitic nematodes, living in the intestinal tract or within tissues of theirs hosts, are constantly exposed to an array of immune effector mechanisms. One strategy to cope with the immune response is the release of immunomodulatory components that block effector mechanisms or interact with the cytokine network. Among the secreted nematode immunomodulators, cysteine protease inhibitors (cystatins) are shown to be of major importance. Nematode cystatins inhibit, among others, proteases involved in antigen processing and presentation, which leads to a reduction of T cell responses. At the same time nematode cystatins modulate cytokine responses, the most prominent trait being the upregulation of IL-10, a Th2 cytokine, by macrophages. In this situation, IL-10 leads among others to downregulation of costimulatory surface molecules of macrophages. These properties contribute to induction of an anti-inflammatory environment, concomitant with a strong inhibition of cellular proliferation. This setting is believed to favour the survival of worms. An opposite activity of nematode cystatins is the upregulation of production of inducible nitric oxide by IFN-gamma activated macrophages, an intrinsic property of natural cysteine protease inhibitors. This shows that these proteins can act as proinflammatory molecules under certain circumstances. A comparison of the immunomodulatory effects of cystatins of filarial nematodes with homologous proteins of the free-living nematode Caenorhabditis elegans revealed distinct differences. Caenorhabditis elegans cystatins induce the production of the Th1 cytokine IL-12, in contrast to filarial cystatins that upregulate IL-10. Caenorhabditis elegans cystatins hardly inhibit cellular proliferation. These data suggest that cystatins of parasitic nematodes have multiple, specific capacities for immunomodulation, acting in parallel on different immune effector mechanisms. Elucidation of the mechanisms involved might be useful in the development of immunotherapeutic reagents in the future.     

Parasite glycans and antibody-mediated immune responses in Schistosoma infection

Schistosome infections in humans are characterized by the development of chronic disease and high re-infection rates after treatment due to the slow development of immunity. It appears that anti-schistosome antibodies are at least partially mediating protective mechanisms. Efforts to develop a vaccine based on immunization with surface-exposed or secreted larval or worm proteins are ongoing. Schistosomes also express a large number of glycans as part of their glycoprotein and glycolipid repertoire, and antibody responses to those glycans are mounted by the infected host. This observation raises the question if glycans might also form novel vaccine targets for immune intervention in schistosomiasis. This review summarizes current knowledge of antibody responses and immunity in experimental and natural infections with Schistosoma, the expression profiles of schistosome glycans (the glycome), and antibody responses to individual antigenic glycan motifs. Future directions to study anti-glycan responses in schistosomiasis in more detail in order to address more precisely the possible role of glycans in antibody-mediated immunity are discussed.     

Epstein-Barr病毒的免疫调控与逃逸机制北大核心CSCD

EB病毒(Epstein-Barr Virus,EBV)属于γ疱疹病毒科,是第一个被发现与人类肿瘤相关的DNA病毒。EB病毒通过激活Toll样受体(Toll like receptors,TLRs)信号通路,诱导I型干扰素的大量释放和功能性的自噬机制,从而引起机体的免疫应答。然而,相对于其他疱疹病毒,EB病毒已进化出更为精细且错综复杂的机制来破坏和逃逸宿主的免疫系统,如限制自身蛋白表达、活化宿主的泛素-蛋白酶体系统、干扰或逆转自噬与泛素化修饰等。这些机制会引发EB病毒在宿主体内的持续性感染,导致宿主免疫功能失调,引发EB病毒相关疾病(如鼻咽癌、传染性单核细胞增多症等)。因此,研究EB病毒特异性的免疫调控机制不仅对深入理解EB病毒的潜伏性感染和致癌性至关重要,而且还将为EB病毒诱发的相关疾病的免疫预防与治疗鉴定出新的潜在靶点。此文主要阐述了EB病毒调控宿主免疫应答和逃逸先天免疫应答的分子机制。     

Manipulation of host innate immune responses by the malaria parasite

It has long been known that malaria infection causes host immune modulation by various mechanisms. However, the role of Toll-like receptors (TLRs) in mediating innate immune responses to parasite-derived components during the blood stages of malaria has only recently been described. TLRs might have an important role in pathogenesis during malaria infection, as supported by genetic analyses in mice and humans. Moreover, recent findings revealed that sporozoites can partially differentiate in lymph nodes and that liver stages induce the formation of previously unknown parasite-filled vesicles (merosomes) that could function as immune escape machinery. Elucidation of the mechanisms by which the host innate immune system responds to, and/or is manipulated by, Plasmodium infection will hopefully lead to discoveries of potential targets that will ultimately prevent and/or intervene in malaria infection.     

Coevolution of hytrosaviruses and host immune responses

Background

Hytrosaviruses (SGHVs; Hytrosaviridae family) are double-stranded DNA (dsDNA) viruses that cause salivary gland hypertrophy (SGH) syndrome in flies. Two structurally and functionally distinct SGHVs are recognized; Glossina pallidipes SGHV (GpSGHV) and Musca domestica SGHV (MdSGHV), that infect the hematophagous tsetse fly and the filth-feeding housefly, respectively. Genome sizes and gene contents of GpSGHV (~ 190 kb; 160–174 genes) and MdSGHV (~ 124 kb; 108 genes) may reflect an evolution with the SGHV-hosts resulting in differences in pathobiology. Whereas GpSGHV can switch from asymptomatic to symptomatic infections in response to certain unknown cues, MdSGHV solely infects symptomatically. Overt SGH characterizes the symptomatic infections of SGHVs, but whereas MdSGHV induces both nuclear and cellular hypertrophy (enlarged non-replicative cells), GpSGHV induces cellular hyperplasia (enlarged replicative cells). Compared to GpSGHV’s specificity to Glossina species, MdSGHV infects other sympatric muscids. The MdSGHV-induced total shutdown of oogenesis inhibits its vertical transmission, while the GpSGHV’s asymptomatic and symptomatic infections promote vertical and horizontal transmission, respectively. This paper reviews the coevolution of the SGHVs and their hosts (housefly and tsetse fly) based on phylogenetic relatedness of immune gene orthologs/paralogs and compares this with other virus-insect models.

Results

Whereas MdSGHV is not vertically transmitted, GpSGHV is both vertically and horizontally transmitted, and the balance between the two transmission modes may significantly influence the pathogenesis of tsetse virus. The presence and absence of bacterial symbionts (Wigglesworthia and Sodalis) in tsetse and Wolbachia in the housefly, respectively, potentially contributes to the development of SGH symptoms. Unlike MdSGHV, GpSGHV contains not only host-derived proteins, but also appears to have evolutionarily recruited cellular genes from ancestral host(s) into its genome, which, although may be nonessential for viral replication, potentially contribute to the evasion of host’s immune responses. Whereas MdSGHV has evolved strategies to counteract both the housefly’s RNAi and apoptotic responses, the housefly has expanded its repertoire of immune effector, modulator and melanization genes compared to the tsetse fly.

Conclusions

The ecologies and life-histories of the housefly and tsetse fly may significantly influence coevolution of MdSGHV and GpSGHV with their hosts. Although there are still many unanswered questions regarding the pathogenesis of SGHVs, and the extent to which microbiota influence expression of overt SGH symptoms, SGHVs are attractive ‘explorers’ to elucidate the immune responses of their hosts, and the transmission modes of other large DNA viruses.

     

Modeling systems-level regulation of host immune responses

Many pathogens are able to manipulate the signaling pathways responsible for the generation of host immune responses. Here we examine and model a respiratory infection system in which disruption of host immune functions or of bacterial factors changes the dynamics of the infection. We synthesize the network of interactions between host immune components and two closely related bacteria in the genus Bordetellae. We incorporate existing experimental information on the timing of immune regulatory events into a discrete dynamic model, and verify the model by comparing the effects of simulated disruptions to the experimental outcome of knockout mutations. Our model indicates that the infection time course of both Bordetellae can be separated into three distinct phases based on the most active immune processes. We compare and discuss the effect of the species-specific virulence factors on disrupting the immune response during their infection of naive, antibody-treated, diseased, or convalescent hosts. Our model offers predictions regarding cytokine regulation, key immune components, and clearance of secondary infections; we experimentally validate two of these predictions. This type of modeling provides new insights into the virulence, pathogenesis, and host adaptation of disease-causing microorganisms and allows systems-level analysis that is not always possible using traditional methods.     

How Mycobacterium tuberculosis subverts host immune responses

Mycobacterium tuberculosis is the causative agent of pulmonary tuberculosis which has infected one third of the mankind and causes 2-3 million deaths worldwide each year. The persistence of the infection ensues from the ability of M. tuberculosis to subvert host immune responses in favor of survival and growth of mycobacteria in macrophages. The mechanisms by which M. tuberculosis manipulates the host immune system have only recently come to light. These activities are attributed to lipoarabinomannans (LAM) and their precursors lipomannans (LM), two predominant glycolipids of M. tuberculosis cell wall. LM are able to skew anti-mycobacterial immune responses into un-protective ones, while LAM evoke immunosupression upon binding to macrophage and dendritic cell receptors specialized in binding to "self" host components. A newly emerging idea implicates plasma membrane rafts in LM and LAM signaling. Depending on acylation patterns, the glycolipids may either directly incorporate into the raft membrane via mannosylphosphatidylinositol anchors or interact with raft-associated proteins to affect the assembly of receptor signaling complexes.     

Modulation of host immune responses by clinically relevant human DNA and RNA viruses

Numerous mechanisms allow viruses to evade host immune surveillance, and new evasion strategies continue to be identified. In addition to interference with antigen processing and presentation, direct viral modulation of host immune responses can also be achieved by altering the host cytokine milieu and the development of immunoregulatory cells. A better understanding of these viral evasion strategies will help to define critical host defense mechanisms and will lead to novel immune-based therapeutic strategies in the future.     

Yersinia type III effectors perturb host innate immune responses

The innate immune system is the first line of defense against invading pathogens. Innate immune cells recognize molecular patterns from the pathogen and mount a response to resolve the infection. The production of proinflammatory cytokines and reactive oxygen species, phagocytosis, and induced programmed cell death are processes initiated by innate immune cells in order to combat invading pathogens. However, pathogens have evolved various virulence mechanisms to subvert these responses. One strategy utilized by Gram-negative bacterial pathogens is the deployment of a complex machine termed the type III secretion system (T3SS). The T3SS is composed of a syringe-like needle structure and the effector proteins that are injected directly into a target host cell to disrupt a cellular response. The three human pathogenic Yersinia spp. (Y. pestis, Y. enterocolitica, and Y. pseudotuberculosis) are Gram-negative bacteria that share in common a 70 kb virulence plasmid which encodes the T3SS. Translocation of the Yersinia effector proteins (YopE, YopH, YopT, YopM, YpkA/YopO, and YopP/J) into the target host cell results in disruption of the actin cytoskeleton to inhibit phagocytosis, downregulation of proinflammatory cytokine/chemokine production, and induction of cellular apoptosis of the target cell. Over the past 25 years, studies on the Yersinia effector proteins have unveiled tremendous knowledge of how the effectors enhance Yersinia virulence. Recently, the long awaited crystal structure of YpkA has been solved providing further insights into the activation of the YpkA kinase domain. Multisite autophosphorylation by YpkA to activate its kinase domain was also shown and postulated to serve as a mechanism to bypass regulation by host phosphatases. In addition, novel Yersinia effector protein targets, such as caspase-1, and signaling pathways including activation of the inflammasome were identified. In this review, we summarize the recent discoveries made on Yersinia effector proteins and their contribution to Yersinia pathogenesis.     

Shigella deploy multiple countermeasures against host innate immune responses

Although the intestinal epithelium is equipped with multiple defense systems that sense bacterial components, transmit alarms to the immune system, clear the bacteria, and renew the injured epithelial lining, mucosal bacterial pathogens are capable of efficiently colonizing the intestinal epithelium, because they have evolved systems that modulate the inflammatory and immune responses of the host and exploit the harmful environments as replicative niches. In this review we highlight current topics concerning Shigella's tactics that interfere with the innate immune systems.     

Escherichia coli heme oxygenase modulates host innate immune responses

Induction of mammalian heme oxygenase (HO)‐1 and exposure of animals to carbon monoxide (CO) ameliorates experimental colitis. When enteric bacteria, including Escherichia coli, are exposed to low iron conditions, they express an HO‐like enzyme, chuS, and metabolize heme into iron, biliverdin and CO. Given the abundance of enteric bacteria residing in the intestinal lumen, our postulate was that commensal intestinal bacteria may be a significant source of CO and those that express chuS and other Ho‐like molecules suppress inflammatory immune responses through release of CO. According to real‐time PCR, exposure of mice to CO results in changes in enteric bacterial composition and increases E. coli 16S and chuS DNA. Moreover, the severity of experimental colitis correlates positively with E. coli chuS expression in IL‐10 deficient mice. To explore functional roles, E. coli were genetically modified to overexpress chuS or the chuS gene was deleted. Co‐culture of chuS‐overexpressing E. coli with bone marrow‐derived macrophages resulted in less IL‐12p40 and greater IL‐10 secretion than in wild‐type or chuS‐deficient E. coli. Mice infected with chuS‐overexpressing E. coli have more hepatic CO and less serum IL‐12 p40 than mice infected with chuS‐deficient E. coli. Thus, CO alters the composition of the commensal intestinal microbiota and expands populations of E. coli that harbor the chuS gene. These bacteria are capable of attenuating innate immune responses through expression of chuS. Bacterial HO‐like molecules and bacteria‐derived CO may represent novel targets for therapeutic intervention in inflammatory conditions.     

Shiga toxins expressed by human pathogenic bacteria induce immune responses in host cells

Shiga toxins are a family of genetically and structurally related toxins that are the primary virulence factors produced by the bacterial pathogens Shigella dysenteriae serotype 1 and certain Escherichia coli strains. The toxins are multifunctional proteins inducing protein biosynthesis inhibition, ribotoxic and ER stress responses, apoptosis, autophagy, and inflammatory cytokine and chemokine production. The regulated induction of inflammatory responses is key to minimizing damage upon injury or pathogen-mediated infections, requiring the concerted activation of multiple signaling pathways to control cytokine/chemokine expression. Activation of host cell signaling cascades is essential for Shiga toxin-mediated proinflammatory responses and the contribution of the toxins to virulence. Many studies have been reported defining the inflammatory response to Shiga toxins in vivo and in vitro, including production and secretion of tumor necrosis factor alpha (TNF-α), interleukin-1β (IL-1β), macrophage inflammatory protein-1α/β (MIP-1α/β), macrophage chemoattractant monocyte chemoattractant protein 1 (MCP-1), interleukin 8 (IL-8), interleukin 6 (IL-6), and Groβ. These cytokines and chemokines may contribute to damage in the colon and development of life threatening conditions such as acute renal failure (hemolytic uremic syndrome) and neurological abnormalities. In this review, we summarize recent findings in Shiga toxin-mediated inflammatory responses by different types of cells in vitro and in animal models. Signaling pathways involved in the inflammatory responses are briefly reviewed.     

申克孢子丝菌毒力因子及宿主抗感染免疫的研究进展

申克孢子丝菌是一种重要的双相型真菌,其引起的孢子丝菌病是一种常见的侵袭性皮肤感染.研究该菌毒力因子及宿主对其抗感染免疫对于深入了解其致病性及防治该病具有重要意义.该文介绍了申克孢子丝菌毒力因子及宿主对其抗感染免疫方面的研究进展.     

Candida albicans cell wall glycans, host receptors and responses: elements for a decisive crosstalk

Candida albicans has adapted to live on the mucosal surfaces of animals. The human species has accepted it. By contrast to numerous other commensals, C. albicans has a prominent ability to invade virtually all tissues of a host presenting with natural or acquired defects in homeostasis. C. albicans uses considerable energy to synthesize glycans, which are present either as polymers or as glyconjugates. These glycan molecules play a prominent role in the biology of C. albicans by controlling the structure and plasticity of the cell wall, and are also involved in yeast-host interactions. These glycans are recognized as 'non-self' by host innate and adaptative immunity. The signal they induce in the host depends on the 'glycan code', which is determined by the nature of the sugar, the anomer type of linkage and branching, and the length of the oligosaccharide chains. However, this model is not static because the nature of the C. albicans molecule carrying such glycan codes and their expression at the cell wall surface also determines the host response, and, in turn, the regulation of cell wall glycan arrangement dynamics in C. albicans depends on host stimuli. Candida glycans therefore play an important role in the continuous interchange that regulates the balance between saprophytism and parasitism, and resistance and infection. A goal of current research concerning the virulence attributes of C. albicans will be to determine to what extent this species is able to regulate its glycan code as a response to the host.     

Trafficking at the host cell surface during plant immune responses

The plasma membrane (PM) of eukaryotic cells is not only an outermost covering to contain and protect inner molecules required for cell viability but also a place where communications dynamically occur with adjacent cells and environments including pathogens. However the selective permeability limits the free translocation of information across the PM between cells. Therefore, eukaryotic cells have invented an elaborate machinery to safely export and import proteins and small molecules within a membrane-wrapped container called a vesicle. Upon infection, a host plant cell also actively interacts with a phytopathogen to achieve its goal, defense to frustrate the pathogen attempt. To understand communications between pathogens and plants, hence this review is mainly focused on molecular transport events that occur at the host PM during plant immune responses.     

Harnessing host immune responses to preneoplasia: promise and challenges

Preneoplastic lesions are more common than clinical cancer and define a population at increased risk for the development of malignancy. Recent studies suggest that the immune system has the capacity to recognize these lesions, and enrichment of preneoplasia-specific immune effectors can be detected in the tumor bed of some preneoplastic lesions such as monoclonal gammopathies. Here, I discuss the promise and challenges of harnessing the immune response against preneoplasia. Approaches to boost the natural host response to these lesions may have a major impact on reducing net cancer burden.