Showing papers in "Current Topics in Microbiology and Immunology in 2015"

Leptospirosis in Humans

Abstract: Leptospirosis is a widespread and potentially fatal zoonosis that is endemic in many tropical regions and causes large epidemics after heavy rainfall and flooding. Infection results from direct or indirect exposure to infected reservoir host animals that carry the pathogen in their renal tubules and shed pathogenic leptospires in their urine. Although many wild and domestic animals can serve as reservoir hosts , the brown rat (Rattus norvegicus) is the most important source of human infections. Individuals living in urban slum environments characterized by inadequate sanitation and poor housing are at high risk of rat exposure and leptospirosis. The global burden of leptospirosis is expected to rise with demographic shifts that favor increases in the number of urban poor in tropical regions subject to worsening storms and urban flooding due to climate change. Data emerging from prospective surveillance studies suggest that most human leptospiral infections in endemic areas are mild or asymptomatic. Development of more severe outcomes likely depends on three factors: epidemiological conditions, host susceptibility, and pathogen virulence (Fig. 1). Mortality increases with age, particularly in patients older than 60 years of age. High levels of bacteremia are associated with poor clinical outcomes and, based on animal model and in vitro studies, are related in part to poor recognition of leptospiral LPS by human TLR4. Patients with severe leptospirosis experience a cytokine storm characterized by high levels of IL-6, TNF-alpha, and IL-10. Patients with the HLA DQ6 allele are at higher risk of disease, suggesting a role for lymphocyte stimulation by a leptospiral superantigen. Leptospirosis typically presents as a nonspecific, acute febrile illness characterized by fever, myalgia, and headache and may be confused with other entities such as influenza and dengue fever. Newer diagnostic methods facilitate early diagnosis and antibiotic treatment. Patients progressing to multisystem organ failure have widespread hematogenous dissemination of pathogens. Nonoliguric (high output) renal dysfunction should be supported with fluids and electrolytes. When oliguric renal failure occurs, prompt initiation of dialysis can be life saving. Elevated bilirubin levels are due to hepatocellular damage and disruption of intercellular junctions between hepatocytes, resulting in leaking of bilirubin out of bile caniliculi. Hemorrhagic complications are common and are associated with coagulation abnormalities. Severe pulmonary hemorrhage syndrome due to extensive alveolar hemorrhage has a fatality rate of >50 %. Readers are referred to earlier, excellent summaries related to this subject (Adler and de la Pena-Moctezuma 2010; Bharti et al. 2003; Hartskeerl et al. 2011; Ko et al. 2009; Levett 2001; McBride et al. 2005).

EBV Persistence—Introducing the Virus

Abstract: Persistent infection by EBV is explained by the germinal center model (GCM) which provides a satisfying and currently the only explanation for EBVs disparate biology. Since the GCM touches on every aspect of the virus, this chapter will serve as an introduction to the subsequent chapters. EBV is B lymphotropic, and its biology closely follows that of normal mature B lymphocytes. The virus persists quiescently in resting memory B cells for the lifetime of the host in a non-pathogenic state that is also invisible to the immune response. To access this compartment, the virus infects naive B cells in the lymphoepithelium of the tonsils and activates these cells using the growth transcription program. These cells migrate to the GC where they switch to a more limited transcription program, the default program, which helps rescue them into the memory compartment where the virus persists. For egress, the infected memory cells return to the lymphoepithelium where they occasionally differentiate into plasma cells activating viral replication. The released virus can either infect more naive B cells or be amplified in the epithelium for shedding. This cycle of infection and the quiescent state in memory B cells allow for lifetime persistence at a very low level that is remarkably stable over time. Mathematically, this is a stable fixed point where the mechanisms regulating persistence drive the state back to equilibrium when perturbed. This is the GCM of EBV persistence. Other possible sites and mechanisms of persistence will also be discussed.

Envelope Structures of Gram-Positive Bacteria

Abstract: Gram-positive organisms, including the pathogens Staphylococcus aureus, Streptococcus pneumoniae, and Enterococcus faecalis, have dynamic cell envelopes that mediate interactions with the environment and serve as the first line of defense against toxic molecules. Major components of the cell envelope include peptidoglycan (PG), which is a well-established target for antibiotics, teichoic acids (TAs), capsular polysaccharides (CPS), surface proteins, and phospholipids. These components can undergo modification to promote pathogenesis, decrease susceptibility to antibiotics and host immune defenses, and enhance survival in hostile environments. This chapter will cover the structure, biosynthesis, and important functions of major cell envelope components in gram-positive bacteria. Possible targets for new antimicrobials will be noted.

Anti-virulence Strategies to Target Bacterial Infections.

Abstract: Resistance of important bacterial pathogens to common antimicrobial therapies and the emergence of multidrug-resistant bacteria are increasing at an alarming rate and constitute one of our greatest challenges in the combat of bacterial infection and accompanied diseases. The current shortage of effective drugs, lack of successful prevention measures and only a few new antibiotics in the clinical pipeline demand the development of novel treatment options and alternative antimicrobial therapies. Our increasing understanding of bacterial virulence strategies and the induced molecular pathways of the infectious disease provides novel opportunities to target and interfere with crucial pathogenicity factors or virulence-associated traits of the bacteria while bypassing the evolutionary pressure on the bacterium to develop resistance. In the past decade, numerous new bacterial targets for anti-virulence therapies have been identified, and structure-based tailoring of intervention strategies and screening assays for small-molecule inhibitors of such pathways were successfully established. In this chapter, we will take a closer look at the bacterial virulence-related factors and processes that present promising targets for anti-virulence therapies, recently discovered inhibitory substances and their promises and discuss the challenges, and problems that have to be faced.

The Latent Membrane Protein 1 (LMP1)

Abstract: Almost exactly twenty years after the discovery of Epstein-Barr virus (EBV), the latent membrane protein 1 (LMP1) entered the EBV stage, and soon thereafter, it was recognized as the primary transforming gene product of the virus. LMP1 is expressed in most EBV-associated lymphoproliferative diseases and malignancies, and it critically contributes to pathogenesis and disease phenotypes. Thirty years of LMP1 research revealed its high potential as a deregulator of cellular signal transduction pathways leading to target cell proliferation and the simultaneous subversion of cell death programs. However, LMP1 has multiple roles beyond cell transformation and immortalization, ranging from cytokine and chemokine induction, immune modulation, the global alteration of gene and microRNA expression patterns to the regulation of tumor angiogenesis, cell-cell contact, cell migration, and invasive growth of tumor cells. By acting like a constitutively active receptor, LMP1 recruits cellular signaling molecules associated with tumor necrosis factor receptors such as tumor necrosis factor receptor-associated factor (TRAF) proteins and TRADD to mimic signals of the costimulatory CD40 receptor in the EBV-infected B lymphocyte. LMP1 activates NF-κB, mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase (PI3-K), IRF7, and STAT pathways. Here, we review LMP1's molecular and biological functions, highlighting the interface between LMP1 and the cellular signal transduction network as an important factor of virus-host interaction and a potential therapeutic target.

History of leptospirosis and leptospira.

Abstract: Leptospira was isolated and identified as the causative agent of the severe human syndrome Weil's disease about 100 years ago almost simultaneously, but independently, by workers in Japan and Europe Since that time leptospires have been isolated from almost all mammalian species on every continent except Antarctica, with leptospirosis now recognized as the most widespread zoonosis worldwide and also a major cause of disease in many domestic animal species Recent advances in molecular taxonomy have facilitated the development of a rational classification system, while the availability of genome sequences and the development of mutagenesis systems have begun to shed light on mechanisms of pathogenesis that appear to be unique to Leptospira

Primary Immunodeficiencies Associated with EBV Disease.

Abstract: Epstein-Barr virus (EBV) infects nearly all humans and usually is asymptomatic, or in the case of adolescents and young adults, it can result in infectious mononucleosis. EBV-infected B cells are controlled primarily by NK cells, iNKT cells, CD4 T cells, and CD8 T cells. While mutations in proteins important for B cell function can affect EBV infection of these cells, these mutations do not result in severe EBV infection. Some genetic disorders affecting T and NK cell function result in failure to control EBV infection, but do not result in increased susceptibility to other virus infections. These include mutations in SH2D1A, BIRC4, ITK, CD27, MAGT1, CORO1A, and LRBA. Since EBV is the only virus that induces proliferation of B cells, the study of these diseases has helped to identify proteins critical for interactions of T and/or NK cells with B cells. Mutations in three genes associated with hemophagocytic lymphohistocytosis, PRF1, STXBP2, and UNC13D, can also predispose to severe chronic active EBV disease. Severe EBV infection can be associated with immunodeficiencies that also predispose to other viral infections and in some cases other bacterial and fungal infections. These include diseases due to mutations in PIK3CD, PIK3R1, CTPS1, STK4, GATA2, MCM4, FCGR3A, CARD11, ATM, and WAS. In addition, patients with severe combined immunodeficiency, which can be due to mutations in a number of different genes, are at high risk for various infections as well as EBV B cell lymphomas. Identification of proteins important for control of EBV may help to identify new targets for immunosuppressive therapies.

Immune Evasion by Epstein-Barr Virus.

Abstract: Epstein-Bar virus (EBV) is widespread within the human population with over 90% of adults being infected. In response to primary EBV infection, the host mounts an antiviral immune response comprising both innate and adaptive effector functions. Although the immune system can control EBV infection to a large extent, the virus is not cleared. Instead, EBV establishes a latent infection in B lymphocytes characterized by limited viral gene expression. For the production of new viral progeny, EBV reactivates from these latently infected cells. During the productive phase of infection, a repertoire of over 80 EBV gene products is expressed, presenting a vast number of viral antigens to the primed immune system. In particular the EBV-specific CD4+ and CD8+ memory T lymphocytes can respond within hours, potentially destroying the virus-producing cells before viral replication is completed and viral particles have been released. Preceding the adaptive immune response, potent innate immune mechanisms provide a first line of defense during primary and recurrent infections. In spite of this broad range of antiviral immune effector mechanisms, EBV persists for life and continues to replicate. Studies performed over the past decades have revealed a wide array of viral gene products interfering with both innate and adaptive immunity. These include EBV-encoded proteins as well as small noncoding RNAs with immune-evasive properties. The current review presents an overview of the evasion strategies that are employed by EBV to facilitate immune escape during latency and productive infection. These evasion mechanisms may also compromise the elimination of EBV-transformed cells, and thus contribute to malignancies associated with EBV infection.

Innate Immune Sensing and Response to Influenza

Abstract: Influenza viruses pose a substantial threat to human and animal health worldwide. Recent studies in mouse models have revealed an indispensable role for the innate immune system in defense against influenza virus. Recognition of the virus by innate immune receptors in a multitude of cell types activates intricate signaling networks, functioning to restrict viral replication. Downstream effector mechanisms include activation of innate immune cells and, induction and regulation of adaptive immunity. However, uncontrolled innate responses are associated with exaggerated disease, especially in pandemic influenza virus infection. Despite advances in the understanding of innate response to influenza in the mouse model, there is a large knowledge gap in humans, particularly in immunocompromised groups such as infants and the elderly. We propose here, the need for further studies in humans to decipher the role of innate immunity to influenza virus, particularly at the site of infection. These studies will complement the existing work in mice and facilitate the quest to design improved vaccines and therapeutic strategies against influenza.

BTK Signaling in B Cell Differentiation and Autoimmunity

Abstract: Since the original identification of Bruton’s tyrosine kinase (BTK) as the gene defective in the primary immunodeficiency X-linked agammaglobulinemia (XLA) in 1993, our knowledge on the physiological function of BTK has expanded impressively. In this review, we focus on the role of BTK during B cell differentiation in vivo, both in the regulation of expansion and in the developmental progression of pre-B cells in the bone marrow and as a crucial signal transducer of signals downstream of the IgM or IgG B cell antigen receptor (BCR) in mature B cells governing proliferation, survival, and differentiation. In particular, we highlight BTK function in B cells in the context of host defense and autoimmunity. Small-molecule inhibitors of BTK have very recently shown impressive anti-tumor activity in clinical studies in patients with various B cell malignancies. Since promising effects of BTK inhibition were also seen in experimental animal models for lupus and rheumatoid arthritis, BTK may be a good target for controlling autoreactive B cells in patients with systemic autoimmune disease.

EBV and Autoimmunity.

Abstract: Although a role of EBV in autoimmunity is biologically plausible and evidence of altered immune responses to EBV is abundant in several autoimmune diseases, inference on causality requires the determination that disease risk is higher in individuals infected with EBV than in those uninfected and that in the latter it increases following EBV infection. This determination has so far been possible only for multiple sclerosis (MS) and, to some extent, for systemic lupus erythematosus (SLE), whereas evidence is either lacking or not supportive for other autoimmune conditions. In this chapter, we present the main epidemiological findings that justify the conclusion that EBV is a component cause of MS and SLE and possible mechanisms underlying these effects.

Systematics of Leptospiraceae

Abstract: Leptospires are spirochetes that may be free-living saprophytes found in freshwater or may cause acute or chronic infection of animals. The family Leptospiraceae comprises three genera: Leptospira , Leptonema , and Turneriella . Within the genus Leptospira, three clades can be distinguished, of pathogens, nonpathogens, and an intermediate group. Leptospires are further divided into serovars; antigenically related serovars are clustered into serogroups for convenience.

NK cells and cancer immunoediting

Abstract: Natural killer (NK) cells are innate lymphoid cells (ILC) known for their ability to recognize and rapidly eliminate infected or transformed cells. Consequently, NK cells are fundamental for host protection against virus infections and malignancies. Even though the critical role of NK cells in cancer immunosurveillance was suspected years ago, the underlying mechanisms took time to be unraveled. Today, it is clear that anti-tumor functions of NK cells are tightly regulated and expand far beyond the simple killing of malignant cells. In spite of tremendous steps made in understanding the NK cell biology, further work is warranted to fully exploit the anticancer potential of these cells. Indeed, tumor-mediated immune suppression hampers NK cell activity, thus complicating their stimulation for therapeutic purposes. Herein, we review the current knowledge of NK cell functions in anti-tumor immunity . We discuss NK cell activity in the cancer immunoediting process with particular emphasis on the elimination and escape phases.

Vaccines against leptospirosis.

Abstract: Vaccines against leptospirosis followed within a year of the first isolation of Leptospira, with the first use of a killed whole cell bacterin vaccine in guinea pigs published in 1916. Since then, bacterin vaccines have been used in humans, cattle, swine, and dogs and remain the only vaccines licensed at the present time. The immunity elicited is restricted to serovars with related lipopolysaccharide (LPS) antigen. Likewise, vaccines based on LPS antigens have clearly demonstrated protection in animal models, which is also at best serogroup specific. The advent of leptospiral genome sequences has allowed a reverse vaccinology approach for vaccine development. However, the use of inadequate challenge doses and inappropriate statistical analysis invalidates many of the claims of protection with recombinant proteins.

The Effector T Cell Response to Influenza Infection

Abstract: Influenza virus infection induces a potent initial innate immune response, which serves to limit the extent of viral replication and virus spread. However, efficient (and eventual) viral clearance within the respiratory tract requires the subsequent activation, rapid proliferation, recruitment, and expression of effector activities by the adaptive immune system, consisting of antibody producing B cells and influenza-specific T lymphocytes with diverse functions. The ensuing effector activities of these T lymphocytes ultimately determine (along with antibodies) the capacity of the host to eliminate the viruses and the extent of tissue damage. In this review, we describe this effector T cell response to influenza virus infection. Based on information largely obtained in experimental settings (i.e., murine models), we will illustrate the factors regulating the induction of adaptive immune T cell responses to influenza, the effector activities displayed by these activated T cells, the mechanisms underlying the expression of these effector mechanisms, and the control of the activation/differentiation of these T cells, in situ, in the infected lungs.

EBV Noncoding RNAs.

Abstract: EBV expresses a number of viral noncoding RNAs (ncRNAs) during latent infection, many of which have known regulatory functions and can post-transcriptionally regulate viral and/or cellular gene expression. With recent advances in RNA sequencing technologies, the list of identified EBV ncRNAs continues to grow. EBV-encoded RNAs (EBERs) , the BamHI-A rightward transcripts (BARTs) , a small nucleolar RNA (snoRNA) , and viral microRNAs (miRNAs) are all expressed during EBV infection in a variety of cell types and tumors. Recently, additional novel EBV ncRNAs have been identified. Viral miRNAs, in particular, have been under extensive investigation since their initial identification over ten years ago. High-throughput studies to capture miRNA targets have revealed a number of miRNA-regulated viral and cellular transcripts that tie into important biological networks. Functions for many EBV ncRNAs are still unknown; however, roles for many EBV miRNAs in latency and in tumorigenesis have begun to emerge. Ongoing mechanistic studies to elucidate the functions of EBV ncRNAs should unravel additional roles for ncRNAs in the viral life cycle. In this chapter, we will discuss our current knowledge of the types of ncRNAs expressed by EBV, their potential roles in viral latency, and their potential involvement in viral pathogenesis.

Nasopharyngeal Carcinoma: An Evolving Role for the Epstein-Barr Virus.

Abstract: The Epstein–Barr herpesvirus (EBV) is an important human pathogen that is closely linked to several major malignancies including the major epithelial tumor, undifferentiated nasopharyngeal carcinoma (NPC). This important tumor occurs with elevated incidence in specific areas, particularly in southern China but also in Mediterranean Africa and some regions of the Middle East. Regardless of tumor prevalence, undifferentiated NPC is consistently associated with EBV. The consistent detection of EBV in all cases of NPC, the maintenance of the viral genome in every cell, and the continued expression of viral gene products suggest that EBV is a necessary factor for the malignant growth in vivo. However, the molecular characterization of the infection and identification of critical events have been hampered by the difficulty in developing in vitro models of NPC. Epithelial cell infection is difficult in vitro and in contrast to B-cell infection does not result in immortalization and transformation. Cell lines established from NPC usually do not retain the genome, and the successful establishment of tumor xenografts is difficult. However, critical genetic changes that contribute to the onset and progression of NPC and key molecular properties of the viral genes expressed in NPC have been identified. In some cases, viral expression becomes increasingly restricted during tumor progression and tumor cells may express only the viral nuclear antigen EBNA1 and viral noncoding RNAs. As NPC develops in the immunocompetent, the continued progression of deregulated growth likely reflects the combination of expression of viral oncogenes in some cells and viral noncoding RNAs that likely function synergistically with changes in cellular RNA and miRNA expression.

Epstein-Barr Virus Lytic Cycle Reactivation

Abstract: Epstein-Barr virus, which mainly infects B cells and epithelial cells, has two modes of infection: latent and lytic. Epstein-Barr virus infection is predominantly latent; however, lytic infection is detected in healthy seropositive individuals and becomes more prominent in certain pathological conditions. Lytic infection is divided into several stages: early gene expression, DNA replication, late gene expression, assembly, and egress. This chapter summarizes the most recent progress made toward understanding the molecular mechanisms that regulate the different lytic stages leading to production of viral progeny. In addition, the chapter highlights the potential role of lytic infection in disease development and current attempts to purposely induce lytic infection as a therapeutic approach.

Targeting HIV Transcription: The Quest for a Functional Cure

Abstract: Open image in new window HIV Transcription and Tat Protein. HIV Tat protein (A), bound to the TAR RNA stem–loop structure, binds to the P-TEFb complex (B), activating transcriptional elongation by RNA polymerase (C). The illustration also shows HIV Rev (D) bound to the Rev-response element and CRM1 (E), a cellular protein involved in transport through the nuclear pore

Latent Membrane Protein 2 (LMP2).

Abstract: LMP2A is an EBV-encoded protein with three domains: (a) an N-terminal cytoplasmic domain, which has PY motifs that bind to WW domain-containing E3 ubiquitin ligases and an ITAM that binds to SH2 domain-containing proteins, (b) a transmembrane domain with 12 transmembrane segments that localizes LMP2A in cellular membranes, and (c) a 27-amino acid C-terminal domain which mediates homodimerization and heterodimerization of LMP2 protein isoforms. The most prominent two isoforms of the protein are LMP2A and LMP2B. The LMP2B isoform lacks the 19-amino acid N-terminal domain found in LMP2A, which modulates cellular signaling resulting in a baseline activation of B cells and degradation of cellular kinases leading to the downregulation of normal B cell signaling pathways. These two seemingly contradictory processes allow EBV to establish and maintain latency. LMP2 is expressed in many EBV-associated malignancies. While its antigenic properties may be useful in developing LMP2-specific immunity, the LMP2A N-terminal motifs also provide a basis to target LMP2A-modulated cellular kinases for the development of treatment strategies.

Development, Homeostasis, and Heterogeneity of NK Cells and ILC1

Abstract: Natural killer (NK) cells are a population of cytotoxic innate lymphocytes that evolved prior to their adaptive counterparts and constitute one of the first lines of defense against infected or mutated cells NK cells are rapidly activated, expressing an array of germ-line encoded receptors that allow them to scan for protein irregularities on cells and kill those deemed "altered-self" NK cells rapidly produce a broad range of cytokines and chemokines following activation by virus, bacterial, or parasitic infection and are thus key in orchestrating inflammation NK cells have previously been viewed to represent a relatively homogeneous group of IFN-γ-producing cells that express the surface markers NK11 and natural killer cell p46-related protein (NKp46 or NCR1 encoded by Ncr1) and depend on the transcription factor T-bet for their development Recently, a second subset of T-bet-dependent innate cells, the group 1 innate lymphoid cells (ILC1), has been discovered which share many attributes of conventional NK (cNK) cells Despite the similarities between ILC1 and cNK cells , they differ in several important aspects including their localization, transcriptional regulation, and phenotype suggesting each subset has distinct origins and functions in immune responses Previously, the ability to detect and spontaneously kill cells that exhibit "altered-self" which is central to tumor and viral immunity has been thought to be an attribute restricted solely to cNK cells The identification of ILC1 challenges this notion and suggests that key contributions from ILC1 may have gone unrecognized Thus, understanding the different rules that govern the behavior of ILC1 and cNK cells in immune responses may potentially open unexpected doorways to uncover novel strategies to manipulate these cells in treating disease Here, we review recent advances in our understanding of peripheral cNK cell and ILC1 heterogeneity in terms of their development, phenotype, homeostasis, and effector functions

The Role of Two-Component Signal Transduction Systems in Staphylococcus aureus Virulence Regulation

Abstract: Staphylococcus aureus is a versatile, opportunistic human pathogen that can asymptomatically colonize a human host but can also cause a variety of cutaneous and systemic infections. The ability of S. aureus to adapt to such diverse environments is reflected in the presence of complex regulatory networks fine-tuning metabolic and virulence gene expression. One of the most widely distributed mechanisms is the two-component signal transduction system (TCS) which allows a pathogen to alter its gene expression profile in response to environmental stimuli. The simpler TCSs consist of only a transmembrane histidine kinase (HK) and a cytosolic response regulator. S. aureus encodes a total of 16 conserved pairs of TCSs that are involved in diverse signalling cascades ranging from global virulence gene regulation (e.g. quorum sensing by the Agr system), the bacterial response to antimicrobial agents, cell wall metabolism, respiration and nutrient sensing. These regulatory circuits are often interconnected and affect each other’s expression, thus fine-tuning staphylococcal gene regulation. This manuscript gives an overview of the current knowledge of staphylococcal environmental sensing by TCS and its influence on virulence gene expression and virulence itself. Understanding bacterial gene regulation by TCS can give major insights into staphylococcal pathogenicity and has important implications for knowledge-based drug design and vaccine formulation.

The EBNA3 Family: Two Oncoproteins and a Tumour Suppressor that Are Central to the Biology of EBV in B Cells.

Abstract: Epstein-Barr virus nuclear antigens EBNA3A , EBNA3B and EBNA3C are a family of three large latency-associated proteins expressed in B cells induced to proliferate by the virus. Together with the other nuclear antigens (EBNA-LP, EBNA2 and EBNA1), they are expressed from a polycistronic transcription unit that is probably unique to B cells. However, compared with the other EBNAs, hitherto the EBNA3 proteins were relatively neglected and their roles in EBV biology rather poorly understood. In recent years, powerful new technologies have been used to show that these proteins are central to the latency of EBV in B cells, playing major roles in reprogramming the expression of host genes affecting cell proliferation, survival, differentiation and immune surveillance. This indicates that the EBNA3s are critical in EBV persistence in the B cell system and in modulating B cell lymphomagenesis. EBNA3A and EBNA3C are necessary for the efficient proliferation of EBV-infected B cells because they target important tumour suppressor pathways--so operationally they are considered oncoproteins. In contrast, it is emerging that EBNA3B restrains the oncogenic capacity of EBV, so it can be considered a tumour suppressor--to our knowledge the first to be described in a tumour virus. Here, we provide a general overview of the EBNA3 genes and proteins. In particular, we describe recent research that has highlighted the complexity of their functional interactions with each other, with specific sites on the human genome and with the molecular machinery that controls transcription and epigenetic states of diverse host genes.

Biology of IgE Production: IgE Cell Differentiation and the Memory of IgE Responses

Abstract: The generation of long-lived plasma cells and memory B cells producing high-affinity antibodies depends on the maturation of B cell responses in germinal centers. These processes are essential for long-lasting antibody-mediated protection against infections. IgE antibodies are important for defense against parasites and toxins and can also mediate anti-tumor immunity. However, high-affinity IgE is also the main culprit responsible for the manifestations of allergic disease, including life-threatening anaphylaxisAnaphylaxis . Thus, generation of high-affinity IgE must be tightly regulated. Recent studies of IgE B cell biology have unveiled two mechanisms that limit high-affinity IgE memory responses: First, B cells that have recently switched to IgE production are programmed to rapidly differentiate into plasma cells,Plasma cells and second, IgE germinal centerGerminal center cells are transient and highly apoptotic. Opposing these processes, we now know that germinal center-derived IgG B cells can switch to IgE production, effectively becoming IgE-producing plasma cells. In this chapter, we will discuss the unique molecular and cellular pathways involved in the generation of IgE antibodies.

Nucleocapsid Protein: A Desirable Target for Future Therapies Against HIV-1.

Abstract: Open image in new window HIV reverse transcription and nucleocapsid. After the capsid has entered the cell, reverse transcriptase (A) creates a DNA copy (green) of the HIV RNA genome (yellow), using a cellular transfer RNA (B) as a primer. HIV nucleocapsid protein (C) acts as a chaperone to unfold the RNA secondary structure. The ribonuclease activity of RT removes the viral RNA after the DNA strand is created. Interaction of HIV Vif (D) with cellular APOBEC (E) is also shown

Diversification and Functional Specialization of Human NK Cell Subsets.

Abstract: Natural killer (NK) cells are lymphocytes that participate in different facets of immunity. They can act as innate sentinels through recognition and eradication of infected or transformed target cells, so-called immunosurveillance. In addition, they can contain immune responses through the killing of other activated immune cells, so-called immunoregulation. Furthermore, they instruct and regulate immune responses by producing pro-inflammatory cytokines such as IFN-γ, either upon direct target cell recognition or by relaying cytokine cues from various cell types. Recent studies in mouse and man have uncovered infection-associated expansions of NK cell subsets with specific receptor repertoires and diverse patterns of intracellular signaling molecule expression. Moreover, distinct attributes of NK cells in tissues, including tissue-resident subsets, are being further elucidated. Findings support an emerging theme of ever-increasing diversification and functional specialization among different NK cell subsets, with a functional dichotomy between subsets involved in immunoregulation or immunosurveillance. The epigenetic landscapes and transcriptional profiles of different NK cell subsets are providing insights into the molecular regulation of effector functions. Here, we review phenotypic, functional, and developmental characteristics of a spectrum of human NK cell subsets. We also discuss the molecular underpinnings of different NK cell subsets and their potential contributions to immunity as well as disease susceptibility.

EBNA2 and Its Coactivator EBNA-LP.

Abstract: While all herpesviruses can switch between lytic and latent life cycle, which are both driven by specific transcription programs, a unique feature of latent EBV infection is the expression of several distinct and well-defined viral latent transcription programs called latency I, II, and III. Growth transformation of B-cells by EBV in vitro is based on the concerted action of Epstein-Barr virus nuclear antigens (EBNAs) and latent membrane proteins(LMPs). EBV growth-transformed B-cells express a viral transcriptional program, termed latency III, which is characterized by the coexpression of EBNA2 and EBNA-LP with EBNA1, EBNA3A, -3B, and -3C as well as LMP1, LMP2A, and LMP2B. The focus of this review will be to discuss the current understanding of how two of these proteins, EBNA2 and EBNA-LP, contribute to EBV-mediated B-cell growth transformation.

Fidelity Variants and RNA Quasispecies.

Abstract: By now, it is well established that the error rate of the RNA-dependent RNA polymerase (RdRp) that replicates RNA virus genomes is a primary driver of the mutation frequencies observed in RNA virus populations-the basis for the RNA quasispecies. Over the last 10 years, a considerable amount of work has uncovered the molecular determinants of replication fidelity in this enzyme. The isolation of high- and low-fidelity variants for several RNA viruses, in an expanding number of viral families, provides evidence that nature has optimized the fidelity to facilitate genetic diversity and adaptation, while maintaining genetic integrity and infectivity. This chapter will provide an overview of what fidelity variants tell us about RNA virus biology and how they may be used in antiviral approaches.

Adoptive T-Cell Immunotherapy.

Abstract: Epstein-Barr virus (EBV) is associated with a range of malignancies involving B cells, T cells, natural killer (NK) cells, epithelial cells, and smooth muscle. All of these are associated with the latent life cycles of EBV, but the pattern of latency-associated viral antigens expressed in tumor cells depends on the type of tumor. EBV-specific T cells (EBVSTs) have been explored as prophylaxis and therapy for EBV-associated malignancies for more than two decades. EBVSTs have been most successful as prophylaxis and therapy for post-transplant lymphoproliferative disease (PTLD) , which expresses the full array of latent EBV antigens (type 3 latency), in hematopoietic stem-cell transplant (HSCT) recipients. While less effective, clinical studies have also demonstrated their therapeutic potential for PTLD post-solid organ transplant and for EBV-associated malignancies such as Hodgkin's lymphoma, non-Hodgkin's lymphoma, and nasopharyngeal carcinoma (NPC) that express a limited array of latent EBV antigens (type 2 latency). Several approaches are actively being pursued to improve the antitumor activity of EBVSTs including activation and expansion of T cells specific for the EBV antigens expressed in type 2 latency, genetic approaches to render EBVSTs resistant to the immunosuppressive tumor environment, and combination approaches with other immune-modulating modalities. Given the recent advances and renewed interest in cell therapy, we hope that EBVSTs will become an integral part of our treatment armamentarium against EBV-positive malignancies in the near-future.

Role of Calcium Signaling in B Cell Activation and Biology.

Abstract: Increase in intracellular levels of calcium ions (Ca2+) is one of the key triggering signals for the development of B cell response to the antigen. The diverse Ca2+ signals finely controlled by multiple factors participate in the regulation of gene expression, B cell development, and effector functions. B cell receptor (BCR)-initiated Ca2+ mobilization is sourced from two pathways: one is the release of Ca2+ from the intracellular stores, endoplasmic reticulum (ER), and other is the prolonged influx of extracellular Ca2+ induced by depleting the stores via store-operated calcium entry (SOCE) and calcium release-activated calcium (CRAC) channels. The identification of stromal interaction molecule 1(STIM1), the ER Ca2+ sensor, and Orai1, a key subunit of the CRAC channel pore, has now provided the tools to understand the mode of Ca2+ influx regulation and physiological relevance. Herein, we discuss our current understanding of the molecular mechanisms underlying BCR-triggered Ca2+ signaling as well as its contribution to the B cell biological processes and diseases.