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Interplay Between microRNAs, Toll-like Receptors, and HIV-1: Potential Implications in HIV-1 Replication and Chronic Immune Activation

Abstract: MicroRNAs (miRNAs) are important cellular, small non-coding RNAs that regulate host gene expression and have well-characterized roles in inflammation and infectious diseases. It has become apparent as well that cellular miRNAs can play crucial roles in controlling HIV-1 infection and replication. Whether HIV-1 encodes and is able to express viral miRNAs in infected cells remains controversial. HIV-1 can manipulate the biogenesis of miRNAs as well as the expression profiles of cellular miRNAs. Toll-Like receptors (TLRs) are important pathogen recognition receptors that sense invading pathogens orchestrating innate and adaptive immune responses. Innate immune recognition of HIV-1 infection leads to activation of TLR7/8. Recent evidence has shown that certain miRNAs can also be recognized by TLR7/8 leading to immune activation. However, the potential TLR7/8-mediated recognition of HIV-1 encoded miRNAs and/or cellular miRNAs modulated in HIV-1 infected cells has not been experimentally explored. In this review, we summarize the current literature on HIV-1 infection and miRNAs. Furthermore, we underscore the need for future research on potential miRNA-induced activation of TLR7/8, which might contribute to the chronic immune activation observed in HIV-1 infected patients. ... Read more

Point-of-Care Diagnostics for HIV and Tuberculosis: Landscape, Pipeline, and Unmet Needs

Abstract: Early diagnosis and rapid initiation of treatment remains a key strategy to control both HIV and tuberculosis (TB). However, HIV and TB control programs have had completely contrasting successes, especially with the development and deployment of point-of-care (POC) diagnostics. Clinicians, researchers, and public health staff who work at the frontlines of HIV care and control have had access to an outstanding array of POC diagnostics at their disposal, including those used for screening, initial diagnosis, staging, treatment monitoring, and early infant diagnosis. The field has also advanced to consider over-the-counter, self-testing options for HIV and the use of multiplexed platforms that allow for simultaneous detection of infections associated with HIV. In sharp contrast to HIV, suboptimal and delayed diagnosis of TB has perpetuated the epidemic in many high-burden countries. Although the TB diagnostics pipeline is substantially better today than it was even five years ago, absence of a simple POC test continues to be a gaping hole in the pipeline. In this review, we compare the POC diagnostics landscape and pipelines for these two important infectious diseases, and highlight gaps and unmet needs. ... Read more

Circadian Clocks in Mammalian Reproductive Physiology: Effects of the "Other" Biological Clock on Fertility

Abstract: As a discipline, chronobiology has come of age in the last 25 years. There has been an exponential increase in our understanding of the molecular mechanism underlying circadian rhythms of gene expression, physiology, and behavior. While the mammalian clock mechanism has not yet been fully described, most of the primary gears have probably been identified; however, there remains a large submerged portion of this physiological iceberg. What is the extent of "clock-controlled gene" expression in the myriad cell types in mammals? What are the cell specific physiological processes that depend either directly or indirectly on the clock? These questions remain largely unanswered, but recent advances suggest a substantial link between basic clock function and physiology in several systems. In the reproductive system, there has been a recent surge in research on molecular clock function in neuroendocrine and endocrine tissues. This makes sense a priori, given the established link between the circadian clock, behavior (including reproductive behavior), and endocrine physiology. By understanding the role of the clock in basic mammalian reproductive physiology, we can begin to explore its role in the onset and progression of diseases that negatively affect fertility. Advances in this area will certainly yield novel insights into the etiology of these disorders and may provide new and exciting avenues for clinical research in reproduction and fertility. ... Read more

The Development of Anti-inflammatory Drugs for Infectious Diseases

Abstract: Traditionally, disease is thought to result from an insufficient response of the host to infection, leading to increased replication of microorganisms and consequently disease. However, infection may not necessarily lead to disease and disease is not only the result of uncontrolled replication of a microorganism. Indeed, the inflammatory response triggered by certain infections is frequently the cause of tissue damage and death. The present review argues that it is possible to separate mechanisms necessary for the host response to deal with infection from those which cause unwanted inflammation and drive disease. By understanding mechanisms which drive disease and where/how interaction leads to disease, we may be able to devise novel therapies to alleviate suffering of patients. Below, we will describe three situations -- influenza, dengue and sepsis -- in which unwanted (excessive, misplaced or altered) inflammation is responsible for disease induction. In these three situations, we will also describe some examples of molecules which have been found to drive disease but appear not to be essential for the ability of the host to control infection. ... Read more

Mechanisms of Autoimmune Liver Disease

Abstract: The immune system of the liver is characterized by a predominant innate component. Several innate immune cell populations have been implicated in the pathogenesis of immune-mediated hepatic diseases, which are frequently associated with systemic symptoms or with co-morbidities affecting other organ systems. Thus, next to tissue-specific factors, general tolerance mechanisms are affected in devastating hepatic disorders like primary sclerosing cholangitis (PSC), autoimmune hepatitis (AIH), or primary biliary cirrhosis (PBC). The innate immune cell populations abundantly detected within the liver and endowed with potent immunomodulatory capacities include innate lymphoid cells (ILCs) and natural killer T (NKT) cells. While both ILCs and NKT cells can be activated by different cytokines and/or chemokines, NKT cells also respond to (glyco-) lipid antigens engaging their canonical, semi-invariant TCR. Once activated, ILCs and NKT cells release copious amounts of Th1, Th2, and/or Th17 cytokines that shape subsequent innate and adaptive immune responses. Those immunomodulatory features as well as the recently described antigen-presenting capacity of ILCs and/or the bi-directional functional role of NKT cells might not only underlie the pathogenic mechanisms in the respective disorders, but also provide promising targets for clinical intervention. We will discuss these novel aspects as well as the role of alarmin-like cytokines such as IL-33 in the context of ILC and NKT cell activation and the consequences for the induction and progress of hepatic tissue damage and fibrosis. ... Read more

MicroRNAs Regulate Immune System Via Multiple Targets

Abstract: MicroRNAs (miRNAs) represent the most abundant class of regulators of gene expression. Each miRNA may suppress multiple mRNA targets, while one mRNA can be targeted by many miRNAs for precise control of a wide range of cellular processes. The important role of miRNAs in the immune system is highlighted by the conditional Dicer knockout mouse, which exhibited profound aberrant development and function of immune cells. One particular miRNA, miR-155, is highly expressed and plays important role in lymphocytes. In this review we focused on the role of miRNA, especially miR-155, via their predicted and known mRNA targets in innate and adaptive immunity. Finally, we discussed the potential of miRNAs as novel targets for the diagnosis and therapy of immune system diseases. ... Read more

Inflammatory Disease and the Human Microbiome

Abstract: The human body is a superorganism in which thousands of microbial genomes continually interact with the human genome. A range of physical and neurological inflammatory diseases are now associated with shifts in microbiome composition. Seemingly disparate inflammatory conditions may arise from similar disruption of microbiome homeostasis. Intracellular pathogens long associated with inflammatory disease are able to slow the innate immune response by dysregulating activity of the VDR nuclear receptor. This facilitates the ability of other species to gradually accumulate in tissue and blood, where they generate proteins and metabolites that significantly interfere with the body’s metabolic processes. The microbes that contribute to this dysfunction are often inherited from family members. Immunosuppressive therapies for inflammatory disease allow pathogens driving these processes to spread with greater ease. In contrast to immunosuppression, treatments that stimulate the immune system seem to allow for reversal of this pathogen-induced genomic dysregulation. ... Read more

All Eyes on the Next Generation of HIV Vaccines: Strategies for Inducing a Broadly Neutralizing Antibody Response

Abstract: HIV-1 broadly neutralizing antibodies (BNAbs) develop after several years of infection through a recursive process of memory B cell adaptation and maturation against co-evolving virus quasispecies. Advances in single-cell sorting and memory B cell antibody cloning methods have identified many new HIV BNAbs targeting conserved epitopes on the HIV envelope (env) protein. 3D crystal structures and biophysical analyses of BNAbs bound to invariant virus structures expressed on monomeric gp120, epitope scaffolds, core structures, and native trimers have helped us to visualize unique binding interactions and paratope orientations that have been instrumental in guiding vaccine design. A paradigm shift in the approach to structure-based design of HIV-1 envelope immunogens came recently after several laboratories discovered that native viral envelopes or "env-structures" reverse-engineered to bind with high affinity to a handful of broadly neutralizing antibodies did not in fact bind the predicted germline precursors of these broadly neutralizing antibodies. A major challenge for HIV-1 B cell vaccine development moving forward is the design of new envelope immunogens that can trigger the selection and expansion of germline precursor and intermediate memory B cells to recapitulate B cell ontogenies associated with the maturation of a broadly neutralizing antibody response. Equally important for vaccine development is the identification of delivery systems, prime-boost strategies, and synergistic adjuvant combinations that can induce the magnitude and quality of antigen-specific T follicular helper (TFH) cell responses needed to drive somatic hypermutation (SHM) and B cell maturation against heterologous primary virus envelopes. Finding the combination of multi-protein envelope immunogens and immunization strategies that can evolve a potent broadly neutralizing antibody response portends to require a complex vaccine regimen that might be difficult to implement on any scale. This perspective strives to integrate recent insights into mechanisms associated with the evolution of an HIV-1 broadly neutralizing antibody response with current immunogen design and proffers a novel immunization strategy for skewing TH17/TFH cell responses that can drive B cell adaptation and affinity maturation associated with a broadly neutralizing antibody response. ... Read more

Interferon-gamma and Systemic Autoimmunity

Abstract: The term interferon describes a family of proteins consisting of three major types (I, II, and III) which differ in their primary protein sequences, cognate receptors, genetic loci, and cell types responsible for their production. The interferons, including types I and II, overlap significantly in the genes they control resulting in a shared spectrum of diverse biological effects which includes regulation of both the innate and adaptive immune responses. As such, the interferons are major effectors in the pathogenesis of autoimmunity, especially systemic autoimmunity. The type I IFNs, because they are produced during the early stages of the innate immune response, are thought to play the foremost role in autoimmune responses. However, numerous studies have found that the single type II IFN, IFN-γ, plays an essential role in the development and severity of systemic autoimmunity, particularly systemic lupus erythematosus. This is supported by animal studies where IFN-γ is uniformly required in both spontaneous and induced models of lupus. Although expression of IFN-γ in cells of the innate immune system is almost immediate after activation, expression in adaptive immunity requires a complex orchestration of cellular interactions, signaling events, and epigenetic modifications. The multifaceted nature of IFN-γ in adaptive immunity identifies numerous possible therapeutic targets that, because of the essential contribution of IFN-γ to systemic autoimmunity, have the potential for producing benefits. ... Read more

Elusive Alzheimer's Disease: Can Immune Signatures Help Our Understanding of This Challenging Disease? Part 2: New Immune Paradigm

Abstract: Alzheimer's disease (AD) is the most common form of dementia. Its most important pathological hallmarks are profound neuronal loss, presence of intracellular neurofibrillary tangles, and extracellular deposition of beta-amyloid protein (Aβ) as beta-amyloid plaques. One of the most important risk factors for AD is age and with the increase of life-expectancy AD has become the most common form of dementia. The current "Holy Grail" is to be able to diagnose variants of AD before they manifest clinically and before irreparable brain damage is done. To be able to do so, we need robust and reliable biomarkers which reflect the pathogenesis of AD. This is essential because such biomarkers might indicate pathways that could be targeted for interventions aiming at disease prevention or amelioration. Although much attention has been focused on Aβ in this respect, it may not be as attractive a target as thought if current doubts concerning its causative role are substantiated. This review will be in two parts, the first part dealt with the current clinical knowledge and the questions raised by the Aβ cascade hypothesis in the pathogenesis of AD and this second part aims to synthesize our current knowledge and new data suggesting how immunity may contribute to the development of AD and may itself be targeted in future treatments. ... Read more

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