Showing papers in "Pathogenetics in 2013"
TL;DR: If the metabolisms of cholesterol and bile acids by the gut microbiota are known for decades, their consequences on human health and disease are poorly understood and only start to be considered.
Abstract: The human gastro-intestinal tract hosts a complex and diverse microbial community, whose collective genetic coding capacity vastly exceeds that of the human genome. As a consequence, the gut microbiota produces metabolites from a large range of molecules that host's enzymes are not able to convert. Among these molecules, two main classes of steroids, cholesterol and bile acids, denote two different examples of bacterial metabolism in the gut. Therefore, cholesterol is mainly converted into coprostanol, a non absorbable sterol which is excreted in the feces. Moreover, this conversion occurs in a part of the human population only. Conversely, the primary bile acids (cholic and chenodeoxycholic acids) are converted to over twenty different secondary bile acid metabolites by the gut microbiota. The main bile salt conversions, which appear in the gut of the whole human population, include deconjugation, oxidation and epimerization of hydroxyl groups at C3, C7 and C12, 7-dehydroxylation, esterification and desulfatation. If the metabolisms of cholesterol and bile acids by the gut microbiota are known for decades, their consequences on human health and disease are poorly understood and only start to be considered.
412 citations
TL;DR: A comprehensive analysis of the literature from a historic perspective commenting on the contribution of the different models and discussing future venues and new approaches that can be merged with more traditional techniques in order to model biofilm-infections and efficiently fight them is undertaken.
Abstract: The influence of microorganisms growing as sessile communities in a large number of human infections has been extensively studied and recognized for 30-40 years, therefore warranting intense scientific and medical research. Nonetheless, mimicking the biofilm-life style of bacteria and biofilm-related infections has been an arduous task. Models used to study biofilms range from simple in vitro to complex in vivo models of tissues or device-related infections. These different models have progressively contributed to the current knowledge of biofilm physiology within the host context. While far from a complete understanding of the multiple elements controlling the dynamic interactions between the host and biofilms, we are nowadays witnessing the emergence of promising preventive or curative strategies to fight biofilm-related infections. This review undertakes a comprehensive analysis of the literature from a historic perspective commenting on the contribution of the different models and discussing future venues and new approaches that can be merged with more traditional techniques in order to model biofilm-infections and efficiently fight them.
380 citations
TL;DR: The aim of this review is to provide the readers with an update on goblet cell biology and current understanding on the role of mucins in host defense in enteric infections.
Abstract: Goblet cells reside throughout the gastrointestinal (GI) tract and are responsible for the production and preservation of a protective mucus blanket by synthesizing and secreting high molecular weight glycoproteins known as mucins. The concept of the mucus layer functioning as a dynamic protective barrier is suggested by studies showing changes in mucins in inflammatory conditions of the GI tract, by the altered goblet cell response in germ-free animals, and by the enhanced mucus secretion seen in response to infections. The mucin-containing mucus layer coating the GI epithelium is the front line of innate host defense. Mucins are likely to be the first molecules that invading pathogens interact with at the cell surface and thus, can limit binding to other glycoproteins and neutralize the pathogen. This review will focus on what is known about goblet cell response in various GI infections and the regulatory networks that mediate goblet cell function and mucin production in response to intestinal insults. In addition, we describe the current knowledge on the role of mucins in intestinal innate defense. It is the aim of this review to provide the readers with an update on goblet cell biology and current understanding on the role of mucins in host defense in enteric infections.
204 citations
TL;DR: The latest findings regarding the role of β-defensin in relevant human infectious and non-infectious diseases of the colonic mucosa and its antimicrobial role in a variety of disease processes are focused on.
Abstract: β-defensins are small cationic antimicrobial peptides secreted by diverse cell types including colonic epithelial cells. Human β-defensins form an essential component of the intestinal lumen in innate immunity. The defensive mechanisms of β-defensins include binding to negatively charged microbial membranes that cause cell death and chemoattraction of immune cells. The antimicrobial activity of β-defensin is well reported in vitro against several enteric pathogens and in non-infectious processes such as inflammatory bowel diseases, which alters β-defensin production. However, the role of β-defensin in vivo in its interaction with other immune components in host defense against bacteria, viruses and parasites with more complex membranes is still not well known. This review focuses on the latest findings regarding the role of β-defensin in relevant human infectious and non-infectious diseases of the colonic mucosa. In addition, we summarize the most significant aspects of β-defensin and its antimicrobial role in a variety of disease processes.
60 citations
TL;DR: The pathways of oxalate throughout the body and the mammalian gut as a series of differentiated ecosystems that facilitate oxalATE degradation are discussed and the mechanisms and functions of microbialOxalate degradation are explored.
Abstract: Oxalate-degrading bacteria comprise a functional group of microorganisms, commonly found in the gastrointestinal tract of mammals. Oxalate is a plant secondary compound (PSC) widely produced by all major taxa of plants and as a terminal metabolite by the mammalian liver. As a toxin, oxalate can have a significant impact on the health of mammals, including humans. Mammals do not have the enzymes required to metabolize oxalate and rely on their gut microbiota for this function. Thus, significant metabolic interactions between the mammalian host and a complex gut microbiota maintain the balance of oxalate in the body. Over a dozen species of gut bacteria are now known to degrade oxalate. This review focuses on the host-microbe and microbe-microbe interactions that regulate the degradation of oxalate by the gut microbiota. We discuss the pathways of oxalate throughout the body and the mammalian gut as a series of differentiated ecosystems that facilitate oxalate degradation. We also explore the mechanisms and functions of microbial oxalate degradation along with the implications for the ecological and evolutionary interactions within the microbiota and for mammalian hosts. Throughout, we consider questions that remain, as well as recent technological advances that can be employed to answer them.
58 citations
TL;DR: This review summarizes the most important steps taken in HBoV research to date and addresses open questions that need to be answered in the future to provide a better understanding of the role of a virus that is difficult to grow in cell culture and is suspected to be a pathogen, although it has not yet fulfilled Koch’s postulates.
Abstract: Human bocavirus (HBoV) was identified as the second human parvovirus with pathogenic potential in 2005 in respiratory samples from children suffering from viral respiratory infections of unknown etiology. Since its first description, a large number of clinical studies have been performed that address the clinical significance of HBoV detection and the molecular biology of the virus. This review summarizes the most important steps taken in HBoV research to date and addresses open questions that need to be answered in the future to provide a better understanding of the role of a virus that is difficult to grow in cell culture and is suspected to be a pathogen, although it has not yet fulfilled Koch’s postulates.
54 citations
TL;DR: This review focuses on the current literature on RSV and hMPV infection and the role of PRRs in establishing/mediating the infection in both in vitro and in vivo models to lead to efficient prophylactic and therapeutic treatments, as well as the development of adequate vaccines.
Abstract: Acute respiratory tract infection (RTI) is a leading cause of morbidity and mortality worldwide and the majority of RTIs are caused by viruses, among which respiratory syncytial virus (RSV) and the closely related human metapneumovirus (hMPV) figure prominently. Host innate immune response has been implicated in recognition, protection and immune pathological mechanisms. Host-viral interactions are generally initiated via host recognition of pathogen-associated molecular patterns (PAMPs) of the virus. This recognition occurs through host pattern recognition receptors (PRRs) which are expressed on innate immune cells such as epithelial cells, dendritic cells, macrophages and neutrophils. Multiple PRR families, including Toll-like receptors (TLRs), RIG-I-like receptors (RLRs) and NOD-like receptors (NLRs), contribute significantly to viral detection, leading to induction of cytokines, chemokines and type I interferons (IFNs), which subsequently facilitate the eradication of the virus. This review focuses on the current literature on RSV and hMPV infection and the role of PRRs in establishing/mediating the infection in both in vitro and in vivo models. A better understanding of the complex interplay between these two viruses and host PRRs might lead to efficient prophylactic and therapeutic treatments, as well as the development of adequate vaccines.
50 citations
TL;DR: Recent work on Drosophila host defense to infection by expanding its main focus on systemic immunity signaling pathways to include the study of organ homeostasis in health and disease shapes a new notion that epithelially emanating cytokines and growth factors can directly act on the intestinal stem cell niche to promote “regenerative inflammation” and potentially cancer.
Abstract: Intestinal inflammation is widely recognized as a pivotal player in health and disease. Defined cytologically as the infiltration of leukocytes in the lamina propria layer of the intestine, it can damage the epithelium and, on a chronic basis, induce inflammatory bowel disease and potentially cancer. The current view thus dictates that blood cell infiltration is the instigator of intestinal inflammation and tumor-promoting inflammation. This is based partially on work in humans and mice showing that intestinal damage during microbially mediated inflammation activates phagocytic cells and lymphocytes that secrete inflammatory signals promoting tissue damage and tumorigenesis. Nevertheless, extensive parallel work in the Drosophila midgut shows that intestinal epithelium damage induces inflammatory signals and growth factors acting mainly in a paracrine manner to induce intestinal stem cell proliferation and tumor formation when genetically predisposed. This is accomplished without any apparent need to involve Drosophila hemocytes. Therefore, recent work on Drosophila host defense to infection by expanding its main focus on systemic immunity signaling pathways to include the study of organ homeostasis in health and disease shapes a new notion that epithelially emanating cytokines and growth factors can directly act on the intestinal stem cell niche to promote "regenerative inflammation" and potentially cancer.
50 citations
TL;DR: Curcumin effectively rescues the cells from apoptosis and decreases the ROS level caused by subsequent co-incubation with prion amyloid fibrils in mouse neuroblastoma cells.
Abstract: Misfolding and aggregation into amyloids of the prion protein (PrP) is responsible for the development of fatal transmissible neurodegenerative diseases. Various studies on curcumin demonstrate promise for the prevention of Alzheimer’s disease and inhibition of PrPres accumulation. To evaluate the effect of curcumin on amyloid fibrillation of prion protein, we first investigated the effect of curcumin on mouse prion protein (mPrP) in a cell-free system. Curcumin reduced the prion fibril formation significantly. Furthermore, we monitored the change in apoptosis and reactive oxygen species (ROS) level upon curcumin treatment in mouse neuroblastoma cells (N2a). Curcumin effectively rescues the cells from apoptosis and decreases the ROS level caused by subsequent co-incubation with prion amyloid fibrils. The assays in cell-free mPrP and in N2a cells of this work verified the promising effect of curcumin on the prevention of transmissible neurodegenerative diseases.
46 citations
TL;DR: A postulated requirement has been the abrogation of free radical formation by numerous natural antioxidant molecules in order to improve musculoskeletal health outcomes, but this notion in this view is in error.
Abstract: Natural medicines are an attractive option for patients diagnosed with common and debilitating musculoskeletal diseases such as Osteoarthritis (OA) or Rheumatoid Arthritis (RA). The high rate of self-medication with natural products is due to (1) lack of an available cure and (2) serious adverse events associated with chronic use of pharmaceutical medications in particular non-steroidal anti-inflammatory drugs (NSAIDs) and high dose paracetamol. Pharmaceuticals to treat pain may disrupt gastrointestinal (GIT) barrier integrity inducing GIT inflammation and a state of and hyper-permeability. Probiotics and prebiotics may comprise plausible therapeutic options that can restore GIT barrier functionality and down regulate pro-inflammatory mediators by modulating the activity of, for example, Clostridia species known to induce pro-inflammatory mediators. The effect may comprise the rescue of gut barrier physiological function. A postulated requirement has been the abrogation of free radical formation by numerous natural antioxidant molecules in order to improve musculoskeletal health outcomes, this notion in our view, is in error. The production of reactive oxygen species (ROS) in different anatomical environments including the GIT by the epithelial lining and the commensal microbe cohort is a regulated process, leading to the formation of hydrogen peroxide which is now well recognized as an essential second messenger required for normal cellular homeostasis and physiological function. The GIT commensal profile that tolerates the host does so by regulating pro-inflammatory and anti-inflammatory GIT mucosal actions through the activity of ROS signaling thereby controlling the activity of pathogenic bacterial species.
44 citations
TL;DR: A growing body of evidence supports the role for Hsp90 inhibitors as adjunctive drugs able to restore susceptibility to traditionally efficacious compounds like chloroquine, as well as heat shock protein 90 and its central role as a chaperone.
Abstract: Malaria continues to exact a great human toll in tropical settings. Antimalarial resistance is rife and the parasite inexorably develops mechanisms to outwit our best drugs, including the now first-line choice, artesunate. Novel strategies to circumvent resistance are needed. Here we detail drug development focusing on heat shock protein 90 and its central role as a chaperone. A growing body of evidence supports the role for Hsp90 inhibitors as adjunctive drugs able to restore susceptibility to traditionally efficacious compounds like chloroquine.
TL;DR: It is suggested that taking into account the co-evolutionary interactions between the host immune system and the parasitic strategies to overcome the immune response might provide a better picture of the selective pressures that shape the evolution of immune functioning.
Abstract: Costs and benefits of the immune response have attracted considerable attention in the last years among evolutionary biologists. Given the cost of parasitism, natural selection should favor individuals with the most effective immune defenses. Nevertheless, there exists huge variation in the expression of immune effectors among individuals. To explain this apparent paradox, it has been suggested that an over-reactive immune system might be too costly, both in terms of metabolic resources and risks of immune-mediated diseases, setting a limit to the investment into immune defenses. Here, we argue that this view neglects one important aspect of the interaction: the role played by evolving pathogens. We suggest that taking into account the co-evolutionary interactions between the host immune system and the parasitic strategies to overcome the immune response might provide a better picture of the selective pressures that shape the evolution of immune functioning. Integrating parasitic strategies of host exploitation can also contribute to understand the seemingly contradictory results that infection can enhance, but also protect from, autoimmune diseases. In the last decades, the incidence of autoimmune disorders has dramatically increased in wealthy countries of the northern hemisphere with a concomitant decrease of most parasitic infections. Experimental work on model organisms has shown that this pattern may be due to the protective role of certain parasites (i.e., helminths) that rely on the immunosuppression of hosts for their persistence. Interestingly, although parasite-induced immunosuppression can protect against autoimmunity, it can obviously favor the spread of other infections. Therefore, we need to think about the evolution of the immune system using a multidimensional trade-off involving immunoprotection, immunopathology and the parasitic strategies to escape the immune response.
TL;DR: The genome sequences of strains infecting humans, animals and ticks from diverse geographic locations are analyzed to provide potential targets to identify human-infective strains and have significance for understanding the selective pressures that lead to emergence of disease in new species.
Abstract: The prevalence of tick-borne diseases is increasing worldwide. One such emerging disease is human anaplasmosis. The causative organism, Anaplasma phagocytophilum, is known to infect multiple animal species and cause human fatalities in the U.S., Europe and Asia. Although long known to infect ruminants, it is unclear why there are increasing numbers of human infections. We analyzed the genome sequences of strains infecting humans, animals and ticks from diverse geographic locations. Despite extensive variability amongst these strains, those infecting humans had conserved genome structure including the pfam01617 superfamily that encodes the major, neutralization-sensitive, surface antigen. These data provide potential targets to identify human-infective strains and have significance for understanding the selective pressures that lead to emergence of disease in new species.
TL;DR: The involvement of MMPs and, in particular, of gelatinases in both protozoan and helminth infections will be described, and in cerebral malaria, M MPs play a role in the pathogenesis of such diseases.
Abstract: Matrix metalloproteinases (MMPs) represent a large family of over twenty different secreted or membrane-bound endopeptidases, involved in many physiological (embryogenesis, precursor or stem cell mobilization, tissue remodeling during wound healing, etc.), as well as pathological (inflammation, tumor progression and metastasis in cancer, vascular pathology, etc.) conditions. For a long time, MMPs were considered only for the ability to degrade extracellular matrix (ECM) molecules (e.g., collagen, laminin, fibronectin) and to release hidden epitopes from the ECM. In the last few years, it has been fully elucidated that these molecules have many other functions, mainly related to the immune response, in consideration of their effects on cytokines, hormones and chemokines. Among others, MMP-2 and MMP-9 are endopeptidases of the MMP family produced by neutrophils, macrophages and monocytes. When infection is associated with leukocyte influx into specific organs, immunopathology and collateral tissue damage may occur. In this review, the involvement of MMPs and, in particular, of gelatinases in both protozoan and helminth infections will be described. In cerebral malaria, for example, MMPs play a role in the pathogenesis of such diseases. Also, trypanosomosis and toxoplasmosis will be considered for protozoan infections, as well as neurocysticercosis and angiostrongyloidosis, as regards helminthiases. All these situations have in common the proteolytic action on the blood brain barrier, mediated by MMPs.
TL;DR: Different animal models of VZV infection as well as an alternative animal model that leverages the infection of Old World macaques with the highly related simian varicella virus (SVV) are described and discussed and their contributions to the understanding of pathogenesis and immunity during VzV infection are discussed.
Abstract: Primary infection with varicella zoster virus (VZV) results in varicella (chickenpox) followed by the establishment of latency in sensory ganglia Declining T cell immunity due to aging or immune suppressive treatments can lead to VZV reactivation and the development of herpes zoster (HZ, shingles) HZ is often associated with significant morbidity and occasionally mortality in elderly and immune compromised patients There are currently two FDA-approved vaccines for the prevention of VZV: Varivax® (for varicella) and Zostavax® (for HZ) Both vaccines contain the live-attenuated Oka strain of VZV Although highly immunogenic, a two-dose regimen is required to achieve a 99% seroconversion rate Zostavax vaccination reduces the incidence of HZ by 51% within a 3-year period, but a significant reduction in vaccine-induced immunity is observed within the first year after vaccination Developing more efficacious vaccines and therapeutics requires a better understanding of the host response to VZV These studies have been hampered by the scarcity of animal models that recapitulate all aspects of VZV infections in humans In this review, we describe different animal models of VZV infection as well as an alternative animal model that leverages the infection of Old World macaques with the highly related simian varicella virus (SVV) and discuss their contributions to our understanding of pathogenesis and immunity during VZV infection
TL;DR: Age, hand hygiene, and work shift were significantly associated with potential pathogen carriage and the associations were pathogen dependent, and the overall hand microbiota structure was associated with the carriage of potential pathogens.
Abstract: One function of skin microbiota is to resist colonization and infection by external microorganisms. We sought to detect whether the structure of the hand microbiota of 34 healthcare workers (HCW) in a surgical intensive care unit mediates or modifies the relationship between demographic and behavioral factors and potential pathogen carriage on hands after accounting for pathogen exposure. We used a taxonomic screen (16S rRNA) to characterize the bacterial community, and qPCR to detect presence of Staphylococcus aureus, Enterococcus spp., methicillin-resistant Staphylococcus aureus (MRSA), and Candida albicans on their dominant hands. Hands were sampled weekly over a 3-week period. Age, hand hygiene, and work shift were significantly associated with potential pathogen carriage and the associations were pathogen dependent. Additionally, the overall hand microbiota structure was associated with the carriage of potential pathogens. Hand microbiota community structure may act as a biomarker of pathogen carriage, and modifying that structure may potentially limit pathogen carriage among HCW.
TL;DR: The results suggest that mycobacterial infections regulate the production of antimicrobial peptides and cytokines, which in conjunction can contribute to the control of the bacilli.
Abstract: Epithelial cells of the cornea and the conjunctiva constitutively produce antimicrobial peptides; however, the production of defensins by other cell types located around the eye has not been investigated. We analyzed the production of beta-defensins (hBD) and cathelicidin LL-37 during the infection of primary limbo-corneal fibroblasts with M. tuberculosis (MTB), M. abscessus (MAB), and M. smegmatis (MSM). The intracellular survival of each mycobacterium, the production of cytokines and the changes on the distribution of the actin filaments during the infection were also analyzed. Fibroblasts produce basal levels of hBD1 and LL-37 and under PMA stimulation they produce hBD2, hBD3 and overexpress hBD1 and LL-37. MAB induced the highest levels of hBD1 and LL-37 and intermediate levels of IL-6; however, MAB was not eliminated. In addition, MAB induced the greatest change to the distribution of the actin filaments. MTB also produced changes in the structure of the cytoskeleton and induced low levels of hBD1 and IL-6, and intermediate levels of LL-37. The balance of these molecules induced by MTB appeared to contribute to the non-replicative state observed in the limbo-corneal cells. MSM induced the lowest levels of hBD1 and LL-37 but the highest levels of IL-6; MSM was eliminated. The results suggest that mycobacterial infections regulate the production of antimicrobial peptides and cytokines, which in conjunction can contribute to the control of the bacilli.
TL;DR: The recently characterized murine animal model is described, which provides the possibility to use numerous and powerful tools available for mice to further decipher henipaviruses immunopathogenesis, prophylaxis, and treatment.
Abstract: The Henipavirus genus contains two highly lethal viruses, the Hendra and Nipah viruses and one, recently discovered, apparently nonpathogenic member; Cedar virus. These three, negative-sense single-stranded RNA viruses, are hosted by fruit bats and use EphrinB2 receptors for entry into cells. The Hendra and Nipah viruses are zoonotic pathogens that emerged in the middle of 90s and have caused severe, and often fatal, neurologic and/or respiratory diseases in both humans and different animals; including spillover into equine and porcine species. Development of relevant models is critical for a better understanding of viral pathogenesis, generating new diagnostic tools, and assessing anti-viral therapeutics and vaccines. This review summarizes available data on several animal models where natural and/or experimental infection has been demonstrated; including pteroid bats, horses, pigs, cats, hamsters, guinea pigs, ferrets, and nonhuman primates. It recapitulates the principal features of viral pathogenesis in these animals and current knowledge on anti-viral immune responses. Lastly it describes the recently characterized murine animal model, which provides the possibility to use numerous and powerful tools available for mice to further decipher henipaviruses immunopathogenesis, prophylaxis, and treatment. The utility of different models to analyze important aspects of henipaviruses-induced disease in humans, potential routes of transmission, and therapeutic approaches are equally discussed.
TL;DR: An important strategy to reduce the development of antimicrobial resistance is to use antimicrobials more appropriately, in ways that will prevent resistance, which involves a consideration of the pharmacokinetic and pharmacodynamics properties of antimicroBials, the possible use of combinations, and more appropriate choice of antimmicrobials.
Abstract: Since their development over 60 years ago, antimicrobials have become an integral part of healthcare practice worldwide. Recently, this has been put in jeopardy by the emergence of widespread antimicrobial resistance, which is one of the major problems facing modern medicine. In the past, the development of new antimicrobials kept us one step ahead of the problem of resistance, but only three new classes of antimicrobials have reached the market in the last thirty years. A time is therefore approaching when we may not have effective treatment against bacterial infections, particularly for those that are caused by Gram-negative organisms. An important strategy to reduce the development of antimicrobial resistance is to use antimicrobials more appropriately, in ways that will prevent resistance. This involves a consideration of the pharmacokinetic and pharmacodynamics properties of antimicrobials, the possible use of combinations, and more appropriate choice of antimicrobials, which may include rapid diagnostic testing and antimicrobial cycling. Examples given in this review include Mycobacterium tuberculosis, Gram-negative and Gram-positive organisms. We shall summarise the current evidence for these strategies and outline areas for future development.
TL;DR: The results suggest that the biochemical strain typing approach here proposed was highly discriminative, although by itself it did not allow us to identify all prion strains analyzed.
Abstract: Prions exist as different strains exhibiting distinct disease phenotypes. Currently, the identification of prion strains is still based on biological strain typing in rodents. However, it has been shown that prion strains may be associated with distinct PrPSc biochemical types. Taking advantage of the availability of several prion strains adapted to a novel rodent model, the bank vole, we investigated if any prion strain was actually associated with distinctive PrPSc biochemical characteristics and if it was possible to univocally identify strains through PrPSc biochemical phenotypes. We selected six different vole-adapted strains (three human-derived and three animal-derived) and analyzed PrPSc from individual voles by epitope mapping of protease resistant core of PrPSc (PrPres) and by conformational stability and solubility assay. Overall, we discriminated five out of six prion strains, while two different scrapie strains showed identical PrPSc types. Our results suggest that the biochemical strain typing approach here proposed was highly discriminative, although by itself it did not allow us to identify all prion strains analyzed.
TL;DR: The physicochemical and biological properties of prions from VPSPr are highlighted and the pathogenesis of VPS prion disease is discussed including the origin and formation of the peculiar prions.
Abstract: Human prion diseases, including sporadic, familial, and acquired forms such as Creutzfeldt-Jakob disease (CJD), are caused by prions in which an abnormal prion protein (PrPSc) derived from its normal cellular isoform (PrPC) is the only known component. The recently-identified variably protease-sensitive prionopathy (VPSPr) is characterized not only by an atypical clinical phenotype and neuropathology but also by the deposition in the brain of a peculiar PrPSc. Like other forms of human prion disease, the pathogenesis of VPSPr also currently remains unclear. However, the findings of the peculiar features of prions from VPSPr and of the possible association of VPSPr with a known genetic prion disease linked with a valine to isoleucine mutation at residue 180 of PrP reported recently, may be of great importance in enhancing our understanding of not only this atypical human prion disease in particular, but also other prion diseases in general. In this review, we highlight the physicochemical and biological properties of prions from VPSPr and discuss the pathogenesis of VPSPr including the origin and formation of the peculiar prions.
TL;DR: The discovery of kuru opened new windows into the realms of human medicine and was instrumental in the later transmission of Creutzfeldt-Jakob disease and Gerstmann-Sträussler-Scheinker disease as well as the relevance that bovine spongiform encephalopathy had for transmission to humans.
Abstract: Kuru, the first human transmissible spongiform encephalopathy was transmitted to chimpanzees by D. Carleton Gajdusek (1923–2008). In this review, I briefly summarize the history of this seminal discovery along its epidemiology, clinical picture, neuropathology and molecular genetics. The discovery of kuru opened new windows into the realms of human medicine and was instrumental in the later transmission of Creutzfeldt-Jakob disease and Gerstmann-Straussler-Scheinker disease as well as the relevance that bovine spongiform encephalopathy had for transmission to humans. The transmission of kuru was one of the greatest contributions to biomedical sciences of the 20th century.
TL;DR: Recent achievements in the field of humanized mouse models of EBV infection are summarized and shown how they have been utilized to analyze EBV pathogenesis and normal and aberrant human immune responses to the virus.
Abstract: Epstein-Barr virus (EBV) is a ubiquitous herpesvirus infecting more than 90% of the adult population of the world. EBV is associated with a variety of diseases including infectious mononucleosis, lymphoproliferative diseases, malignancies such as Burkitt lymphoma and nasopharyngeal carcinoma, and autoimmune diseases including rheumatoid arthritis (RA). EBV in nature infects only humans, but in an experimental setting, a limited species of new-world monkeys can be infected with the virus. Small animal models, suitable for evaluation of novel therapeutics and vaccines, have not been available. Humanized mice, defined here as mice harboring functioning human immune system components, are easily infected with EBV that targets cells of the hematoimmune system. Furthermore, humanized mice can mount both cellular and humoral immune responses to EBV. Thus, many aspects of human EBV infection, including associated diseases (e.g., lymphoproliferative disease, hemophagocytic lymphohistiocytosis and erosive arthritis resembling RA), latent infection, and T-cell-mediated and humoral immune responses have been successfully reproduced in humanized mice. Here we summarize recent achievements in the field of humanized mouse models of EBV infection and show how they have been utilized to analyze EBV pathogenesis and normal and aberrant human immune responses to the virus.
TL;DR: Understanding of the available animal models and the development and refinement of animal models is critical in negating the detrimental impact of TBHFVs on public and animal health.
Abstract: Tick-borne hemorrhagic fever viruses (TBHFV) are detected throughout the African and Eurasian continents and are an emerging or re-emerging threat to many nations. Due to the largely sporadic incidences of these severe diseases, information on human cases and research activities in general have been limited. In the past decade, however, novel TBHFVs have emerged and areas of endemicity have expanded. Therefore, the development of countermeasures is of utmost importance in combating TBHFV as elimination of vectors and interrupting enzootic cycles is all but impossible and ecologically questionable. As in vivo models are the only way to test efficacy and safety of countermeasures, understanding of the available animal models and the development and refinement of animal models is critical in negating the detrimental impact of TBHFVs on public and animal health.
TL;DR: Transmission of Transmissible Mink Encephalopathy to cattle supports the bovine hypothesis for the still controversial origin of TME outbreaks and is the third animal prion strain transmissible to both macaques and humanized transgenic mice, suggesting zoonotic potentials that should be considered in the risk analysis ofAnimal prion diseases for human health.
Abstract: Successful transmission of Transmissible Mink Encephalopathy (TME) to cattle supports the bovine hypothesis for the still controversial origin of TME outbreaks. Human and primate susceptibility to classical Bovine Spongiform Encephalopathy (c-BSE) and the transmissibility of L-type BSE to macaques indicate a low cattle-to-primate species barrier. We therefore evaluated the zoonotic potential of cattle-adapted TME. In less than two years, this strain induced in cynomolgus macaques a neurological disease similar to L-BSE but distinct from c-BSE. TME derived from another donor species (raccoon) induced a similar disease with even shorter incubation periods. L-BSE and cattle-adapted TME were also transmissible to transgenic mice expressing human prion protein (PrP). Secondary transmissions to transgenic mice expressing bovine PrP maintained the features of the three tested bovine strains (cattle TME, c-BSE and L-BSE) regardless of intermediate host. Thus, TME is the third animal prion strain transmissible to both macaques and humanized transgenic mice, suggesting zoonotic potentials that should be considered in the risk analysis of animal prion diseases for human health. Moreover, the similarities between TME and L-BSE are highly suggestive of a link between these strains, and therefore the possible presence of L-BSE for many decades prior to its identification in USA and Europe.
TL;DR: Experimental evidence is provided supporting the importance of incorporating optimized in vivo imaging methods to monitor disease progression and to evaluate the efficacy of therapeutic treatment during bacterial infections and demonstrated, for the first time, simultaneous real time in vivo Imaging of neutrophils and bacteria.
Abstract: Burkholderia mallei, the etiologic agent of glanders, are Category B select agents with biothreat potential, and yet effective therapeutic treatments are lacking. In this study, we showed that CpG administration increased survival, demonstrating protection in the murine glanders model. Bacterial recovery from infected lungs, liver and spleen was significantly reduced in CpG-treated animals as compared with non-treated mice. Reciprocally, lungs of CpG-treated infected animals were infiltrated with higher levels of neutrophils and inflammatory monocytes, as compared to control animals. Employing the B. mallei bioluminescent strain CSM001 and the Neutrophil-Specific Fluorescent Imaging Agent, bacterial dissemination and neutrophil trafficking were monitored in real-time using multimodal in vivo whole body imaging techniques. CpG-treatment increased recruitment of neutrophils to the lungs and reduced bioluminescent bacteria, correlating with decreased bacterial burden and increased protection against acute murine glanders. Our results indicate that protection of CpG-treated animals was associated with recruitment of neutrophils prior to infection and demonstrated, for the first time, simultaneous real time in vivo imaging of neutrophils and bacteria. This study provides experimental evidence supporting the importance of incorporating optimized in vivo imaging methods to monitor disease progression and to evaluate the efficacy of therapeutic treatment during bacterial infections.
TL;DR: A vaccine composed of a chimeric antigen named recNcMIC3-1-R, based on predicted immunogenic domains of the two microneme proteins NcMIC1 and Nc MIC3, and emulsified in saponin adjuvants, significantly reduced the cerebral infection in non-pregnant BALB/c mice.
Abstract: Vertical transmission from an infected cow to its fetus accounts for the vast majority of new Neospora caninum infections in cattle. A vaccine composed of a chimeric antigen named recNcMIC3-1-R, based on predicted immunogenic domains of the two microneme proteins NcMIC1 and NcMIC3, the rhoptry protein NcROP2, and emulsified in saponin adjuvants, significantly reduced the cerebral infection in non-pregnant BALB/c mice. Protection was associated with a mixed Th1/Th2-type cytokine response. However, the same vaccine formulation elicited a Th2-type immune response in pregnant mice and did not prevent vertical transmission or disease, neither in dams nor in offspring mice. In this study, an alternative vaccine formulation containing recNcMIC3-1-R emulsified in Freund’s incomplete adjuvant, a stimulator of the cellular immunity, was investigated. No protection against vertical transmission and cerebral infection in the pregnant mice and a very limited protective effect in the non-pregnant mice were observed. The vaccine induced a Th1-type immune response characterized by high IgG2a titres and strong IFN-γ expression, which appeared detrimental to pregnancy.
TL;DR: The involvement of autophagy in prion disease and the effects of PrPC are described and it is clear that Autophagy-induced cell death is observed in neurodegenerative disorders that exhibit protein aggregations.
Abstract: Cellular prion protein (PrPC) plays an important role in the cellular defense against oxidative stress. However, the exact protective mechanism of PrPC is unclear. Autophagy is essential for survival, differentiation, development, and homeostasis in several organisms. Although the role that autophagy plays in neurodegenerative disease has yet to be established, it is clear that autophagy-induced cell death is observed in neurodegenerative disorders that exhibit protein aggregations. Moreover, autophagy can promote cell survival and cell death under various conditions. In this review, we describe the involvement of autophagy in prion disease and the effects of PrPC.
TL;DR: It is suggested that marmosets are potentially useful for the studies of the pathogenesis of DENV infection, including kidneys, because they recapitulate some aspects of the involvement of kidneys in human dengue virus infection.
Abstract: Common marmosets (Callithrix jacchus) developed high levels of viremia, clinical signs including fever, weight loss, a decrease in activity and hematuria upon inoculation with dengue virus (DENV). Presence of DENV genome in urine samples and pathological changes in kidneys were examined in the present study. Levels of DENV genome were determined in 228 urine samples from 20 primary DENV-inoculated marmosets and in 56 urine samples from four secondary DENV-inoculated marmosets. DENV genome was detected in 75% (15/20) of marmosets after primary DENV infection. No DENV genome was detected in urine samples from the marmosets with secondary infection with homologous DENV (0%, 0/4). Two marmosets demonstrated hematuria. Pathological analysis of the kidneys demonstrated non-suppressive interstitial nephritis with renal tubular regeneration. DENV antigen-positive cells were detected in kidneys. In human dengue virus infections, some patients present renal symptoms. The results indicate that marmosets recapitulate some aspects of the involvement of kidneys in human DENV infection, and suggest that marmosets are potentially useful for the studies of the pathogenesis of DENV infection, including kidneys.
TL;DR: Overall, the order of coinfection influenced life history traits of both H. bakeri and H. microstoma, but changes in survival, growth, and reproduction with order of inoculation were not consistent between the two parasites.
Abstract: Parasite life history may differ during coinfection compared to single infections, and the order of infection may be an important predictor of life history traits. We subjected laboratory mice (Mus musculus) to single and coinfections with Heligmosomoides bakeri and Hymenolepis microstoma and measured life history traits of worms and also hepatobiliary and morphological responses by the host. We found that fewer H. bakeri larvae established, and adult worms were shorter and produced fewer eggs during a coinfection where H. microstoma occurred first. H. microstoma grew more and released more eggs after simultaneous inoculation of both parasites compared to a single H. microstoma infection, despite similar worm numbers. Mouse small intestine mass, but not length, varied with coinfection and bile duct mass was largest when H. microstoma was given alone or first. Mouse serum alkaline phosphatase levels were greatest for mice infected with H. microstoma only but did not vary with number of scolices; no change in mouse serum alanine transaminase levels was observed. Overall, the order of coinfection influenced life history traits of both H. bakeri and H. microstoma, but changes in survival, growth, and reproduction with order of inoculation were not consistent between the two parasites.