Showing papers in "Current Topics in Microbiology and Immunology in 2012"

Group A Streptococcal Diseases and Their Global Burden

Abstract: Group A streptococcus (GAS) or Streptococcus pyogenes has been recognised as an important human pathogen since early days of modern microbiology, and it remains among the top ten causes of mortality from an infectious disease. Clinical manifestations attributable to this organism are perhaps the most diverse of any single human pathogen. These encompass invasive GAS infections, with high mortality rates despite effective antimicrobials, toxin-mediated diseases including scarlet fever and streptococcal toxic shock syndrome, the autoimmune sequelae of rheumatic fever and glomerulonephritis with potential for long-term disability, and nuisance manifestations of superficial skin and pharyngeal infection, which continue to consume a sizable proportion of healthcare resources. Although an historical perspective indicates major overall reductions in GAS infection rates in the modern era, chiefly as a result of widespread improvements in socioeconomic circumstances, this pathogen remains as a leading infectious cause of global morbidity and mortality. More than 18 million people globally are estimated to suffer from serious GAS disease. This burden disproportionally affects least affluent populations, and is a major cause of illness and death among children and young adults, including pregnant women, in low-resource settings. We review GAS transmission characteristics and prevention strategies, historical and geographical trends and report on the estimated global burden disease attributable to GAS. The lack of systematic reporting makes accurate estimation of rates difficult. This highlights the need to support improved surveillance and epidemiological research in low-resource settings, in order to enable better assessment of national and global disease burdens, target control strategies appropriately and assess the success of control interventions.

Genetic Diversity Within Clostridium botulinum Serotypes, Botulinum Neurotoxin Gene Clusters and Toxin Subtypes

Abstract: Clostridium botulinum is a species of spore-forming anaerobic bacteria defined by the expression of any one or two of seven serologically distinct botulinum neurotoxins (BoNTs) designated BoNT/A-G. This Gram-positive bacterium was first identified in 1897 and since then the paralyzing and lethal effects of its toxin have resulted in the recognition of different forms of the intoxication known as food-borne, infant, or wound botulism. Early microbiological and biochemical characterization of C. botulinum isolates revealed that the bacteria within the species had different characteristics and expressed different toxin types. To organize the variable bacterial traits within the species, Group I–IV designations were created. Interestingly, it was observed that isolates within different Groups could express the same toxin type and conversely a single Group could express different toxin types. This discordant phylogeny between the toxin and the host bacteria indicated that horizontal gene transfer of the toxin was responsible for the variation observed within the species. The recent availability of multiple C. botulinum genomic sequences has offered the ability to bioinformatically analyze the locations of the bont genes, the composition of their toxin gene clusters, and the genes flanking these regions to understand their variation. Comparison of the genomic sequences representing multiple serotypes indicates that the bont genes are not in random locations. Instead the analyses revealed specific regions where the toxin genes occur within the genomes representing serotype A, B, C, E, and F C. botulinum strains and C. butyricum type E strains. The genomic analyses have provided evidence of horizontal gene transfer, site-specific insertion, and recombination events. These events have contributed to the variation observed among the neurotoxins, the toxin gene clusters and the bacteria that contain them, and has supported the historical microbiological, and biochemical characterization of the Group classification within the species.

Pasteurella multocida: diseases and pathogenesis.

Abstract: Pasteurella multocida is an enigmatic pathogen. It is remarkable both for the number and range of specific disease syndromes with which it is associated, and the wide range of host species affected. The pathogenic mechanisms involved in causing the different syndromes are, for the most part, poorly understood or completely unknown. The biochemical and serological properties of some organisms responsible for quite different syndromes appear to be similar. Thus, the molecular basis for host predilection remains unknown. The recent development of genetic manipulation systems together with the availability of multiple genome sequences should help to explain the association of particular pathological conditions with particular hosts as well as helping to elucidate pathogenic mechanisms.

Double Receptor Anchorage of Botulinum Neurotoxins Accounts for their Exquisite Neurospecificity

Abstract: The high potency of the botulinum neurotoxins (BoNT) and tetanus neurotoxin (TeNT) is mainly due to their neurospecific binding which is mediated by the interaction with two receptor components. TeNT and all BoNT bind first to complex polysialo-gangliosides abundantly present on the outer leaflet of neuronal membranes. The ganglioside binding occurs in BoNT/A, B, E, F and G via a conserved ganglioside binding pocket within the most carboxyl-terminal 25 kDa domain HCC whereas TeNT, BoNT/C and D display two different ganglioside binding sites within their HCC-domain. Subsequently, upon exocytosis the intraluminal domains of synaptic vesicle proteins are exposed and can be accessed by the surface accumulated neurotoxins. BoNT/B and G bind with their HCC-domain to a 20-mer membrane juxtaposed segment of the intraluminal domain of synaptotagmin-I and -II, respectively. BoNT/A and E employ the intraluminal domain 4 of the synaptic vesicle glycoprotein 2 (SV2) as protein receptor. Whereas the 50 kDa cell binding domain HC of BoNT/A interacts with all three SV2 isoforms, BoNT/E HC only binds SV2A and SV2B. Also, BoNT/D, F, and TeNT employ SV2 for binding and uptake. Thereafter, the synaptic vesicle is recycled and the anchored neurotoxin is endocytosed. Acidification of the vesicle lumen triggers membrane insertion of the translocation domain followed by pore formation and finally translocation of the enzymatically active light chain to its site of action leading to block of neurotransmitter release.

Swine Influenza Virus Vaccines: To Change or Not to Change—That’s the Question

Abstract: Commercial vaccines currently available against swine influenza virus (SIV) are inactivated, adjuvanted, whole virus vaccines, based on H1N1 and/or H3N2 and/or H1N2 SIVs. In keeping with the antigenic and genetic differences between SIVs circulating in Europe and the US, the vaccines for each region are produced locally and contain different strains. Even within a continent, there is no standardization of vaccine strains, and the antigen mass and adjuvants can also differ between different commercial products. Recombinant protein vaccines against SIV, vector, and DNA vaccines, and vaccines attenuated by reverse genetics have been tested in experimental studies, but they have not yet reached the market. In this review, we aim to present a critical analysis of the performance of commercial inactivated and novel generation SIV vaccines in experimental vaccination challenge studies in pigs. We pay special attention to the differences between commercial SIV vaccines and vaccination attitudes in Europe and in North America, to the issue of vaccine strain selection and changes, and to the potential advantages of novel generation vaccines over the traditional killed SIV vaccines.

ADAR Proteins: Double-stranded RNA and Z-DNA Binding Domains

Abstract: Adenosine deaminases acting on RNA (ADAR) catalyze adenosine to inosine editing within double-stranded RNA (dsRNA) substrates. Inosine is read as a guanine by most cellular processes and therefore these changes create codons for a different amino acid, stop codons or even a new splice-site allowing protein diversity generated from a single gene. We review here the current structural and molecular knowledge on RNA editing by the ADAR family of protein. We focus especially on two types of nucleic acid binding domains present in ADARs, namely the dsRNA and Z-DNA binding domains.

Mechanisms of vessel regression: toward an understanding of the resolution of angiogenesis.

Abstract: Physiological angiogenesis refers to a naturally occurring process of blood vessel growth and regression, and it occurs as an integral component of tissue repair and regeneration. During wound healing, sprouting and branching results in an extensive yet immature and leaky neovascular network that ultimately resolves by systematic pruning of extraneous vessels to yield a stable, well-perfused vascular network ideally suited to maintain tissue homeostasis. While the molecular mechanisms of blood vessel growth have been explored in numerous cell and animal models in remarkable detail, the endogenous factors that prevent further angiogenesis and control vessel regression have not received much attention and are largely unknown. In this review, we introduce the relevant literature from various disciplines to fill the gaps in the current limited understanding of the major molecular and biomechanical inducers of vascular regression. The processes are described in the context of endothelial cell biology during wound healing: hypoxia-driven activation and sprouting followed by apoptosis or maturation of cells comprising the vasculature. We discuss and integrate the likely roles of a variety of endogenous factors, including oxygen availability, vessel perfusion and shear stress, intracellular negative feedback mechanisms (Spry2, vasohibin), soluble cytokines (CXCL10), matrix-binding proteins (TSP, PEDF), protein cleavage products (angiostatin, vasostatin), matrix-derived anti-angiogenic peptides (endostatin, arresten, canstatin, tumstatin), and the biomechanical properties of remodeling the extra-cellular matrix itself. These factors aid in the spatio-temporal control of blood vessel pruning by inducing specific anti-angiogenic signaling pathways in activated endothelial cells, pathways which compete with pro-angiogenic and maturation signals in the resolving wound. Gaining more insight into these mechanisms is bound to shed light on unresolved questions regarding scar formation, tissue regeneration, and increase our understanding of the many diseases with angiogenic phenotypes, especially cancer.

Production of Recombinant Antigens and Antibodies in Nicotiana benthamiana Using ‘Magnifection’ Technology: GMP-Compliant Facilities for Small- and Large-Scale Manufacturing

Abstract: This review describes the adaptation of the plant virus-based transient expression system, magnICON® for the at-scale manufacturing of pharmaceutical proteins. The system utilizes so-called “deconstructed” viral vectors that rely on Agrobacterium-mediated systemic delivery into the plant cells for recombinant protein production. The system is also suitable for production of hetero-oligomeric proteins like immunoglobulins. By taking advantage of well established R&D tools for optimizing the expression of protein of interest using this system, product concepts can reach the manufacturing stage in highly competitive time periods. At the manufacturing stage, the system offers many remarkable features including rapid production cycles, high product yield, virtually unlimited scale-up potential, and flexibility for different manufacturing schemes. The magnICON system has been successfully adaptated to very different logistical manufacturing formats: (1) speedy production of multiple small batches of individualized pharmaceuticals proteins (e.g. antigens comprising individualized vaccines to treat NonHodgkin’s Lymphoma patients) and (2) large-scale production of other pharmaceutical proteins such as therapeutic antibodies. General descriptions of the prototype GMP-compliant manufacturing processes and facilities for the product formats that are in preclinical and clinical testing are provided.

Epidemiology and Pathogenicity of Zoonotic Streptococci

Abstract: Zoonotic infections caused by Streptococcus spp. have been neglected in spite of the fact that frequency and severity of outbreaks increased dramatically in recent years. This may be due to non-identification since respective species are often not considered in human medical diagnostic procedures. On the other hand, an expanding human population concomitant with an increasing demand for food and the increased number of companion animals favour conditions for host species adaptation of animal streptococci. This review aims to give an overview on streptococcal zoonoses with focus on epidemiology and pathogenicity of four major zoonotic species, Streptococcus canis, Streptococcus equi sub. zooepidemicus, Streptococcus iniae and Streptococcus suis.

Epidemiology of henipavirus disease in humans

Abstract: All seven recognized human cases of Hendra virus (HeV) infection have occurred in Queensland, Australia. Recognized human infections have all resulted from a HeV infected horse that was unusually efficient in transmitting the virus and a person with a high exposure to infectious secretions. In the large outbreak in Malaysia where Nipah virus (NiV) was first identified, most human infections resulted from close contact with NiV infected pigs. Outbreak investigations in Bangladesh have identified drinking raw date palm sap as the most common pathway of NiV transmission from Pteropus bats to people, but person-to-person transmission of NiV has been repeatedly identified in Bangladesh and India. Although henipaviruses are not easily transmitted to people, these newly recognized, high mortality agents warrant continued scientific attention.

Animal Challenge Models of Henipavirus Infection and Pathogenesis

Abstract: The henipaviruses, Hendra virus (HeV), and Nipah virus (NiV), are enigmatic emerging pathogens that causes severe and often fatal neurologic and/or respiratory disease in both animals and humans. Amongst people, case fatality rates range between 40 and 75% and there are no vaccines or treatments approved for human use. A number of species of animals including guinea pigs, hamsters, cats, ferrets, pigs, and African green monkeys have been employed as animal models of human henipavirus infection. Here, we review the development of animal models for henipavirus infection, discuss the pathology and pathogenesis of these models, and assess the utility of each model to recapitulate important aspects of henipavirus-mediated disease seen in humans.

Inositol Polyphosphate Phosphatases in Human Disease

Abstract: Phosphoinositide signalling molecules interact with a plethora of effector proteins to regulate cell proliferation and survival, vesicular trafficking, metabolism, actin dynamics and many other cellular functions. The generation of specific phosphoinositide species is achieved by the activity of phosphoinositide kinases and phosphatases, which phosphorylate and dephosphorylate, respectively, the inositol headgroup of phosphoinositide molecules. The phosphoinositide phosphatases can be classified as 3-, 4- and 5-phosphatases based on their specificity for dephosphorylating phosphates from specific positions on the inositol head group. The SAC phosphatases show less specificity for the position of the phosphate on the inositol ring. The phosphoinositide phosphatases regulate PI3K/Akt signalling, insulin signalling, endocytosis, vesicle trafficking, cell migration, proliferation and apoptosis. Mouse knockout models of several of the phosphoinositide phosphatases have revealed significant physiological roles for these enzymes, including the regulation of embryonic development, fertility, neurological function, the immune system and insulin sensitivity. Importantly, several phosphoinositide phosphatases have been directly associated with a range of human diseases. Genetic mutations in the 5-phosphatase INPP5E are causative of the ciliopathy syndromes Joubert and MORM, and mutations in the 5-phosphatase OCRL result in Lowe’s syndrome and Dent 2 disease. Additionally, polymorphisms in the 5-phosphatase SHIP2 confer diabetes susceptibility in specific populations, whereas reduced protein expression of SHIP1 is reported in several human leukaemias. The 4-phosphatase, INPP4B, has recently been identified as a tumour suppressor in human breast and prostate cancer. Mutations in one SAC phosphatase, SAC3/FIG4, results in the degenerative neuropathy, Charcot-Marie-Tooth disease. Indeed, an understanding of the precise functions of phosphoinositide phosphatases is not only important in the context of normal human physiology, but to reveal the mechanisms by which these enzyme families are implicated in an increasing repertoire of human diseases.

One Health: Its Origins and Future

Abstract: One Health is an emerging concept that aims to bring together human, animal, and environmental health. Achieving harmonized approaches for disease detection and prevention is difficult because traditional boundaries of medical and veterinary practice must be crossed. In the nineteenth and early twentieth centuries, this was not the case—then researchers like Louis Pasteur and Robert Koch and physicians like William Osler and Rudolph Virchow crossed the boundaries between animal and human health. More recently, Calvin Schwabe revived the concept of One Medicine. This was critical for the advancement of the field of epidemiology, especially as applied to zoonotic diseases. The future of One Health is at a crossroad with the need to more clearly define its boundaries and demonstrate its benefits. Interestingly, the greatest acceptance of One Health is seen in the developing world where it is having significant impacts on control of infectious diseases.

Assembly and function of the botulinum neurotoxin progenitor complex.

Abstract: Botulinum neurotoxins (BoNTs) are among the most poisonous substances known to man, but paradoxically, BoNT-containing medicines and cosmetics have been used with great success in the clinic. Accidental BoNT poisoning mainly occurs through oral ingestion of food contaminated with Clostridium botulinum. BoNTs are naturally produced in the form of progenitor toxin complexes (PTCs), which are high molecular weight (up to ~900 kDa) multiprotein complexes composed of BoNT and several non-toxic neurotoxin-associated proteins (NAPs). NAPs protect the inherently fragile BoNTs against the hostile environment of the gastrointestinal (GI) tract and help BoNTs pass through the intestinal epithelial barrier before they are released into the general circulation. These events are essential for ingested BoNTs to gain access to motoneurons, where they inhibit neurotransmitter release and cause muscle paralysis. In this review, we discuss the structural basis for assembly of NAPs and BoNT into the PTC that protects BoNT and facilitate its delivery into the bloodstream.

Genetics, evolution, and the zoonotic capacity of European Swine influenza viruses.

Abstract: The European swine influenza virus lineage differs genetically from the classical swine influenza viruses and the triple reassortants found in North America and Asia. The avian-like swine H1N1 viruses emerged in 1979 after an avian-to-swine transmission and spread to all major European pig-producing countries. Reassortment of these viruses with seasonal H3N2 viruses led to human-like swine H3N2 viruses which appeared in 1984. Finally, human-like swine H1N2 viruses emerged in 1994. These are triple reassortants comprising genes of avian-like H1N1, seasonal H1N1, and seasonal H3N2 viruses. All three subtypes established persistent infection chains and became prevalent in the European pig population. They successively replaced the circulating classical swine H1N1 viruses of that time and gave rise to a number of reassortant viruses including the pandemic (H1N1) 2009 virus. All three European lineages have the capacity to infect humans but zoonotic infections are benign.

What Distinguishes Highly Pathogenic Staphylococci from Medium- and Non-pathogenic?

Abstract: Members of the genus Staphylococcus are widespread as commensals of humans and animals where they colonize the skin or mucous membranes. While this coexistence remains mostly untroubled, especially for the healthy host, the bacteria may pose a serious threat for the human or animal host when they get access to inner layers of the body through breaches in skin or membranes. Among the members of the genus a wide span exists in the ability to cope with the hostile conditions encountered in the bloodstream of the living host as a scarce supply of certain nutrients, attacks of the immune system, or anti-infective measures undertaken in the clinical field. In this respect, Staphylococcus aureus is by far the most versatile species of the genus. Its equipment with a huge repertoire of different virulence factors and additional supportive gene products that increase the capability to survive within the living host makes S. aureus the leading pathogen not only within the genus but also one of the most threatening microorganisms regarding hospitally and community-acquired infections. Compared with S. aureus, the other virulent species of the genus like S. epidermidis, S. lugdunensis, S. saprophyticus, and S. haemolyticus have a more limited arsenal of virulence factors resulting in a specialized spectrum of diseases and a generally lower degree of pathogenicity. Besides the highly and medium-pathogenic staphylococci, the genus comprises also species like S. carnosus, S. xylosus, and S. equorum that are generally inconspicuous regarding clinical occurrences. Some strains of this group are used in the food industry and can be graded as non-pathogenic. This review aims to work out the differences between the pathogenic properties of highly and medium-pathogenic staphylococcal species and to draw a comparison between the pathogenic species and the food-grade S. carnosus TM300.

Clostridial neurotoxin light chains: devices for SNARE cleavage mediated blockade of neurotransmission.

Abstract: Seven serologically distinct botulinum neurotoxins and tetanus neurotoxin which cause the diseases botulism and tetanus constitute the clostridial neurotoxin family. Like many other bacterial protein toxins they exhibit a modular structure. One domain mediates highly specific binding to target cells and endocytosis, while the second translocates the third, a catalytic domain across the endosomal membrane to the target cell cytosol. In case of Clostridial neurotoxins (CNT), the latter acts as extremely specific Zn2+-dependent metalloproteinase. The various serotypes proteolyze each one particular peptide bond in one of the three SNARE proteins, which are the core of the membrane fusion apparatus for synaptic vesicles. SNARE cleavage causes the blockade of neurotransmitter release. This chapter details the molecular basis for the highly selective substrate recognition and cleavage mechanism of CNT.

Overview of influenza viruses.

Abstract: The influenza virus (IV) is still of great importance as it poses an immanent threat to humans and animals. Among the three IV-types (A, B, and C) influenza A viruses are clinically the most important being responsible for severe epidemics in humans and domestic animals. Aerosol droplets transmit the virus that causes a respiratory disease in humans that can lead to severe pneumonia and ultimately death. The high mutation rate combined with the high replication rate allows the virus to rapidly adapt to changes in the environment. Thereby, IV escape the existing immunity and become resistant to drugs targeting the virus. This causes annual epidemics and demands for new compositions of the yearly vaccines. Furthermore, due to the nature of their segmented genome, IV can recombine segments. This can eventually lead to the generation of a virus with the ability to replicate in humans and with novel antigenic properties that can be the cause of a pandemic outbreak. For its propagation the virus binds to the target cells and enters the cell to replicate its genome. Newly produced viral proteins and genomes are packaged at the cell membrane where progeny virions are released. As all viruses IV depends on cellular functions and factors for their own propagation, and therefore intensively interact with the cells. This dependency opens new possibilities for anti-viral strategies.

Ecological aspects of hendra virus.

Abstract: Hendra virus, a novel and fatally zoonotic member of the family Paramyxoviridae, was first described in Australia in 1994. Periodic spillover from its natural host (fruit bats) results in catastrophic disease in horses and occasionally the subsequent infection of humans. Prior to 2011, 14 equine incidents involving seven human cases (four fatal) were recorded. The year 2011 saw a dramatic departure from the sporadic incidents of the previous 16 years, with a cluster of 18 incidents in a single 3-month period. The fundamental difference in 2011 was the total number of incidents, the geographic clustering, and the expanded geographic range. The 2011 cluster more than doubled the total number of incidents previously reported, and poses the possibility of a new HeV infection paradigm. Epidemiologic evidence suggests that compelling additional host and/or environmental factors were at play.

Recent advances on NOTCH signaling in T-ALL.

Abstract: NOTCH1 receptor signaling plays a central role in T-cell lineage specification and in supporting the growth and proliferation of immature T-cell progenitors in the thymus during lymphoid development. In T-cell acute lymphoblastic leukemia (T-ALL), a tumor resulting from the malignant transformation of T-cell progenitors, aberrant and constitutively active NOTCH1 signaling triggered by activating mutations in the NOTCH1 gene contributes to oncogenic transformation and is a hallmark of this disease. Most notably, small molecule γ-secretase inhibitors (GSIs) can effectively block NOTCH1 signaling in T-ALL, and could be exploited as a targeted therapy in this disease. In addition, a number of emerging anti-NOTCH therapeutic strategies including anti-NOTCH1 inhibitory antibodies, small peptide inhibitors of NOTCH signaling and combination therapies with GSIs and glucocorticoids, have recently been proposed. Finally, the identification of NOTCH1 mutations in solid tumors and chronic lymphocytic leukemias has increased even further the clinical relevance of NOTCH signaling as a therapeutic target in human cancer. Here we review our current understanding of NOTCH1-induced transformation, the mechanisms of action of oncogenic NOTCH1 in T-ALL and the therapeutic and prognostic implications of NOTCH1 mutations in T-ALL.

Teleost fish as a model system to study successful regeneration of the central nervous system.

Abstract: Traumatic brain injury and spinal cord injury are devastating conditions that may result in death or long-term disability. A promising strategy for the development of effective cell replacement therapies involves the study of regeneration-competent organisms. Among this group, teleost fish are distinguished by their excellent potential to regenerate nervous tissue and to regain function after injury to the central nervous system. In this chapter, we summarize our current understanding of the cellular processes that mediate this regenerative potential, and we show that several of these processes are shared with the normal development of the intact central nervous system; we describe how the spontaneous self-repair of the teleostean central nervous system leads to functional recovery, at physiological and behavioral levels; we discuss the possible function of molecular factors associated with the degenerative and regenerative processes after injury; and, finally, we speculate on evolutionary aspects of adult neurogenesis and neuronal regeneration, and on how a better understanding of these aspects could catalyze the development of therapeutic strategies to overcome the regenerative limits of the mammalian CNS.

Henipavirus receptor usage and tropism.

Abstract: Nipah (NiV) and Hendra (HeV) viruses are the deadliest human pathogens within the Paramyxoviridae family, which include human and animal pathogens of global biomedical importance. NiV and HeV infections cause respiratory and encephalitic illness with high mortality rates in humans. Henipaviruses (HNV) are the only Paramyxoviruses classified as biosafety level 4 (BSL4) pathogens due to their extreme pathogenicity, potential for bioterrorism, and lack of licensed vaccines and therapeutics. HNV use ephrin-B2 and ephrin-B3, highly conserved proteins, as viral entry receptors. This likely accounts for their unusually broad species tropism, and also provides opportunities to study how receptor usage, cellular tropism, and end-organ pathology relates to the pathobiology of HNV infections. The clinical and pathologic manifestations of NiV and HeV virus infections are reviewed in the chapters by Wong et al. and Geisbert et al. in this issue. Here, we will review the biology of the HNV receptors, and how receptor usage relates to HNV cell tropism in vitro and in vivo.

Shiga toxin pathogenesis: kidney complications and renal failure

Abstract: The kidneys are the major organs affected in diarrhea-associated hemolytic uremic syndrome (D+HUS). The pathophysiology of renal disease in D+HUS is largely the result of the interaction between bacterial virulence factors such as Shiga toxin and lipopolysaccharide and host cells in the kidney and in the blood circulation. This chapter describes in detail the current knowledge of how these bacterial toxins may lead to kidney disease and renal failure. The toxin receptors expressed by specific blood and resident renal cell types are also discussed as are the actions of the toxins on these cells.

Uptake of botulinum neurotoxin in the intestine.

Abstract: Foodborne and intestinal botulism are the most common forms of human botulism; both result from the absorption of botulinum neurotoxin (BoNT) from the digestive tract into the circulation. BoNT is a large protein toxin (approximately 150 kDa), but it is able to pass through the epithelial barrier in the digestive tract. Recent cellular and molecular biology studies have begun to unravel the mechanisms by which this large protein toxin crosses the intestinal epithelial barrier. This review provides an overview of current knowledge relating to the absorption of botulinum toxins (BoNT and BoNT complex) from the gastrointestinal tract, with particular emphasis on the interaction of these toxins with the intestinal epithelial barrier.

Notch signaling during human T cell development.

Abstract: Notch signaling is critical during multiple stages of T cell development in both mouse and human. Evidence has emerged in recent years that this pathway might regulate T-lineage differentiation differently between both species. Here, we review our current understanding of how Notch signaling is activated and used during human T cell development. First, we set the stage by describing the developmental steps that make up human T cell development before describing the expression profiles of Notch receptors, ligands, and target genes during this process. To delineate stage-specific roles for Notch signaling during human T cell development, we subsequently try to interpret the functional Notch studies that have been performed in light of these expression profiles and compare this to its suggested role in the mouse.

Mycobacterium tuberculosis metabolism and host interaction: mysteries and paradoxes.

Abstract: Metabolism is a widely recognized facet of all host–pathogen interactions. Knowledge of its roles in pathogenesis, however, remains comparatively incomplete. Existing studies have emphasized metabolism as a cell autonomous property of pathogens used to fuel replication in a quantitative, rather than qualitatively specific, manner. For Mycobacterium tuberculosis, however, matters could not be more different. M. tuberculosis is a chronic facultative intracellular pathogen that resides in humans as its only known host. Within humans, M. tuberculosis resides chiefly within the macrophage phagosome, the cell type, and compartment most committed to its eradication. M. tuberculosis has thus evolved its metabolic network to both maintain and propagate its survival as a species within a single host. The specific ways in which its metabolic network serves these distinct, through interdependent, functions, however, remain incompletely defined. Here, we review existing knowledge of the M. tuberculosis–host interaction, highlighting the distinct phases of its natural life cycle and the diverse microenvironments encountered therein.

Wound Healing in Mammals and Amphibians: Toward Limb Regeneration in Mammals

Abstract: Mammalian fetal skin regenerates perfectly, but adult skin repairs by the formation of scar tissue. The cause of this imperfect repair by adult skin is not understood. In contrast, wounded adult amphibian (urodeles and anurans) skin is like mammalian fetal skin in that it repairs by regeneration, not scarring. Scar-free wound repair in adult Xenopus is associated with expression of the paired homeobox transcription factor Prx1 by mesenchymal cells of the wound, a feature shared by mesenchymal cells of the regeneration blastema of the axolotl limb. Furthermore, mesenchymal cells of Xenopus skin wounds that harbor the mouse Prx1-limb-enhancer as a transgene exhibit activation of the enhancer despite the fact that they are Xenopus cells, suggesting that the mouse Prx1 enhancer possesses all elements required for its activation in skin wound healing, even though activation of the same enhancer in the mouse is not seen in the wounded skin of an adult mouse. Elucidation of the role of the Prx1 gene in amphibian skin wound healing will help to clarify the molecular mechanisms of scarless wound healing. Shifting the molecular mechanism of wound repair in mammals to that of amphibians, including reactivation of the Prx1-limb-enhancer, will be an important clue to stimulate scarless wound repair in mammalian adult skin. Finding or creating Prx1-positive stem cells in adult mammal skin by activating the Prx1-limb-enhancer may be a fast and reliable way to provide for scarless skin wound repair, and even directly lead to limb regeneration in mammals.

Japanese Encephalitis: On the One Health Agenda

Abstract: Japanese encephalitis (JE) is one of the most well studied arthropod zoonotic diseases with human and animal research and their integration spanning 6–7 decades. JE research and policy in some Asian countries has epitomized the ‘One Health’ strategy of attainment of optimal health for people, animals, and the environment. However, despite significant mitigation of JE in some Asian countries primarily due to vaccination programs and infrastructural development, JE continues to be a major disease burden in the Asian region. Arthropod-borne zoonotic infections such as JE present some of the greatest challenges to animal and human health globally. Their emergence involves a complex interplay of vectors, hosts, environment, climate, and anthropogenic factors. Therefore, the integrated management of infectious agents that affect both humans and animals is perhaps the most highly coveted strategy that public health policy makers aspire to attain in the twenty-first century. This is in response to the seemingly growing challenges of controling the burden of emerging infectious diseases such as shrinking financial budgets and resources, increasing demand for public health deliverables, demographic shifts and mobility, global trade economies, and climate and landscape changes. Thus, while JE research and policy is an excellent example of the One Health strategy in action, further work is required to address the obstinate burden of transmission.

Clostridium difficile infection in humans and piglets: a 'One Health' opportunity.

Abstract: Clostridium difficile causes infectious diarrhoea in humans and animals. It has been found in both diarrhoeal and non-diarrhoeal pigs, horses and cattle, suggesting a potential reservoir for human insection, and in 20–40 % of meat products in Canada and the USA, suggesting the possibility, albeit not proven, of food-borne transmission. Although it is not yet completely clear, it is likely that excessive antimicrobial exposure is driving the establishment of C. difficile in animals, in a manner analogous to human infection, rather than the organism just being normal flora of the animal gastrointestinal tract. PCR ribotype 078 is the most common ribotype of C. difficile found in pigs (83 % in one study in the USA) and cattle (up to 100 %) and this ribotype is now the third most common ribotype of C. difficile found in human infection in Europe. Human and pig strains of C. difficile are genetically identical in Europe confirming that a zoonosis exists. Rates of community-acquired C. difficile infection (CDI) are increasing world wide, a fact that sits well with the notion that animals are a reservoir for human infection. Thus, there are three problems that require resolution: a human health issue, an animal health issue and the factor common to both these problems, environmental contamination. To successfully deal with these recent changes in the epidemiology of CDI will require a ‘one health’ approach involving human health physicians, veterinarians and environmental scientists.

Targeting Oncogenic BRAF in Human Cancer

Abstract: Mitogen Activated Protein Kinase (MAPK) pathway activation is a frequent event in human cancer and is often the result of activating mutations in the BRAF and RAS oncogenes. BRAF missense mutations, the vast majority of which are V600E, occur in approximately 8% of human tumors. These kinase domain mutations, which are non-overlapping in distribution with RAS mutations, are observed most frequently in melanoma but are also common in tumors arising in the colon, thyroid, lung, and other sites. Supporting its classification as an oncogene, (V600E)BRAF stimulates ERK signaling, induces proliferation, and is capable of promoting transformation. Given the frequent occurrence of BRAF mutations in human cancer and the continued requirement for BRAF activity in the tumors in which it is mutated, efforts are underway to develop targeted inhibitors of BRAF and its downstream effectors. These agents offer the possibility of greater efficacy and less toxicity than the systemic therapies currently available for tumors driven by activating mutations of MAPK pathway components. Early clinical results with the BRAF-selective inhibitors PLX4032 and GSK2118436 suggest that this strategy will prove successful in a select group of patients whose tumors are driven by oncogenic BRAF.