DNA viruses often persist in the body of their host, becoming latent and recurring many months or years later. By contrast, most RNA viruses cause acute infections that are cleared from the host as ...they lack the mechanisms to persist. However, it is becoming clear that viral RNA can persist after clinical recovery and elimination of detectable infectious virus. This persistence can either be asymptomatic or associated with late progressive disease or nonspecific lingering symptoms, such as may be the case following infection with Ebola or Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Why does viral RNA sometimes persist after recovery from an acute infection? Where does the RNA come from? And what are the consequences?
Measles is an important cause of child mortality that has a seemingly paradoxical interaction with the immune system. In most individuals, the immune response is successful in eventually clearing ...measles virus (MV) infection and in establishing life-long immunity. However, infection is also associated with persistence of viral RNA and several weeks of immune suppression, including loss of delayed type hypersensitivity responses and increased susceptibility to secondary infections. The initial T-cell response includes CD8⁺ and T-helper 1 CD4⁺ T cells important for control of infectious virus. As viral RNA persists, there is a shift to a T-helper 2 CD4⁺ T-cell response that likely promotes B-cell maturation and durable antibody responses but may suppress macrophage activation and T-helper 1 responses to new infections. Suppression of mitogen-induced lymphocyte proliferation can be induced by lymphocyte infection with MV or by lymphocyte exposure to a complex of the hemagglutinin and fusion surface glycoproteins without infection. Dendritic cells (DCs) are susceptible to infection and can transmit infection to lymphocytes. MV-infected DCs are unable to stimulate a mixed lymphocyte reaction and can induce lymphocyte unresponsiveness through expression of MV glycoproteins. Thus, multiple factors may contribute both to measles-induced immune suppression and to the establishment of durable protective immunity.
The pathways that comprise cellular metabolism are highly interconnected, and alterations in individual enzymes can have far-reaching effects. As a result, global profiling methods that measure gene ...expression are of limited value in predicting how the loss of an individual function will affect the cell. In this work, we employed a new method of global phenotypic profiling to directly define the genes required for the growth of Mycobacterium tuberculosis. A combination of high-density mutagenesis and deep-sequencing was used to characterize the composition of complex mutant libraries exposed to different conditions. This allowed the unambiguous identification of the genes that are essential for Mtb to grow in vitro, and proved to be a significant improvement over previous approaches. To further explore functions that are required for persistence in the host, we defined the pathways necessary for the utilization of cholesterol, a critical carbon source during infection. Few of the genes we identified had previously been implicated in this adaptation by transcriptional profiling, and only a fraction were encoded in the chromosomal region known to encode sterol catabolic functions. These genes comprise an unexpectedly large percentage of those previously shown to be required for bacterial growth in mouse tissue. Thus, this single nutritional change accounts for a significant fraction of the adaption to the host. This work provides the most comprehensive genetic characterization of a sterol catabolic pathway to date, suggests putative roles for uncharacterized virulence genes, and precisely maps genes encoding potential drug targets.
Measles is an acute systemic viral infection with immune system interactions that play essential roles in multiple stages of infection and disease. Measles virus (MeV) infection does not induce type ...1 interferons, but leads to production of cytokines and chemokines associated with nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) signaling and activation of the NACHT, LRR and PYD domains-containing protein (NLRP3) inflammasome. This restricted response allows extensive virus replication and spread during a clinically silent latent period of 10-14 days. The first appearance of the disease is a 2-3 day prodrome of fever, runny nose, cough, and conjunctivitis that is followed by a characteristic maculopapular rash that spreads from the face and trunk to the extremities. The rash is a manifestation of the MeV-specific type 1 CD4⁺ and CD8⁺ T cell adaptive immune response with lymphocyte infiltration into tissue sites of MeV replication and coincides with clearance of infectious virus. However, clearance of viral RNA from blood and tissues occurs over weeks to months after resolution of the rash and is associated with a period of immunosuppression. However, during viral RNA clearance, MeV-specific antibody also matures in type and avidity and T cell functions evolve from type 1 to type 2 and 17 responses that promote B cell development. Recovery is associated with sustained levels of neutralizing antibody and life-long protective immunity.
The therapeutic potential of donor-derived mesenchymal stromal cells (MSCs) has been investigated in diverse diseases
, including steroid-resistant acute graft versus host disease (SR-aGvHD)
. ...However, conventional manufacturing approaches are hampered by challenges with scalability and interdonor variability, and clinical trials have shown inconsistent outcomes
. Induced pluripotent stem cells (iPSCs) have the potential to overcome these challenges, due to their capacity for multilineage differentiation and indefinite proliferation
. Nonetheless, human clinical trials of iPSC-derived cells have not previously been completed. CYP-001 (iPSC-derived MSCs) is produced using an optimized, good manufacturing practice (GMP)-compliant manufacturing process. We conducted a phase 1, open-label clinical trial (no. NCT02923375) in subjects with SR-aGvHD. Sixteen subjects were screened and sequentially assigned to cohort A or cohort B (n = 8 per group). One subject in cohort B withdrew before receiving CYP-001 and was excluded from analysis. All other subjects received intravenous infusions of CYP-001 on days 0 and 7, at a dose level of either 1 × 10
cells per kg body weight, to a maximum of 1 × 10
cells per infusion (cohort A), or 2 × 10
cells per kg body weight, to a maximum dose of 2 × 10
cells per infusion (cohort B). The primary objective was to assess the safety and tolerability of CYP-001, while the secondary objectives were to evaluate efficacy based on the proportion of participants who showed a complete response (CR), overall response (OR) and overall survival (OS) by days 28/100. CYP-001 was safe and well tolerated. No serious adverse events were assessed as related to CYP-001. OR, CR and OS rates by day 100 were 86.7, 53.3 and 86.7%, respectively. The therapeutic application of iPSC-derived MSCs may now be explored in diverse inflammatory and immune-mediated diseases.
Protein concentration gradients encode spatial information across cells and tissues and often depend on spatially localized protein synthesis. Here, we report that a different mechanism underlies the ...MEX-5 gradient. MEX-5 is an RNA-binding protein that becomes distributed in a cytoplasmic gradient along the anterior-to-posterior axis of the one-cell
C. elegans embryo. We demonstrate that the MEX-5 gradient is a direct consequence of an underlying gradient in MEX-5 diffusivity. The MEX-5 diffusion gradient arises when the PAR-1 kinase stimulates the release of MEX-5 from slow-diffusive, RNA-containing complexes in the posterior cytoplasm. PAR-1 directly phosphorylates MEX-5 and is antagonized by the spatially uniform phosphatase PP2A. Mathematical modeling and in vivo observations demonstrate that spatially segregated phosphorylation and dephosphorylation reactions are sufficient to generate stable protein concentration gradients in the cytoplasm. The principles demonstrated here apply to any spatially segregated modification cycle that affects protein diffusion and do not require protein synthesis or degradation.
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► A gradient in diffusion rates underlies the MEX-5 gradient in the
C. elegans zygote ► RNA binding retards diffusion of the MEX-5 protein ► PAR-1 kinase and PP2A phosphatase antagonistically regulate MEX-5 diffusion ► PAR-1 kinase acts asymmetrically in the cytoplasm to increase MEX-5 diffusion
Localized activation of a kinase, which regulates the diffusion rate of its substrate protein, presents a new paradigm for protein concentration gradient formation that does not require localized protein synthesis or degradation
¿Es suficiente la información sobre la naturaleza, la ubicación y la incidencia de delitos contra los turistasvisitantes para desarrollar una política significativa de seguridad de los ...visitantes? ¿Las opiniones de los principales grupos interesados (los stakeholders) en el turismo son de utilidad para mejorar la política de seguridad de los visitantes y la sensación de seguridad? Para responder a estas preguntas, este estudio analiza 24 años de datos de delitos registrados cometidos contra los visitantes de Barbados y los datos de investigación de grupos de actores clave del turismo, y concluye: 1) que la información sobre la naturaleza, localización y la incidencia de los delitos contra los visitantes es necesario pero no suficiente para influir la política de seguridad de los visitantes, y 2) que las opiniones y aportaciones de las principales partes interesadas son esenciales para que los destinos serán más eficaces en la mejora de seguridad de los visitantes.
Cell-surface glycans are a diverse class of macromolecules that participate in many key biological processes, including cell-cell communication, development, and disease progression. Thus, the ...ability to modulate the structures of glycans on cell surfaces provides a powerful means not only to understand fundamental processes but also to direct activity and elicit desired cellular responses. Here, we describe methods to sculpt glycans on cell surfaces and highlight recent successes in which artificially engineered glycans have been employed to control biological outcomes such as the immune response and stem cell fate.
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•Glycan engineering enables the manipulation of cellular processes•Genetic approaches can reveal glycan structures required for biological processes•Metabolic oligosaccharide engineering allows the installation of nonnatural moieties•De novo glycan display permits the large-scale remodeling of surface carbohydrates
Cellular surfaces are decorated with glycans, and their composition and architectures is an important determinant of cell fate. Griffin and Hsieh-Wilson discuss how chemical methods are enabling the study of structure and function of glycans in cellular and developmental processes.
A wide range of viruses from different virus families in different geographical areas, may cause immediate or delayed neuropathological changes and neurological manifestations in humans and animals. ...Infection by neurotropic viruses as well as the resulting immune response can irreversibly disrupt the complex structural and functional architecture of the central nervous system, frequently leaving the patient or affected animal with a poor or fatal prognosis. Mechanisms that govern neuropathogenesis and immunopathogenesis of viral infections are highlighted, using examples of well-studied virus infections that are associated with these alterations in different populations throughout the world. A better understanding of the molecular, epidemiological and biological characteristics of these infections and in particular of mechanisms that underlie their clinical manifestations may be expected to provide tools for the development of more effective intervention strategies and treatment regimens.
Measles Moss, William J, Dr; Griffin, Diane E, MD
The Lancet (British edition),
01/2012, Letnik:
379, Številka:
9811
Journal Article
Recenzirano
Summary Measles is a highly contagious disease caused by measles virus and is one of the most devastating infectious diseases of man—measles was responsible for millions of deaths annually worldwide ...before the introduction of the measles vaccines. Remarkable progress in reducing the number of people dying from measles has been made through measles vaccination, with an estimated 164 000 deaths attributed to measles in 2008. This achievement attests to the enormous importance of measles vaccination to public health. However, this progress is threatened by failure to maintain high levels of measles vaccine coverage. Recent measles outbreaks in sub-Saharan Africa, Europe, and the USA show the ease with which measles virus can re-enter communities if high levels of population immunity are not sustained. The major challenges for continued measles control and eventual eradication will be logistical, financial, and the garnering of sufficient political will. These challenges need to be met to ensure that future generations of children do not die of measles.
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