Echinocandin resistance and population structure of invasive Candida glabrata isolates from two university hospitals in Germany and Austria.

Echinocandin resistance in Candida glabrata is emerging and is associated with the presence of FKS mutations. In this study, we analysed the antifungal susceptibility, presence of FKS mutations and clonality of C. glabrata blood culture isolates from two hospitals in Germany and Austria.

Antiviral Activities of Different Interferon Types and Subtypes against Hepatitis E Virus Replication.

Hepatitis E virus (HEV) is the causative agent of hepatitis E in humans and a member of the genusOrthohepevirusin the familyHepeviridae HEV infections are the common cause of acute hepatitis but can also take chronic courses. Ribavirin is the treatment of choice for most patients, and type I interferon (IFN) has been evaluated in a few infected transplant patientsin vivo In this study, the antiviral effects of different exogenously administered interferons were investigated by using state-of-the-art subgenomic replicon and full-length HEV genome cell culture models. Hepatitis C virus (HCV) subgenomic replicons based on the genotype 2a JFH1 isolate served as the reference.

Identification of a Human Respiratory Syncytial Virus Cell Entry Inhibitor by Using a Novel Lentiviral Pseudotype System.

Unlabelled: Lentiviral budding is governed by group-specific antigens (Gag proteins) and proceeds in the absence of cognate viral envelope proteins, which has been exploited to create pseudotypes incorporating envelope proteins from nonlentiviral families. Here, we report the generation of infectious lentiviral pseudoparticles incorporating human respiratory syncytial virus (hRSV) F protein alone (hRSV-Fpp) or carrying SH, G, and F proteins (hRSV-SH/G/Fpp). These particles recapitulate key infection steps of authentic hRSV particles, including utilization of glycosaminoglycans and low-pH-independent cell entry.

Frequent presence of hepaci and pegiviruses in commercial equine serum pools.

Novel viruses belonging to the genera Hepacivirus and Pegivirus have recently been discovered in horses and other animal species. Viral genomes of non-primate hepaciviruses (NPHV), equine pegivirus 1 (EPgV 1) and Theiler's disease associated virus (TDAV) were detected in a horse serum routinely used for cell culture propagation in our laboratory. Therefore, a study was carried out to further investigate the presence of these human Hepatitis C virus (HCV) related viruses in equine serum based products used in veterinary medicine and for research and to characterize the viral genomes.

Cellular Antiviral Factors that Target Particle Infectivity of HIV-1.

Background: In the past decade, the identification and characterization of antiviral genes with the ability to interfere with virus replication has established cell-intrinsic innate immunity as a third line of antiviral defense in addition to adaptive and classical innate immunity. Understanding how cellular factors have evolved to inhibit HIV-1 reveals particularly vulnerable points of the viral replication cycle. Many, but not all, antiviral proteins share type I interferon-upregulated expression and sensitivity to viral counteraction or evasion measures.

CD4+ T Cell Tolerance to Tissue-Restricted Self Antigens Is Mediated by Antigen-Specific Regulatory T Cells Rather Than Deletion.

Deletion of self-antigen-specific T cells during thymic development provides protection from autoimmunity. However, it is unclear how efficiently this occurs for tissue-restricted self antigens, or how immune tolerance is maintained for self-antigen-specific T cells that routinely escape deletion. Here we show that endogenous CD4+ T cells with specificity for a set of tissue-restricted self antigens were not deleted at all.

The LasB Elastase of Pseudomonas aeruginosa Acts in Concert with Alkaline Protease AprA To Prevent Flagellin-Mediated Immune Recognition.

The opportunistic pathogen Pseudomonas aeruginosa is capable of establishing severe and persistent infections in various eukaryotic hosts. It encodes a wide array of virulence factors and employs several strategies to evade immune detection. In the present study, we screened the Harvard Medical School transposon mutant library of P.

Distinct Escape Pathway by Hepatitis C Virus Genotype 1a from a Dominant CD8+ T Cell Response by Selection of Altered Epitope Processing.

Unlabelled: Antiviral CD8(+) T cells are a key component of the adaptive immune response against HCV, but their impact on viral control is influenced by preexisting viral variants in important target epitopes and the development of viral escape mutations. Immunodominant epitopes highly conserved across genotypes therefore are attractive for T cell based prophylactic vaccines. Here, we characterized the CD8(+) T cell response against the highly conserved HLA-B*51-restricted epitope IPFYGKAI1373-1380 located in the helicase domain of NS3 in people who inject drugs (PWID) exposed predominantly to HCV genotypes 1a and 3a.

Synergy between CD40 and MyD88 Does Not Influence Host Survival to Salmonella Infection.

Previous studies using purified toll-like receptor (TLR) ligands plus agonistic anti-CD40 antibodies showed that TLRs and CD40 can act synergistically on dendritic cells (DCs) to optimize T cell activation and Th1 differentiation. However, a synergistic effect of TLRs and CD40 during bacterial infection is not known. Here, we show that mice lacking the TLR adaptor MyD88 alone, or lacking both MyD88 and CD40 [double knockout (DKO) mice], are compromised in survival to Salmonella infection but have intact recruitment of neutrophils and inflammatory monocytes as well as unaltered abundance of DC subsets and DC activation in infected tissues.

Diverse recruitment strategies result in different participation percentages in a web-based study, but in similar compliance.

Objectives: We compared participation and compliance with a web-based data collection on infections among population-based samples recruited in different ways.

Methods: Individuals were recruited from participants in the German National Cohort study (Group A, n = 279) or persons who were invited to this study but did not participate (Group B, n = 53). A third group was invited to the web-based study only (Group C, n = 145).

RNAseq expression analysis of resistant and susceptible mice after influenza A virus infection identifies novel genes associated with virus replication and important for host resistance to infection.

Background: The host response to influenza A infections is strongly influenced by host genetic factors. Animal models of genetically diverse mouse strains are well suited to identify host genes involved in severe pathology, viral replication and immune responses. Here, we have utilized a dual RNAseq approach that allowed us to investigate both viral and host gene expression in the same individual mouse after H1N1 infection.

The impact of distance and duration of travel on participation rates and participants' satisfaction: results from a pilot study at one study centre in Pretest 2 of the German National Cohort.

Objectives: In this pilot study within the Pretest 2 phase of the German National Cohort, we aimed to (1) test the hypothesis that distance and duration of travel to a study centre may affect participation rates and participants' satisfaction and (2) to obtain data that would help to select recruitment areas around the study centre Hannover with the greatest projected participation rate for the main study.

Setting: Mixed urban/suburban environment in Northern Germany with approximately 600,000 inhabitants. 4 recruitment areas with divergent estimated mean distances (range, 7-40 km) and duration of travel to the study centre Hannover were selected.

Improved coverage and timing of childhood vaccinations in two post-Soviet countries, Armenia and Kyrgyzstan.

Background: Timing of childhood vaccinations has received close attention in many countries. Little is known about the trends in correctly timed vaccination in former Soviet countries. We examined trends in vaccination coverage and correct timing of vaccination in two post-Soviet countries, Armenia and Kyrgyzstan, and analyzed factors associated with delayed vaccinations.

A frequent hypofunctional IRAK2 variant is associated with reduced spontaneous hepatitis C virus clearance.

Unlabelled: Patients carrying very rare loss-of-function mutations in interleukin-1 receptor-associated kinase 4 (IRAK4), a critical signaling mediator in Toll-like receptor signaling, are severely immunodeficient, highlighting the paramount role of IRAK kinases in innate immunity. We discovered a comparatively frequent coding variant of the enigmatic human IRAK2, L392V (rs3844283), which is found homozygously in ∼15% of Caucasians, to be associated with a reduced ability to induce interferon-alpha in primary human plasmacytoid dendritic cells in response to hepatitis C virus (HCV). Cytokine production in response to purified Toll-like receptor agonists was also impaired.

Selective Expression of the MAPK Phosphatase Dusp9/MKP-4 in Mouse Plasmacytoid Dendritic Cells and Regulation of IFN-β Production.

Plasmacytoid dendritic cells (pDCs) efficiently produce large amounts of type I IFN in response to TLR7 and TLR9 ligands, whereas conventional DCs (cDCs) predominantly secrete high levels of the cytokines IL-10 and IL-12. The molecular basis underlying this distinct phenotype is not well understood. In this study, we identified the MAPK phosphatase Dusp9/MKP-4 by transcriptome analysis as selectively expressed in pDCs, but not cDCs.

Hematological parameters in the early phase of influenza A virus infection in differentially susceptible inbred mouse strains.

Background: Hematological parameters have not received much attention in small animal models of infection, particularly at very early time points. We therefore studied changes in leukocyte and thrombocyte numbers in a mouse model of influenza A virus (IAV) infection, including measurements within the first 24 h after infection, and also assessing effects, if any, of the infection/anesthesia procedure on these parameters.

Methods: DBA/2J and C57BL/6J mice (n = 5-8 per observation) were evaluated in a time course experiment of IAV infection, focusing on early time points.

Interferon-inducible cholesterol-25-hydroxylase restricts hepatitis C virus replication through blockage of membranous web formation.

Unlabelled: Hepatitis C virus (HCV) is a positive-strand RNA virus that primarily infects human hepatocytes. Infections with HCV constitute a global health problem, with 180 million people currently chronically infected. Recent studies have reported that cholesterol 25-hydroxylase (CH25H) is expressed as an interferon-stimulated gene and mediates antiviral activities against different enveloped viruses through the production of 25-hydroxycholesterol (25HC).

Control of hepatitis C virus replication in mouse liver-derived cells by MAVS-dependent production of type I and type III interferons.

Unlabelled: Hepatitis C virus (HCV) efficiently infects only humans and chimpanzees. Although the detailed mechanisms responsible for this narrow species tropism remain elusive, recent evidence has shown that murine innate immune responses efficiently suppress HCV replication. Therefore, poor adaptation of HCV to evade and/or counteract innate immune responses may prevent HCV replication in mice.

Mechanisms of methods for hepatitis C virus inactivation.

Virus inactivation by chemical disinfectants is an important instrument for infection control in medical settings, but the mechanisms involved are poorly understood. In this study, we systematically investigated the effects of several antiviral treatments on hepatitis C virus (HCV) particles as model for enveloped viruses. Studies were performed with authentic cell culture-derived viruses, and the influence of chemical disinfectants, heat, and UV treatment on HCV was analyzed by the determination of infectious particles in a limiting-dilution assay, by quantitative reverse transcription-PCR, by core enzyme-linked immunosorbent assay, and by proteolytic protection assay.

Evaluation of invalid vaccine doses in 31 countries of the WHO African Region.

We examined (a) the fraction of and extent to which vaccinations were administered earlier than recommended (age-invalid) or with too short intervals between vaccine doses (interval-invalid) in countries of the World Health Organisation (WHO) African Region and (b) individual- and community-level factors associated with invalid vaccinations using multilevel techniques. Data from the Demographic and Health Surveys conducted in the last 10 years in 31 countries were used. Information about childhood vaccinations was based on vaccination records (n=134,442).

Biosimilars: the science of extrapolation.

Despite the establishment of a specific approval pathway, the issuance of detailed scientific guidelines for the development of similar biological medicinal products (so-called "biosimilars") and the approval of several biosimilars in the European Union, acceptance of biosimilars in the medical community continues to be low. This is especially true in therapeutic indications for which no specific clinical trials with the biosimilar have been performed and that have been licensed based on extrapolation of efficacy and safety data from other indications. This article addresses the concerns frequently raised in the medical community about the use of biosimilars in such extrapolated indications and explains the underlying scientific and regulatory decision making including some real-life examples from recently licensed biosimilars.

A roadmap toward clinical translation of genetically-modified stem cells for treatment of HIV.

During the past decade, successful gene therapies for immunodeficiencies were finally brought to the clinic. This was accomplished through new gene therapy vectors and improved procedures for genetic modification of autologous hematopoietic stem cells. For HIV, autologous hematopoietic stem cell (HSC) gene therapy with 'anti-HIV genes' promises a functional cure for the disease.

Methicillin-sensitive and methicillin-resistant Staphylococcus aureus nasal carriage in a random sample of non-hospitalized adult population in northern Germany.

Objective: The findings from truly randomized community-based studies on Staphylococcus aureus nasal colonization are scarce. Therefore we have examined point prevalence and risk factors of S. aureus nasal carriage in a non-hospitalized population of Braunschweig, northern Germany.

Assessing the suppressive activity of Foxp3⁺ regulatory T cells.

Foxp3(+) regulatory T cells (Tregs) balance the mammalian immune system by mechanisms that are yet to be elucidated in their entirety. Methods employed to quantify the regulatory activity of Tregs in vitro are an important tool in cellular immunology, but can be technically demanding and subjected to variation. In this manuscript, we describe in detail a robust Treg suppression assay based on the flow cytometric quantification of both CD4(+) and CD8(+) effector T cell functions.