Fatal Dengue in Patients with Sickle Cell Disease or Sickle Cell Anemia in Curaçao: Two Case Reports

<p>Fatal Dengue in Patients with Sickle Cell Disease or Sickle Cell Anemia in Curaçao: Two Case Reports</p

Antibodies against the Envelope Glycoprotein Promote Infectivity of Immature Dengue Virus Serotype 2

Cross-reactive dengue virus (DENV) antibodies directed against the envelope (E) and precursor membrane (prM) proteins are believed to contribute to the development of severe dengue disease by facilitating antibody-dependent enhancement of infection. We and others recently demonstrated that anti-prM antibodies render essentially non-infectious immature DENV infectious in Fcγ-receptor-expressing cells. Immature DENV particles are abundantly present in standard (st) virus preparations due to inefficient processing of prM to M during virus maturation. Structural analysis has revealed that the E protein is exposed in immature particles and this prompted us to investigate whether antibodies to E render immature particles infectious. To this end, we analyzed the enhancing properties of 27 anti-E antibodies directed against distinct structural domains. Of these, 23 bound to immature particles, and 15 enhanced infectivity of immature DENV in a furin-dependent manner. The significance of these findings was subsequently tested in vivo using the well-established West Nile virus (WNV) mouse model. Remarkably, mice injected with immature WNV opsonized with anti-E mAbs or immune serum produced a lethal infection in a dose-dependent manner, whereas in the absence of antibody immature WNV virions caused no morbidity or mortality. Furthermore, enhancement infection studies with standard (st) DENV preparations opsonized with anti-E mAbs in the presence or absence of furin inhibitor revealed that prM-containing particles present within st virus preparations contribute to antibody-dependent enhancement of infection. Taken together, our results support the notion that antibodies against the structural proteins prM and E both can promote pathogenesis by enhancing infectivity of prM-containing immature and partially mature flavivirus particles

A Therapeutic Antibody against West Nile Virus Neutralizes Infection by Blocking Fusion within Endosomes

Defining the precise cellular mechanisms of neutralization by potently inhibitory antibodies is important for understanding how the immune system successfully limits viral infections. We recently described a potently inhibitory monoclonal antibody (MAb E16) against the envelope (E) protein of West Nile virus (WNV) that neutralizes infection even after virus has spread to the central nervous system. Herein, we define its mechanism of inhibition. E16 blocks infection primarily at a post-attachment step as antibody-opsonized WNV enters permissive cells but cannot escape from endocytic compartments. These cellular experiments suggest that E16 blocks the acid-catalyzed fusion step that is required for nucleocapsid entry into the cytoplasm. Indeed, E16 directly inhibits fusion of WNV with liposomes. Additionally, low-pH exposure of E16–WNV complexes in the absence of target membranes did not fully inactivate infectious virus, further suggesting that E16 prevents a structural transition required for fusion. Thus, a strongly neutralizing anti–WNV MAb with therapeutic potential is potently inhibitory because it blocks viral fusion and thereby promotes clearance by delivering virus to the lysosome for destruction

The interaction of genetic determinants in the outcome of HCV infection: evidence for discrete immunological pathways

Diversity within the innate and adaptive immune response to hepatitis C is important in determining spontaneous resolution (SR) and treatment response. The aim of this study was to analyze how these variables interact in combination; furthering our understanding of the mechanisms that drive successful immunological clearance. Multivariate analysis was performed on retrospectively collected data for 357 patients previously genotyped for interferon (IFN)-?3/4, killer cell immunoglobulin (KIR), human leukocyte antigen (HLA) class I and II and tapasin. High resolution KIR genotyping was performed for individuals with chronic infection and haplotypes determined. Outcomes for SR, IFN response and cirrhosis were examined. Statistical analysis included univariate methods, ?2 test for trend, multivariate logistic regression, synergy and principal component analysis (PCA). Although KIR2DL3:HLA-C1C1 (P = 0.027), IFN-?3/4 rs12979860 CC (P = 0.027), tapasin G in individuals with aspartate at residue 114 of HLA-B (TapG:HLA-B114D) (P = 0.007) and HLA-DRB1*04:01 (P = 0.014) were associated with SR with a strong additive influence (?2 test for trend P &lt; 0.0001); favorable polymorphisms did not interact synergistically, nor did patients cluster by outcome. In the treatment cohort, IFN-?3/4 rs12979860 CC was protective in hepatitis C virus (HCV) G1 infection and KIR2DL3:HLA-C1 in HCV G2/3. In common with SR, variables did not interact synergistically. Polymorphisms predictive of viral clearance did not predict disease progression. In summary, different individuals resolve HCV infection using discrete and non-interacting immunological pathways. These pathways are influenced by viral genotype. This work provides novel insights into the complexity of the interaction between host and viral factors in determining the outcome of HCV infection

Secondary Metabolome and Transcriptome of Streptomyces albus J1074 in Liquid Medium SG2

Koshla OT, Rokytskyy IV, Ostash IS, et al. Secondary Metabolome and Transcriptome of Streptomyces albus J1074 in Liquid Medium SG2. CYTOLOGY AND GENETICS. 2019;53(1):1-7.Streptomyces albus J1074 is one of the most popular chassis for heterologous expression of actino-bacterial biosynthetic gene clusters (BGCs). Considerable efforts are invested into understanding all the physiological and genetic aspects of secondary metabolism of J1074 in order to maximize the expression of heterologous BGCs. It has to be noted that the J1074 genome itself is home to numerous (> 20) BGCs, whose expression varies widely. Therefore, the identification of the factors limiting the expression of J1074 BGCs might help improve this strain for heterologous expression purposes. As first steps towards this goal, herein we describe the secondary metabolome of J1074 in liquid medium SG2, previously shown by us to support the production of antibacterial and antifungal compounds. We compare the results of metabolomic studies with the transcriptome of J1074 in SG2 after 60 h of growth. Results of our studies are discussed in the context of current knowledge on the J1074 transcriptome and metabolome data

Vermijdbare sterfte in Nederlandse ziekenhuizen niet verder gedaald.

De potentieel vermijdbare sterfte bij in Nederlandse ziekenhuizen overleden patiënten was 2,6% in 2011/2012. De nieuwe Monitor Zorggerelateerde Schade wijst uit dat dit percentage niet significant is gewijzigd, maar op een aantal veiligheidsthema’s zijn wel verbeteringen te zien. Een kwart van de patiënten die zijn overleden door potentieel vermijdbare schade, had een geschatte levensverwachting van meer dan vijf jaar en 80% van meer dan een jaar