Overview of latest articles and publications on ebola in PubMed. PubMed is a service of the US National Library of Medicine that includes over 18 million citations from MEDLINE and other life science journals.
- Reaction mechanism of the dengue virus serine protease: a QM/MM study.
Lima MC, Seabra GM Reaction mechanism of the dengue virus serine protease: a QM/MM study. [JOURNAL ARTICLE]Phys Chem Chem Phys 2016 Jun 24.The dengue virus (DENV) is the causative agent of the viral infection dengue fever. In spite of all the efforts made to prevent the spread of the disease, once it is contracted, there is no specific treatment for dengue and the WHO guidelines are limited to rest and symptomatic treatment. In its reproductive cycle, DENV utilizes the NS2B-NS3pro, a serine protease, to cleave the viral polyprotein into its constituents. This enzyme is essential for the virus lifecycle, and presents an attractive target for the development of specific dengue treatments. Here we used a hybrid Quantum Mechanics and Molecular Mechanics (QM/MM) Molecular Dynamics approach and Umbrella Sampling to study the first step (acylation) of the reaction catalyzed by NS2B-NS3pro, using the Pairwise Distance Directed Gaussian PM3 (PDDG/PM3) semi-empirical Hamiltonian for the QM subsystem, and Amber ff99SB for the MM subsystem. Our results indicate that the nucleophilic attack on the substrate by Ser135 occurs in a stepwise manner, in which a proton transfer to His51 first activates Ser135, which only later attacks the substrate. The rate-determining step is the Ser135 activation, with a barrier of 24.1 kcal mol(-1). Water molecules completing the oxyanion hole stabilize the negative charge formed on the carbonyl oxygen of the substrate. The final step in the process is a proton transfer from His51 to the substrate's nitrogen, which happens with a lower barrier of 5.1 kcal mol(-1), and leads directly to the breakage of the peptide bond.
- Relative Contribution of Dengue IgG Antibodies Acquired during Gestation or Breastfeeding in Mediating Dengue Disease Enhancement and Protection in Type I Interferon Receptor-Deficient Mice.
Lee PX, Ong LC, Libau EA, et al. Relative Contribution of Dengue IgG Antibodies Acquired during Gestation or Breastfeeding in Mediating Dengue Disease Enhancement and Protection in Type I Interferon Receptor-Deficient Mice. [JOURNAL ARTICLE]PLoS Negl Trop Dis 2016 Jun; 10(6):e0004805.Dengue virus (DENV) causes a spectrum of diseases ranging from self-limiting dengue fever to severe conditions such as haemorrhagic fever and dengue shock syndrome. Antibody-dependent enhancement (ADE) is thought to explain the occurrence of severe dengue whereby pre-existing binding but non-neutralising antibodies enhance DENV infection. The ADE phenomenon is supported by epidemiological findings that infants that born to dengue immune mothers are at greater risk to develop severe dengue upon primary infection. The role of maternally acquired dengue-specific antibodies in disease enhancement was recently recapitulated in a mouse model where mice born to DENV1-immune mothers experienced enhanced disease severity upon DENV2 infection. Here, this study investigates the relative contribution of maternal dengue-specific antibodies acquired during gestation and breastfeeding in dengue disease. Using a surrogate breastfeeding mother experimental approach, we showed that majority of the maternal dengue-specific antibodies were acquired during breastfeeding and conferred an extended enhancement window. On the other hand, in the context of homologous infection, breastfeeding conferred protection. Furthermore, measurement of dengue-specific antibody titres over time in mice born to dengue immune mothers revealed a biphasic pattern of antibody decay as reported in humans. Our work provides evidence of the potential contribution of breast milk-acquired dengue-specific IgG antibodies in enhancement and protection against dengue. Should such contribution be established in humans as well, it may have important implications for the development of guidelines to dengue-immune breastfeeding mothers.
- Dengue virus sero-cross-reactivity drives antibody-dependent enhancement of infection with zika virus.
Dejnirattisai W, Supasa P, Wongwiwat W, et al. Dengue virus sero-cross-reactivity drives antibody-dependent enhancement of infection with zika virus. [JOURNAL ARTICLE]Nat Immunol 2016 Jun 23.Zika virus (ZIKV) was discovered in 1947 and was thought to lead to relatively mild disease. The recent explosive outbreak of ZIKV in South America has led to widespread concern, with reports of neurological sequelae ranging from Guillain Barré syndrome to microcephaly. ZIKV infection has occurred in areas previously exposed to dengue virus (DENV), a flavivirus closely related to ZIKV. Here we investigated the serological cross-reaction between the two viruses. Plasma immune to DENV showed substantial cross-reaction to ZIKV and was able to drive antibody-dependent enhancement (ADE) of ZIKV infection. Using a panel of human monoclonal antibodies (mAbs) to DENV, we showed that most antibodies that reacted to DENV envelope protein also reacted to ZIKV. Antibodies to linear epitopes, including the immunodominant fusion-loop epitope, were able to bind ZIKV but were unable to neutralize the virus and instead promoted ADE. Our data indicate that immunity to DENV might drive greater ZIKV replication and have clear implications for disease pathogenesis and future vaccine programs for ZIKV and DENV.
- Structural basis of potent Zika-dengue virus antibody cross-neutralization.
Barba-Spaeth G, Dejnirattisai W, Rouvinski A, et al. Structural basis of potent Zika-dengue virus antibody cross-neutralization. [JOURNAL ARTICLE]Nature 2016 Jun 23.Zika virus is a member of the flavivirus genus that had not been associated with severe disease in humans until the recent outbreaks, when it was linked to microcephaly in newborns in Brazil and to Guillain-Barré syndrome in adults in French Polynesia. Zika virus is related to dengue virus, and we report here that a category of antibodies isolated from dengue patients and targeting a conformational epitope potently neutralize Zika virus. The crystal structure of two of these antibodies in complex with the envelope protein of Zika virus reveals the details of a conserved epitope, which is also the site of interaction of the envelope protein dimer with the precursor prM protein during virus maturation. Comparison of the Zika and dengue virus immunocomplexes provides a lead for rational, epitope-focused design of a universal vaccine capable of eliciting potent cross-neutralizing antibodies to protect against Zika and dengue viruses simultaneously.
- MAIT cells are activated during human viral infections.
van Wilgenburg B, Scherwitzl I, Hutchinson EC, et al. MAIT cells are activated during human viral infections. [Journal Article]Nat Commun 2016.:11653.AbstractPublisher Full TextMucosal-associated invariant T (MAIT) cells are abundant in humans and recognize bacterial ligands. Here, we demonstrate that MAIT cells are also activated during human viral infections in vivo. MAIT cells activation was observed during infection with dengue virus, hepatitis C virus and influenza virus. This activation-driving cytokine release and Granzyme B upregulation-is TCR-independent but dependent on IL-18 in synergy with IL-12, IL-15 and/or interferon-α/β. IL-18 levels and MAIT cell activation correlate with disease severity in acute dengue infection. Furthermore, HCV treatment with interferon-α leads to specific MAIT cell activation in vivo in parallel with an enhanced therapeutic response. Moreover, TCR-independent activation of MAIT cells leads to a reduction of HCV replication in vitro mediated by IFN-γ. Together these data demonstrate MAIT cells are activated following viral infections, and suggest a potential role in both host defence and immunopathology.
- Screening of Blood Donations for Zika Virus Infection - Puerto Rico, April 3-June 11, 2016.
Kuehnert MJ, Basavaraju SV, Moseley RR, et al. Screening of Blood Donations for Zika Virus Infection - Puerto Rico, April 3-June 11, 2016. [Journal Article]MMWR Morb Mortal Wkly Rep 2016; 65(24):627-8.AbstractPublisher Full TextTransfusion-transmitted infections have been documented for several arboviruses, including West Nile and dengue viruses (1). Zika virus, a flavivirus transmitted primarily by Aedes aegypti mosquitoes that has been identified as a cause of congenital microcephaly and other serious brain defects (2), became recognized as a potential threat to blood safety after reports from a 2013-2014 outbreak in French Polynesia. Blood safety concerns were based on very high infection incidence in the population at large during epidemics, the high percentage of persons with asymptomatic infection, the high proportion of blood donations with evidence of Zika virus nucleic acid upon retrospective testing, and an estimated 7-10-day period of viremia (3). At least one instance of transfusion transmission of Zika virus has been documented in Brazil after the virus emerged there, likely in 2014 (4). Rapid epidemic spread has followed to other areas of the Americas, including Puerto Rico.
- In Vitro Infection with Dengue Virus Induces Changes in the Structure and Function of the Mouse Brain Endothelium.
Velandia-Romero ML, Calderón-Peláez MA, Castellanos JE In Vitro Infection with Dengue Virus Induces Changes in the Structure and Function of the Mouse Brain Endothelium. [Journal Article]PLoS One 2016; 11(6):e0157786.AbstractPublisher Full TextThe neurological manifestations of dengue disease are occurring with greater frequency, and currently, no information is available regarding the reasons for this phenomenon. Some viruses infect and/or alter the function of endothelial organs, which results in changes in cellular function, including permeability of the blood-brain barrier (BBB), which allows the entry of infected cells or free viral particles into the nervous system.In the present study, we standardized two in vitro models, a polarized monolayer of mouse brain endothelial cells (MBECs) and an organized co-culture containing MBECs and astrocytes. Using these cell models, we assessed whether DENV-4 or the neuro-adapted dengue virus (D4MB-6) variant infects cells or induces changes in the structure or function of the endothelial barrier.The results showed that MBECs, but not astrocytes, were susceptible to infection with both viruses, although the percentage of infected cells was higher when the neuro-adapted virus variant was used. In both culture systems, DENV infection changed the localization of the tight junction proteins Zonula occludens (ZO-1) and Claudin-1 (Cln1), and this process was associated with a decrease in transendothelial resistance, an increase in macromolecule permeability and an increase in the paracellular passing of free virus particles. MBEC infection led to transcriptional up-regulation of adhesion molecules (VCAM-1 and PECAM) and immune mediators (MCP-1 and TNF- α) that are associated with immune cell transmigration, mainly in D4MB-6-infected cells.These results indicate that DENV infection in MBECs altered the structure and function of the BBB and activated the endothelium, affecting its transcellular and paracellular permeability and favoring the passage of viruses and the transmigration of immune cells. This phenomenon can be harnessed for neurotropic and neurovirulent strains to infect and induce alterations in the CNS.
- Dengue in Malaysia: Factors Associated with Dengue Mortality from a National Registry.
Liew SM, Khoo EM, Ho BK, et al. Dengue in Malaysia: Factors Associated with Dengue Mortality from a National Registry. [Journal Article]PLoS One 2016; 11(6):e0157631.AbstractPublisher Full TextThe increasing incidence and geographical distribution of dengue has had significant impact on global healthcare services and resources. This study aimed to determine the factors associated with dengue-related mortality in a cohort of Malaysian patients.This was a retrospective cohort study of patients in the Malaysian National Dengue Registry of 2013. The outcome measure was dengue-related mortality. Associations between sociodemographic and clinical variables with the outcome were analysed using multivariate analysis.There were 43 347 cases of which 13081 were serologically confirmed. The mean age was 30.0 years (SD 15.7); 60.2% were male. The incidence of dengue increased towards the later part of the calendar year. There were 92 probable dengue mortalities, of which 41 were serologically confirmed. Multivariate analysis in those with positive serology showed that increasing age (OR 1.03; CI:1.01-1.05), persistent vomiting (OR 13.34; CI: 1.92-92.95), bleeding (OR 5.84; CI 2.17-15.70) and severe plasma leakage (OR 66.68; CI: 9.13-487.23) were associated with mortality. Factors associated with probable dengue mortality were increasing age (OR 1.04; CI:1.03-1.06), female gender (OR 1.53; CI:1.01-2.33), nausea and/or vomiting (OR 1.80; CI:1.17-2.77), bleeding (OR 3.01; CI:1.29-7.04), lethargy and/or restlessness (OR 5.97; CI:2.26-15.78), severe plasma leakage (OR 14.72; CI:1.54-140.70), and shock (OR 1805.37; CI:125.44-25982.98), in the overall study population.Older persons and those with persistent vomiting, bleeding or severe plasma leakage, which were associated with mortality, at notification should be monitored closely and referred early if indicated. Doctors and primary care practitioners need to detect patients with dengue early before they develop these severe signs and symptoms.
- Gene Polymorphisms and Serum Levels of Pro- and Anti-Inflammatory Markers in Dengue Viral Infections.
Feitosa RN, Vallinoto AC, Vasconcelos PF, et al. Gene Polymorphisms and Serum Levels of Pro- and Anti-Inflammatory Markers in Dengue Viral Infections. [JOURNAL ARTICLE]Viral Immunol 2016 Jun 23.AbstractPublisher Full TextPublisher Full TextPro- and anti-inflammatory markers (tumor necrosis factor [TNF]-α, TNF-β, interferon [IFN]-γ, interleukin [IL]-6, IL-8, IL-10, and C-reactive protein [CRP]) were investigated in 80 patients infected with dengue viruses, 100 patients presenting with febrile illness but negative for dengue, and 99 healthy subjects. Immunoenzyme methods were used for quantitative assays in the plasma. Polymorphisms of TNF-α, TNF-β, IL-6, IL-8, and IL-10 genes were assessed by polymerase chain reaction (PCR)-restriction fragment length polymorphism and allele-specific oligonucleotide (ASO)-PCR for the IFN-γ. The highest mean serum levels of TNF-α, IFN-γ, IL-8, and CRP were observed in dengue-positive individuals. TNF-β, IL-6, and IL-10 levels were significantly higher in the dengue-negative individuals. No cytokine expression pattern was evidenced according to virus serotype. Genotypic frequency distributions were statistically significant for the polymorphisms of TNF-α and IFN-γ among positive, negative, and control dengue groups and IFN-γ among groups DENV-1, DENV-2, DENV-3, and controls. Modulation of cytokine expression and polymorphisms is a complex matter and needs further explanation considering the ethnic origins of the Brazilian population.
- Surface water areas significantly impacted 2014 dengue outbreaks in Guangzhou, China.
Tian H, Huang S, Zhou S, et al. Surface water areas significantly impacted 2014 dengue outbreaks in Guangzhou, China. [JOURNAL ARTICLE]Environ Res 2016 Jun 20.:299-305.AbstractPublisher Full TextDengue transmission in urban areas is strongly influenced by a range of biological and environmental factors, yet the key drivers still need further exploration. To better understand mechanisms of environment-mosquito-urban dengue transmission, we propose an empirical model parameterized and cross-validated from a unique dataset including viral gene sequences, vector dynamics and human dengue cases in Guangzhou, China, together with a 36-year urban environmental change maps investigated by spatiotemporal satellite image fusion. The dengue epidemics in Guangzhou are highly episodic and were not associated with annual rainfall over time. Our results indicate that urban environmental changes, especially variations in surface area covered by water in urban areas, can substantially alter the virus population and dengue transmission. The recent severe dengue outbreaks in Guangzhou may be due to the surge in an artificial lake construction, which could increase infection force between vector (mainly Aedes albopictus) and host when urban water area significantly increased. Impacts of urban environmental change on dengue dynamics may not have been thoroughly investigated in the past studies and more work needs to be done to better understand the consequences of urbanization processes in our changing world.