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- Generation of Monoclonal Antibodies against Dengue Virus Type 4 and Identification of Enhancing Epitopes on Envelope Protein.
Tang CT, Liao MY, Chiu CY, et al. Generation of Monoclonal Antibodies against Dengue Virus Type 4 and Identification of Enhancing Epitopes on Envelope Protein. [JOURNAL ARTICLE]PLoS One 2015; 10(8):e0136328.AbstractPublisher Full TextThe four serotypes of dengue virus (DENV1-4) pose a serious threat to global health. Cross-reactive and non-neutralizing antibodies enhance viral infection, thereby exacerbating the disease via antibody-dependent enhancement (ADE). Studying the epitopes targeted by these enhancing antibodies would improve the immune responses against DENV infection. In order to investigate the roles of antibodies in the pathogenesis of dengue, we generated a panel of 16 new monoclonal antibodies (mAbs) against DENV4. Using plaque reduction neutralization test (PRNT), we examined the neutralizing activity of these mAbs. Furthermore, we used the in vitro and in vivo ADE assay to evaluate the enhancement of DENV infection by mAbs. The results indicate that the cross-reactive and poorly neutralizing mAbs, DD11-4 and DD18-5, strongly enhance DENV1-4 infection of K562 cells and increase mortality in AG129 mice. The epitope residues of these enhancing mAbs were identified using virus-like particle (VLP) mutants. W212 and E26 are the epitope residues of DD11-4 and DD18-5, respectively. In conclusion, we generated and characterized 16 new mAbs against DENV4. DD11-4 and D18-5 possessed non-neutralizing activities and enhanced viral infection. Moreover, we identified the epitope residues of enhancing mAbs on envelope protein. These results may provide useful information for development of safe dengue vaccine.
- Incomplete penetrance of CD46 mutation causing familial atypical hemolytic uremic syndrome.
Bhatia D, Khandelwal P, Sinha A, et al. Incomplete penetrance of CD46 mutation causing familial atypical hemolytic uremic syndrome. [JOURNAL ARTICLE]Pediatr Nephrol 2015 Aug 26.AbstractPublisher Full TextHemolytic uremic syndrome (HUS) secondary to homozygous mutations in CD46 is uncommon. While heterozygous individuals may remain asymptomatic, homozygous mutations with severely depleted CD46 surface expression without disease manifestation is rare.We report on two siblings with features suggestive of hemolytic uremic syndrome. Estimation of CD46 expression by flow cytometry and gene sequencing were performed in members of this family.Three siblings, two of whom were symptomatic, had markedly decreased (<10 %) cell surface expression of CD46 and homozygous splice site mutation (IVS2 + 2 T > G) in the CD46 gene; the other 10-year-old sibling was asymptomatic. The illness was preceded by dengue shock syndrome in the index case. Both parents and two other siblings were heterozygous for this CD46 mutation.Homozygous IVS2 + 2 T > G mutation in CD46 gene, similar to heterozygous mutation, may be clinically silent at least during childhood. The role of antecedent infections in triggering the disease requires further examination.
- Susceptibility profile of Aedes aegypti from Santiago Island, Cabo Verde, to insecticides.
Rocha HD, Paiva MH, Silva NM, et al. Susceptibility profile of Aedes aegypti from Santiago Island, Cabo Verde, to insecticides. [JOURNAL ARTICLE]Acta Trop 2015 Aug 22.AbstractPublisher Full TextIn 2009, Cabo Verde diagnosed the first dengue cases, with 21,137 cases reported and Aedes aegypti was identified as the vector. Since the outbreak, chemical insecticides and source reduction were used to control the mosquito population. This study aimed to assess the susceptibility of Ae. aegypti populations from Santiago, Cabo Verde to insecticides and identify the mechanisms of resistance. Samples of Ae. aegypti eggs were obtained at two different time periods (2012 and 2014), using ovitraps in different locations in Santiago Island to establish the parental population. F1 larvae were exposed to different concentrations of insecticides (Bacillus thuringiensis var israelensis (Bti), diflubenzuron and temephos) to estimate the lethal concentrations (LC90) and calculate the respective rate of resistance (RR90). Semi-field tests using temephos-ABATE® were performed to evaluate the persistence of the product. Bottle tests using female mosquitos were carried out to determine the susceptibility to the adulticides malathion, cypermethrin and deltamethrin. Biochemical and molecular tests were performed to investigate the presence of metabolic resistance mechanisms, associated with the enzymes glutathione S-transferases (GSTs), esterases and mixed-function oxidases (MFO) and to detect mutations or alterations in the sodium channel and acetylcholinesterase genes. Ae. aegypti mosquitoes from Santiago exhibited resistance to deltamethrin, cypermethrin (mortality <80%) and temephos (RR90 = 4.4) but susceptibility to malathion (mortality ≥98%), Bti and diflubenzuron. The low level of resistance to temephos did not affect the effectiveness of Abate®. The enzymatic analysis conducted in 2012 revealed slight changes in the activities of GST (25%), MFO (18%), α-esterase (19%) and β-esterase (17%), but no significant changes in 2014. Target site resistance mutations were not detected. Our results suggest that the Ae. aegypti population from Santiago is resistant to two major insecticides used for vector control, deltamethrin and temephos. To our knowledge, this is the first report of temephos resistance in an African Ae. aegypti population. The low level of temephos resistance was maintained from 2012 to 2014, which suggested the imposition of selective pressure, although it was not possible to identify the resistance mechanisms involved. These data show that the potential failures in the local mosquito control program are not associated with insecticide resistance.
- Dengue infection with multiorgan dysfunction: SOFA score, arterial lactate and serum albumin levels are predictors of outcome.
Jog S, Prayag S, Rajhans P, et al. Dengue infection with multiorgan dysfunction: SOFA score, arterial lactate and serum albumin levels are predictors of outcome. [JOURNAL ARTICLE]Intensive Care Med 2015 Aug 26.Publisher Full Text
- Epidemiological update on the dengue situation in the Western Pacific Region, 2012.
Arima Y, Chiew M, Matsui T, et al. Epidemiological update on the dengue situation in the Western Pacific Region, 2012. [Journal Article]Western Pac Surveill Response J 2015 Apr-Jun; 6(2):82-9.AbstractPMC Free Full TextDengue has caused a substantial public health burden in the Western Pacific Region. To assess this burden and regional trends, data were collated and summarized from indicator-based surveillance systems on dengue cases and deaths from countries and areas in the Western Pacific Region. In 2012, dengue notifications continued to increase with 356 838 dengue cases reported in the Region (relative to 244 855 cases reported in 2011) of which 1248 died. In the Asia subregion, the notification rate was highest in Cambodia, the Philippines and the Lao People's Democratic Republic (316.2, 198.9 and 162.4 per 100 000 population, respectively), and in the Pacific island countries and areas, the notification rate was highest in Niue, the Marshall Islands and the Federated States of Micronesia (8556.0, 337.0 and 265.1 per 100 000 population, respectively). All four serotypes were circulating in the Region in 2012 with considerable variabilitiy in distribution. Regional surveillance provides important information to enhance situational awareness, conduct risk assessments and improve preparedness activities.
- First round of external quality assessment of dengue diagnostics in the WHO Western Pacific Region, 2013.
Pok KY, Squires RC, Tan LK, et al. First round of external quality assessment of dengue diagnostics in the WHO Western Pacific Region, 2013. [Journal Article]Western Pac Surveill Response J 2015 Apr-Jun; 6(2):73-81.AbstractPMC Free Full TextAccurate laboratory testing is a critical component of dengue surveillance and control. The objective of this programme was to assess dengue diagnostic proficiency among national-level public health laboratories in the World Health Organization (WHO) Western Pacific Region.Nineteen national-level public health laboratories performed routine dengue diagnostic assays on a proficiency testing panel consisting of two modules: one containing commercial serum samples spiked with cultured dengue viruses for the detection of nucleic acid and non-structural protein 1 (NS1) (Module A) and one containing human serum samples for the detection of anti-dengue virus antibodies (Module B). A review of logistics arrangements was also conducted.All 16 laboratories testing Module A performed reverse transcriptase polymerase chain reaction (RT-PCR) for both RNA and serotype detection. Of these, 15 had correct results for RNA detection and all 16 correctly serotyped the viruses. All nine laboratories performing NS1 antigen detection obtained the correct results. Sixteen of the 18 laboratories using IgM assays in Module B obtained the correct results as did the 13 laboratories that performed IgG assays. Detection of ongoing/recent dengue virus infection by both molecular (RT-PCR) and serological methods (IgM) was available in 15/19 participating laboratories.This first round of external quality assessment of dengue diagnostics was successfully conducted in national-level public health laboratories in the WHO Western Pacific Region, revealing good proficiency in both molecular and serological testing. Further comprehensive diagnostic testing for dengue virus and other priority pathogens in the Region will be assessed during future rounds.
- Isolation of dengue serotype 3 virus from the cerebrospinal fluid of an encephalitis patient in Hai Phong, Vietnam in 2013.
Phu Ly MH, Takamatsu Y, Nabeshima T, et al. Isolation of dengue serotype 3 virus from the cerebrospinal fluid of an encephalitis patient in Hai Phong, Vietnam in 2013. [Journal Article]J Clin Virol 2015 Sep.:93-6.AbstractPublisher Full TextDengue encephalitis (DE) is characterized as unusual presentation of dengue infection. Despite the reports that DE accounts for only 1-5% of dengue cases, this disease tends to be increasingly reported to threaten global human health throughout dengue endemic areas particularly in Southeast Asia. The molecular information of clinically characterized, neurotropic dengue virus (DENV) in human beings is extremely scarce despite it playing an important role in deciphering the pathogenesis of dengue-related neurological cases. Here we report a case of DE caused by DENV3 genotype III in a male patient with atypical symptoms of DENV infection in Hai Phong, Vietnam in 2013. The virus isolated from the cerebrospinal fluid of this case-patient was closely related to DENV3 genotype III strains isolated from serum of two other patients, who manifested classical dengue in the same year and residing in the same area as the case-patient. It is noteworthy to mention that in 2013, DENV3 genotype III was detected for the first time in Vietnam.
- Patterns of Flavivirus Seroprevalence in the Human Population of Northern Laos.
Conlan JV, Vongxay K, Khamlome B, et al. Patterns of Flavivirus Seroprevalence in the Human Population of Northern Laos. [JOURNAL ARTICLE]Am J Trop Med Hyg 2015 Aug 24.AbstractPublisher Full TextA total of 1,136 samples from 289 households in four provinces in northern Laos were subjected to Japanese encephalitis virus (JEV) and dengue virus hemagglutination inhibition (DENV HI). Overall, antibodies to JEV were detected by HI in 620 (54.6%) of 1,136 people; of which 217 (19.1%) had HI activity against JEV only. Antibodies to DENV4 were detected by HI in 526 (46.3%) of 1,136 people; of which 124 (10.9%) had HI activity against DENV4 only. Antibodies to DENV1-3 were detected by HI in 296 (26.1%), 274 (24.1%), and 283 (24.9) of 1,136 people, respectively; of which 7, 1, and 0, respectively, had HI activity against DENV1-3 only. JEV was the most prevalent Flavivirus in Oudomxay, Luangprabang, and Huaphan provinces and DENV4 was the most prevalent in Xiengkhouang province. Seroprevalence for JEV increased with increasing age and wealth and was higher in villages where rice was cultivated in paddy fields and highest for people of Lao-Tai ethnicity.
- Cavity Forming Pneumonia Due to Staphylococcus aureus Following Dengue Fever.
Miyata N, Yoshimura Y, Tachikawa N, et al. Cavity Forming Pneumonia Due to Staphylococcus aureus Following Dengue Fever. [JOURNAL ARTICLE]Am J Trop Med Hyg 2015 Aug 24.AbstractPublisher Full TextWhile visiting Malaysia, a 22-year-old previously healthy Japanese man developed myalgia, headache, and fever, leading to a diagnosis of classical dengue fever. After improvement and returning to Japan after a five day hospitalization, he developed productive cough several days after defervescing from dengue. Computed tomography (CT) thorax scan showed multiple lung cavities. A sputum smear revealed leukocytes with phagocytized gram-positive cocci in clusters, and grew an isolate Staphylococcus aureus sensitive to semi-synthetic penicillin; he was treated successfully with ceftriaxone and cephalexin. This second reported case of pneumonia due to S. aureus occurring after dengue fever, was associated both with nosocomial exposure and might have been associated with dengue-associated immunosuppression. Clinicians should pay systematic attention to bacterial pneumonia following dengue fever to establish whether such a connection is causally associated.
- Animal models for studying dengue pathogenesis and therapy.
Chan KW, Watanabe S, Kavishna R, et al. Animal models for studying dengue pathogenesis and therapy. [REVIEW, JOURNAL ARTICLE]Antiviral Res 2015 Aug 21.AbstractPublisher Full TextDevelopment of a suitable animal model for dengue virus disease is critical for understanding pathogenesis and for preclinical testing of antiviral drugs and vaccines. Many laboratory animal models of dengue virus infection have been investigated, but the challenges of recapitulating the complete disease still remain. In this review, we provide a comprehensive coverage of existing models, from man to mouse, with a specific focus on recent advances in mouse models for addressing the mechanistic aspects of severe dengue in humans. This article forms part of a symposium in Antiviral Research on flavivirus drug discovery.