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Search Results: 1 - 10 of 570342 matches for " Aravinda M. de Silva "
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The Human Antibody Response to Dengue Virus Infection
Wahala M. P. B. Wahala,Aravinda M. de Silva
Viruses , 2011, DOI: 10.3390/v3122374
Abstract: Dengue viruses (DENV) are the causative agents of dengue fever (DF) and dengue hemorrhagic fever (DHF). Here we review the current state of knowledge about the human antibody response to dengue and identify important knowledge gaps. A large body of work has demonstrated that antibodies can neutralize or enhance DENV infection. Investigators have mainly used mouse monoclonal antibodies (MAbs) to study interactions between DENV and antibodies. These studies indicate that antibody neutralization of DENVs is a “multi-hit” phenomenon that requires the binding of multiple antibodies to neutralize a virion. The most potently neutralizing mouse MAbs bind to surface exposed epitopes on domain III of the dengue envelope (E) protein. One challenge facing the dengue field now is to extend these studies with mouse MAbs to better understand the human antibody response. The human antibody response is complex as it involves a polyclonal response to primary and secondary infections with 4 different DENV serotypes. Here we review studies conducted with immune sera and MAbs isolated from people exposed to dengue infections. Most dengue-specific antibodies in human immune sera are weakly neutralizing and bind to multiple DENV serotypes. The human antibodies that potently and type specifically neutralize DENV represent a small fraction of the total DENV-specific antibody response. Moreover, these neutralizing antibodies appear to bind to novel epitopes including complex, quaternary epitopes that are only preserved on the intact virion. These studies establish that human and mouse antibodies recognize distinct epitopes on the dengue virion. The leading theory proposed to explain the increased risk of severe disease in secondary cases is antibody dependent enhancement (ADE), which postulates that weakly neutralizing antibodies from the first infection bind to the second serotype and enhance infection of FcγR bearing myeloid cells such as monocytes and macrophages. Here we review results from human, animal and cell culture studies relevant to the ADE hypothesis. By understanding how human antibodies neutralize or enhance DENV, it will be possible to better evaluate existing vaccines and develop the next generation of novel vaccines.
Estimates of Dengue Force of Infection in Children in Colombo, Sri Lanka
Clarence C. Tam ,Hasitha Tissera,Aravinda M. de Silva,Aruna Dharshan De Silva,Harold S. Margolis,Ananda Amarasinge
PLOS Neglected Tropical Diseases , 2013, DOI: 10.1371/journal.pntd.0002259
Abstract: Dengue is the most important vector-borne viral disease worldwide and a major cause of childhood fever burden in Sri Lanka, which has experienced a number of large epidemics in the past decade. Despite this, data on the burden and transmission of dengue virus in the Indian Subcontinent are lacking. As part of a longitudinal fever surveillance study, we conducted a dengue seroprevalence survey among children aged <12 years in Colombo, Sri Lanka. We used a catalytic model to estimate the risk of primary infection among seronegative children. Over 50% of children had IgG antibodies to dengue virus and seroprevalence increased with age. The risk of primary infection was 14.1% per year (95% CI: 12.7%–15.6%), indicating that among initially seronegative children, approximately 1 in 7 experience their first infection within 12 months. There was weak evidence to suggest that the force of primary infection could be lower for children aged 6 years and above. We estimate that there are approximately 30 primary dengue infections among children <12 years in the community for every case notified to national surveillance, although this ratio is closer to 100:1 among infants. Dengue represents a considerable infection burden among children in urban Sri Lanka, with levels of transmission comparable to those in the more established epidemics of Southeast Asia.
Natural Strain Variation and Antibody Neutralization of Dengue Serotype 3 Viruses
Wahala M. P. B. Wahala,Eric F. Donaldson,Ruklanthi de Alwis,Mary Ann Accavitti-Loper,Ralph S. Baric,Aravinda M. de Silva
PLOS Pathogens , 2010, DOI: 10.1371/journal.ppat.1000821
Abstract: Dengue viruses (DENVs) are emerging, mosquito-borne flaviviruses which cause dengue fever and dengue hemorrhagic fever. The DENV complex consists of 4 serotypes designated DENV1-DENV4. Following natural infection with DENV, individuals develop serotype specific, neutralizing antibody responses. Monoclonal antibodies (MAbs) have been used to map neutralizing epitopes on dengue and other flaviviruses. Most serotype-specific, neutralizing MAbs bind to the lateral ridge of domain III of E protein (EDIII). It has been widely assumed that the EDIII lateral ridge epitope is conserved within each DENV serotype and a good target for vaccines. Using phylogenetic methods, we compared the amino acid sequence of 175 E proteins representing the different genotypes of DENV3 and identified a panel of surface exposed amino acids, including residues in EDIII, that are highly variant across the four DENV3 genotypes. The variable amino acids include six residues at the lateral ridge of EDIII. We used a panel of DENV3 mouse MAbs to assess the functional significance of naturally occurring amino acid variation. From the panel of antibodies, we identified three neutralizing MAbs that bound to EDIII of DENV3. Recombinant proteins and naturally occurring variant viruses were used to map the binding sites of the three MAbs. The three MAbs bound to overlapping but distinct epitopes on EDIII. Our empirical studies clearly demonstrate that the antibody binding and neutralization capacity of two MAbs was strongly influenced by naturally occurring mutations in DENV3. Our data demonstrate that the lateral ridge “type specific” epitope is not conserved between strains of DENV3. This variability should be considered when designing and evaluating DENV vaccines, especially those targeting EDIII.
Development and Characterization of a Reverse Genetic System for Studying Dengue Virus Serotype 3 Strain Variation and Neutralization
William B. Messer,Boyd Yount,Kari E. Hacker,Eric F. Donaldson,Jeremy P. Huynh,Aravinda M. de Silva ,Ralph S. Baric
PLOS Neglected Tropical Diseases , 2012, DOI: 10.1371/journal.pntd.0001486
Abstract: Dengue viruses (DENV) are enveloped single-stranded positive-sense RNA viruses transmitted by Aedes spp. mosquitoes. There are four genetically distinct serotypes designated DENV-1 through DENV-4, each further subdivided into distinct genotypes. The dengue scientific community has long contended that infection with one serotype confers lifelong protection against subsequent infection with the same serotype, irrespective of virus genotype. However this hypothesis is under increased scrutiny and the role of DENV genotypic variation in protection from repeated infection is less certain. As dengue vaccine trials move increasingly into field-testing, there is an urgent need to develop tools to better define the role of genotypic variation in DENV infection and immunity. To better understand genotypic variation in DENV-3 neutralization and protection, we designed and constructed a panel of isogenic, recombinant DENV-3 infectious clones, each expressing an envelope glycoprotein from a different DENV-3 genotype; Philippines 1982 (genotype I), Thailand 1995 (genotype II), Sri Lanka 1989 and Cuba 2002 (genotype III) and Puerto Rico 1977 (genotype IV). We used the panel to explore how natural envelope variation influences DENV-polyclonal serum interactions. When the recombinant viruses were tested in neutralization assays using immune sera from primary DENV infections, neutralization titers varied by as much as ~19-fold, depending on the expressed envelope glycoprotein. The observed variability in neutralization titers suggests that relatively few residue changes in the E glycoprotein may have significant effects on DENV specific humoral immunity and influence antibody mediated protection or disease enhancement in the setting of both natural infection and vaccination. These genotypic differences are also likely to be important in temporal and spatial microevolution of DENV-3 in the background of heterotypic neutralization. The recombinant and synthetic tools described here are valuable for testing hypotheses on genetic determinants of DENV-3 immunopathogenesis.
Dengue Viruses Are Enhanced by Distinct Populations of Serotype Cross-Reactive Antibodies in Human Immune Sera
Ruklanthi de Alwis,Katherine L. Williams,Michael A. Schmid,Chih-Yun Lai,Bhumi Patel,Scott A. Smith,James E. Crowe,Wei-Kung Wang,Eva Harris ,Aravinda M. de Silva
PLOS Pathogens , 2014, DOI: doi/10.1371/journal.ppat.1004386
Abstract: Dengue viruses (DENV) are mosquito-borne flaviviruses of global importance. DENV exist as four serotypes, DENV1-DENV4. Following a primary infection, individuals produce DENV-specific antibodies that bind only to the serotype of infection and other antibodies that cross-react with two or more serotypes. People exposed to a secondary DENV infection with another serotype are at greater risk of developing more severe forms of dengue disease. The increased risk of severe dengue in people experiencing repeat DENV infections appear to be due, at least in part, to the ability of pre-existing serotype cross-reactive antibodies to form virus-antibody complexes that can productively infect Fcγ receptor-bearing target cells. While the theory of antibody-dependent enhancement (ADE) is supported by several human and small animal model studies, the specific viral antigens and epitopes recognized by enhancing human antibodies after natural infections have not been fully defined. We used antibody-depletion techniques to remove DENV-specific antibody sub-populations from primary DENV-immune human sera. The effects of removing specific antibody populations on ADE were tested both in vitro using K562 cells and in vivo using the AG129 mouse model. Removal of serotype cross-reactive antibodies ablated enhancement of heterotypic virus infection in vitro and antibody-enhanced mortality in vivo. Further depletion studies using recombinant viral antigens showed that although the removal of DENV E-specific antibodies using recombinant E (rE) protein resulted in a partial reduction in DENV enhancement, there was a significant residual enhancement remaining. Competition ADE studies using prM-specific Fab fragments in human immune sera showed that both rE-specific and prM-specific antibodies in primary DENV-immune sera significantly contribute to enhancement of heterotypic DENV infection in vitro. Identification of the targets of DENV-enhancing antibodies should contribute to the development of safe, non-enhancing vaccines against dengue.
In-Depth Analysis of the Antibody Response of Individuals Exposed to Primary Dengue Virus Infection
Ruklanthi de Alwis,Martina Beltramello,William B. Messer,Soila Sukupolvi-Petty,Wahala M. P. B. Wahala,Annette Kraus,Nicholas P. Olivarez,Quang Pham,James Brian,Wen-Yang Tsai,Wei-Kung Wang,Scott Halstead,Srisakul Kliks,Michael S. Diamond,Ralph Baric,Antonio Lanzavecchia,Federica Sallusto,Aravinda M. de Silva
PLOS Neglected Tropical Diseases , 2011, DOI: 10.1371/journal.pntd.0001188
Abstract: Humans who experience a primary dengue virus (DENV) infection develop antibodies that preferentially neutralize the homologous serotype responsible for infection. Affected individuals also generate cross-reactive antibodies against heterologous DENV serotypes, which are non-neutralizing. Dengue cross-reactive, non-neutralizing antibodies can enhance infection of Fc receptor bearing cells and, potentially, exacerbate disease. The actual binding sites of human antibody on the DENV particle are not well defined. We characterized the specificity and neutralization potency of polyclonal serum antibodies and memory B-cell derived monoclonal antibodies (hMAbs) from 2 individuals exposed to primary DENV infections. Most DENV-specific hMAbs were serotype cross-reactive and weakly neutralizing. Moreover, many hMAbs bound to the viral pre-membrane protein and other sites on the virus that were not preserved when the viral envelope protein was produced as a soluble, recombinant antigen (rE protein). Nonetheless, by modifying the screening procedure to detect rare antibodies that bound to rE, we were able to isolate and map human antibodies that strongly neutralized the homologous serotype of DENV. Our MAbs results indicate that, in these two individuals exposed to primary DENV infections, a small fraction of the total antibody response was responsible for virus neutralization.
Pichia pastoris-Expressed Dengue 2 Envelope Forms Virus-Like Particles without Pre-Membrane Protein and Induces High Titer Neutralizing Antibodies
Shailendra Mani, Lav Tripathi, Rajendra Raut, Poornima Tyagi, Upasana Arora, Tarani Barman, Ruchi Sood, Alka Galav, Wahala Wahala, Aravinda de Silva, Sathyamangalam Swaminathan, Navin Khanna
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0064595
Abstract: Dengue is a mosquito-borne viral disease with a global prevalence. It is caused by four closely-related dengue viruses (DENVs 1–4). A dengue vaccine that can protect against all four viruses is an unmet public health need. Live attenuated vaccine development efforts have encountered unexpected interactions between the vaccine viruses, raising safety concerns. This has emphasized the need to explore non-replicating dengue vaccine options. Virus-like particles (VLPs) which can elicit robust immunity in the absence of infection offer potential promise for the development of non-replicating dengue vaccine alternatives. We have used the methylotrophic yeast Pichia pastoris to develop DENV envelope (E) protein-based VLPs. We designed a synthetic codon-optimized gene, encoding the N-terminal 395 amino acid residues of the DENV-2 E protein. It also included 5’ pre-membrane-derived signal peptide-encoding sequences to ensure proper translational processing, and 3’ 6× His tag-encoding sequences to facilitate purification of the expressed protein. This gene was integrated into the genome of P. pastoris host and expressed under the alcohol oxidase 1 promoter by methanol induction. Recombinant DENV-2 protein, which was present in the insoluble membrane fraction, was extracted and purified using Ni2+-affinity chromatography under denaturing conditions. Amino terminal sequencing and detection of glycosylation indicated that DENV-2 E had undergone proper post-translational processing. Electron microscopy revealed the presence of discrete VLPs in the purified protein preparation after dialysis. The E protein present in these VLPs was recognized by two different conformation-sensitive monoclonal antibodies. Low doses of DENV-2 E VLPs formulated in alum were immunogenic in inbred and outbred mice eliciting virus neutralizing titers >1:1200 in flow cytometry based assays and protected AG129 mice against lethal challenge (p<0.05). The formation of immunogenic DENV-2 E VLPs in the absence of pre-membrane protein highlights the potential of P. pastoris in developing non-replicating, safe, efficacious and affordable dengue vaccine.
Somatic Polymorphism Variation in Crotalaria retusa L. Seeds  [PDF]
Paulo Sérgio de Figueiredo, Natale M. Lindoso Silva
American Journal of Plant Sciences (AJPS) , 2018, DOI: 10.4236/ajps.2018.91005
Abstract: The article describes the somatic polymorphism in Crotalaria retusa L. seeds. Each individual may produce yellow dormant seeds, brown quiescent seeds and unviable dark brown ones. Therefore, regarding physiology it is a dimorphism. We show that autogamy reduces dimorphism, favoring the formation of dormant seeds. However, the significant variation in dimorphism is seasonal as consequence of increased viability of dormant seeds under drier weather conditions. The variation is a phenotypic response to changes of humidity in the environment during plant reproduction, a mechanism inducing the prevalence of dormant seeds in the dry season and quiescent seeds during the rainy season. The seasonal alternation between dormancy and quiescence in seasonally dry environments has an apparent adaptive value. The chromatic polymorphism increases on the more humid coast and during the rainy season, due to increased mortality of dormant seeds under wetter weather conditions. Unviable seeds accumulate oxidized phenols in their seed coat that possibly act as induced chemical defenses. Its proportion increases with humidity, accentuating polymorphism, also in response to the increase in the predation rate by larvae of U. ornatrix during the rainy season.
Nanotecnología y nanomedicina: un nuevo horizonte para el diagnóstico y tratamiento médico Nanotechnology and nanomedicine: a new horizon for medical diagnostics and treatment
M.N. De Silva
Archivos de la Sociedad Espa?ola de Oftalmología , 2007,
Abstract:
A study of air borne fungal distribution and species diversity in Hill Fort Region of Channagiri, Karnataka, India
S. Thirumala,Pradeep Nathu M.,H. B. Aravinda
International Journal of Applied Sciences and Biotechnology , 2013, DOI: 10.3126/ijasbt.v1i2.8203
Abstract: Air borne fungi of Hill fort region of Channagiri is studied with help of Petriplate exposure method using Pottato dextrose agar media, petriplate exposure time is 15min. Sampling is taken in the month of January 2013 total 74 fungal colonies represented 07 fungal types were observed during the present investigation period. Environmental condition plays an importance role in the distribution of the fungal spores. Out of 07 fungal species most numbers of fungi are anamorphic groups. The fungal species were Aspergillus, Pencillium, Curvilaria, Cladosporium, Fusarium Rhizopus, Alternaria species were identified. Aspergillus species (47.2%) showing maximum contribution is observed where as Rhizopus shows minimum contribution.
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