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Search Results: 1 - 10 of 321545 matches for " Lisa F. P. Ng "
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Clustering HLA Class I Superfamilies Using Structural Interaction Patterns
Sumitro Harjanto, Lisa F. P. Ng, Joo Chuan Tong
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0086655
Abstract: Human leukocyte antigen (HLA) class I molecules are critical components of the cell-mediated immune system that bind and present intracellular antigenic peptides to CD8+ T cell receptors. To understand the interaction mechanism underlying human leukocyte antigen (HLA) class I specificity in detail, we studied the structural interaction characteristics of 16,393 nonameric peptides binding to 58 HLA-A and -B molecules. Our analysis showed for the first time that HLA-peptide intermolecular bonding patterns vary among different alleles and may be grouped in a superfamily dependent manner. Through the use of these HLA class I ‘fingerprints’, a high resolution HLA class I superfamily classification schema was developed. This classification is capable of separating HLA alleles into well resolved, non-overlapping clusters, which is consistent with known HLA superfamily definitions. Such structural interaction approach serves as an excellent alternative to the traditional methods of HLA superfamily definitions that use peptide binding motifs or receptor information, and will help identify appropriate antigens suitable for broad-based subunit vaccine design.
HLA Class I Restriction as a Possible Driving Force for Chikungunya Evolution
Joo Chuan Tong,Diane Simarmata,Raymond T. P. Lin,Laurent Rénia,Lisa F. P. Ng
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0009291
Abstract: After two decades of quiescence, epidemic resurgence of Chikungunya fever (CHIKF) was reported in Africa, several islands in the Indian Ocean, South-East Asia and the Pacific causing unprecedented morbidity with some cases of fatality. Early phylogenetic analyses based on partial sequences of Chikungunya virus (CHIKV) have led to speculation that the virus behind recent epidemics may result in greater pathogenicity. To understand the reasons for these new epidemics, we first performed extensive analyses of existing CHIKV sequences from its introduction in 1952 to 2009. Our results revealed the existence of a continuous genotypic lineage, suggesting selective pressure is active in CHIKV evolution. We further showed that CHIKV is undergoing mild positive selection, and that site-specific mutations may be driven by cell-mediated immune pressure, with occasional changes that resulted in the loss of human leukocyte antigen (HLA) class I-restricting elements. These findings provide a basis to understand Chikungunya virus evolution and reveal the power of post-genomic analyses to understand CHIKV and other viral epidemiology. Such an approach is useful for studying the impact of host immunity on pathogen evolution, and may help identify appropriate antigens suitable for subunit vaccine formulations.
Cleavage of the SARS Coronavirus Spike Glycoprotein by Airway Proteases Enhances Virus Entry into Human Bronchial Epithelial Cells In Vitro
Yiu-Wing Kam,Yuushi Okumura,Hiroshi Kido,Lisa F. P. Ng,Roberto Bruzzone,Ralf Altmeyer
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0007870
Abstract: Entry of enveloped viruses into host cells requires the activation of viral envelope glycoproteins through cleavage by either intracellular or extracellular proteases. In order to gain insight into the molecular basis of protease cleavage and its impact on the efficiency of viral entry, we investigated the susceptibility of a recombinant native full-length S-protein trimer (triSpike) of the severe acute respiratory syndrome coronavirus (SARS-CoV) to cleavage by various airway proteases.
Host heterogeneous ribonucleoprotein K (hnRNP K) as a potential target to suppress hepatitis B virus replication.
Ng Lisa F P,Chan Marieta,Chan Soh-Ha,Cheng Paul Chung-Pui
PLOS Medicine , 2005,
Abstract: BACKGROUND: Hepatitis B virus (HBV) infection results in complications such as cirrhosis and hepatocellular carcinoma. Suppressing viral replication in chronic HBV carriers is an effective approach to controlling disease progression. Although antiviral compounds are available, we aimed to identify host factors that have a significant effect on viral replication efficiency. METHODS AND FINDINGS: We studied a group of hepatitis B carriers by associating serum viral load with their respective HBV genomes, and observed a significant association between high patient serum viral load with a natural sequence variant within the HBV enhancer II (Enh II) regulatory region at position 1752. Using a viral fragment as an affinity binding probe, we isolated a host DNA-binding protein belonging to the class of heterogeneous nuclear ribonucleoproteins--hnRNP K--that binds to and modulates the replicative efficiency of HBV. In cell transfection studies, overexpression of hnRNP K augmented HBV replication, while gene silencing of endogenous hnRNP K carried out by small interfering RNAs resulted in a significant reduction of HBV viral load. CONCLUSION: The evidence presented in this study describes a wider role for hnRNP K beyond maintenance of host cellular functions and may represent a novel target for pharmacologic intervention of HBV replication.
Host Heterogeneous Ribonucleoprotein K (hnRNP K) as a Potential Target to Suppress Hepatitis B Virus Replication
Lisa F. P Ng,Marieta Chan,Soh-Ha Chan,Paul Chung-Pui Cheng,Eastwood Hon-Chiu Leung,Wei-Ning Chen,Ee-Chee Ren
PLOS Medicine , 2005, DOI: 10.1371/journal.pmed.0020163
Abstract: Background Hepatitis B virus (HBV) infection results in complications such as cirrhosis and hepatocellular carcinoma. Suppressing viral replication in chronic HBV carriers is an effective approach to controlling disease progression. Although antiviral compounds are available, we aimed to identify host factors that have a significant effect on viral replication efficiency. Methods and Findings We studied a group of hepatitis B carriers by associating serum viral load with their respective HBV genomes, and observed a significant association between high patient serum viral load with a natural sequence variant within the HBV enhancer II (Enh II) regulatory region at position 1752. Using a viral fragment as an affinity binding probe, we isolated a host DNA-binding protein belonging to the class of heterogeneous nuclear ribonucleoproteins—hnRNP K—that binds to and modulates the replicative efficiency of HBV. In cell transfection studies, overexpression of hnRNP K augmented HBV replication, while gene silencing of endogenous hnRNP K carried out by small interfering RNAs resulted in a significant reduction of HBV viral load. Conclusion The evidence presented in this study describes a wider role for hnRNP K beyond maintenance of host cellular functions and may represent a novel target for pharmacologic intervention of HBV replication.
SARS Transmission Pattern in Singapore Reassessed by Viral Sequence Variation Analysis
Jianjun Liu ,Siew Lan Lim,Yijun Ruan,Ai Ee Ling,Lisa F. P Ng,Christian Drosten,Edison T Liu,Lawrence W Stanton,Martin L Hibberd
PLOS Medicine , 2005, DOI: 10.1371/journal.pmed.0020043
Abstract: Background Epidemiological investigations of infectious disease are mainly dependent on indirect contact information and only occasionally assisted by characterization of pathogen sequence variation from clinical isolates. Direct sequence analysis of the pathogen, particularly at a population level, is generally thought to be too cumbersome, technically difficult, and expensive. We present here a novel application of mass spectrometry (MS)–based technology in characterizing viral sequence variations that overcomes these problems, and we apply it retrospectively to the severe acute respiratory syndrome (SARS) outbreak in Singapore. Methods and Findings The success rate of the MS-based analysis for detecting SARS coronavirus (SARS-CoV) sequence variations was determined to be 95% with 75 copies of viral RNA per reaction, which is sufficient to directly analyze both clinical and cultured samples. Analysis of 13 SARS-CoV isolates from the different stages of the Singapore outbreak identified nine sequence variations that could define the molecular relationship between them and pointed to a new, previously unidentified, primary route of introduction of SARS-CoV into the Singapore population. Our direct determination of viral sequence variation from a clinical sample also clarified an unresolved epidemiological link regarding the acquisition of SARS in a German patient. We were also able to detect heterogeneous viral sequences in primary lung tissues, suggesting a possible coevolution of quasispecies of virus within a single host. Conclusion This study has further demonstrated the importance of improving clinical and epidemiological studies of pathogen transmission through the use of genetic analysis and has revealed the MS-based analysis to be a sensitive and accurate method for characterizing SARS-CoV genetic variations in clinical samples. We suggest that this approach should be used routinely during outbreaks of a wide variety of agents, in order to allow the most effective control.
Unique Epitopes Recognized by Antibodies Induced in Chikungunya Virus-Infected Non-Human Primates: Implications for the Study of Immunopathology and Vaccine Development
Yiu-Wing Kam, Wendy W. L. Lee, Diane Simarmata, Roger Le Grand, Hugues Tolou, Andres Merits, Pierre Roques, Lisa F. P. Ng
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0095647
Abstract: Chikungunya virus (CHIKV) is an Alphavirus that causes chronic and incapacitating arthralgia in humans. Although patient cohort studies have shown the production of CHIKV specific antibodies, the fine specificity of the antibody response against CHIKV is not completely defined. The macaque model of CHIKV infection was established due to limitations of clinical specimens. More importantly, its close relation to humans will allow the study of chronic infection and further identify important CHIKV targets. In this study, serum samples from CHIKV-infected macaques collected at different time-points post infection were used to characterize the antibody production pattern and kinetics. Results revealed that anti-CHIKV antibodies were neutralizing and the E2 glycoprotein, Capsid, nsP1, nsP3 and nsP4 proteins were targets of the anti-CHIKV antibody response in macaques. Furthermore, linear B-cell epitopes recognized by these anti-CHIKV antibodies were identified, and mapped to their structural localization. This characterizes the specificity of anti-CHIKV antibody response in macaques and further demonstrates the importance of the different regions in CHIKV-encoded proteins in the adaptive immune response. Information from this study provides critical knowledge that will aid in the understanding of CHIKV infection and immunity, vaccine design, and pre-clinical efficacy studies.
Myeloid Cell Arg1 Inhibits Control of Arthritogenic Alphavirus Infection by Suppressing Antiviral T Cells
Kristina S. Burrack?,Jeslin J. L. Tan?,Mary K. McCarthy?,Zhisheng Her?,Jennifer N. Berger?,Lisa F. P. Ng,Thomas E. Morrison
PLOS Pathogens , 2015, DOI: 10.1371/journal.ppat.1005191
Abstract: Arthritogenic alphaviruses, including Ross River virus (RRV) and chikungunya virus (CHIKV), are responsible for explosive epidemics involving millions of cases. These mosquito-transmitted viruses cause inflammation and injury in skeletal muscle and joint tissues that results in debilitating pain. We previously showed that arginase 1 (Arg1) was highly expressed in myeloid cells in the infected and inflamed musculoskeletal tissues of RRV- and CHIKV-infected mice, and specific deletion of Arg1 from myeloid cells resulted in enhanced viral control. Here, we show that Arg1, along with other genes associated with suppressive myeloid cells, is induced in PBMCs isolated from CHIKV-infected patients during the acute phase as well as the chronic phase, and that high Arg1 expression levels were associated with high viral loads and disease severity. Depletion of both CD4 and CD8 T cells from RRV-infected Arg1-deficient mice restored viral loads to levels detected in T cell-depleted wild-type mice. Moreover, Arg1-expressing myeloid cells inhibited virus-specific T cells in the inflamed and infected musculoskeletal tissues, but not lymphoid tissues, following RRV infection in mice, including suppression of interferon-γ and CD69 expression. Collectively, these data enhance our understanding of the immune response following arthritogenic alphavirus infection and suggest that immunosuppressive myeloid cells may contribute to the duration or severity of these debilitating infections.
IL-1β, IL-6, and RANTES as Biomarkers of Chikungunya Severity
Lisa F. P. Ng, Angela Chow, Yong-Jiang Sun, Dyan J. C. Kwek, Poh-Lian Lim, Frederico Dimatatac, Lee-Ching Ng, Eng-Eong Ooi, Khar-Heng Choo, Zhisheng Her, Philippe Kourilsky, Yee-Sin Leo
PLOS ONE , 2009, DOI: 10.1371/journal.pone.0004261
Abstract: Background Little is known about the immunopathogenesis of Chikungunya virus. Circulating levels of immune mediators and growth factors were analyzed from patients infected during the first Singaporean Chikungunya fever outbreak in early 2008 to establish biomarkers associated with infection and/or disease severity. Methods and Findings Adult patients with laboratory-confirmed Chikungunya fever infection, who were referred to the Communicable Disease Centre/Tan Tock Seng Hospital during the period from January to February 2008, were included in this retrospective study. Plasma fractions were analyzed using a multiplex-microbead immunoassay. Among the patients, the most common clinical features were fever (100%), arthralgia (90%), rash (50%) and conjunctivitis (40%). Profiles of 30 cytokines, chemokines, and growth factors were able to discriminate the clinical forms of Chikungunya from healthy controls, with patients classified as non-severe and severe disease. Levels of 8 plasma cytokines and 4 growth factors were significantly elevated. Statistical analysis showed that an increase in IL-1β, IL-6 and a decrease in RANTES were associated with disease severity. Conclusions This is the first comprehensive report on the production of cytokines, chemokines, and growth factors during acute Chikungunya virus infection. Using these biomarkers, we were able to distinguish between mild disease and more severe forms of Chikungunya fever, thus enabling the identification of patients with poor prognosis and monitoring of the disease.
Chikungunya Virus Neutralization Antigens and Direct Cell-to-Cell Transmission Are Revealed by Human Antibody-Escape Mutants
Chia Yin Lee,Yiu-Wing Kam,Jan Fric,Benoit Malleret,Esther G. L. Koh,Celine Prakash,Wen Huang,Wendy W. L. Lee,Cui Lin,Raymond T. P. Lin,Laurent Renia,Cheng-I Wang,Lisa F. P. Ng,Lucile Warter
PLOS Pathogens , 2011, DOI: 10.1371/journal.ppat.1002390
Abstract: Chikungunya virus (CHIKV) is an alphavirus responsible for numerous epidemics throughout Africa and Asia, causing infectious arthritis and reportedly linked with fatal infections in newborns and elderly. Previous studies in animal models indicate that humoral immunity can protect against CHIKV infection, but despite the potential efficacy of B-cell-driven intervention strategies, there are no virus-specific vaccines or therapies currently available. In addition, CHIKV has been reported to elicit long-lasting virus-specific IgM in humans, and to establish long-term persistence in non-human primates, suggesting that the virus might evade immune defenses to establish chronic infections in man. However, the mechanisms of immune evasion potentially employed by CHIKV remain uncharacterized. We previously described two human monoclonal antibodies that potently neutralize CHIKV infection. In the current report, we have characterized CHIKV mutants that escape antibody-dependent neutralization to identify the CHIKV E2 domain B and fusion loop “groove” as the primary determinants of CHIKV interaction with these antibodies. Furthermore, for the first time, we have also demonstrated direct CHIKV cell-to-cell transmission, as a mechanism that involves the E2 domain A and that is associated with viral resistance to antibody-dependent neutralization. Identification of CHIKV sub-domains that are associated with human protective immunity, will pave the way for the development of CHIKV-specific sub-domain vaccination strategies. Moreover, the clear demonstration of CHIKV cell-to-cell transmission and its possible role in the establishment of CHIKV persistence, will also inform the development of future anti-viral interventions. These data shed new light on CHIKV-host interactions that will help to combat human CHIKV infection and inform future studies of CHIKV pathogenesis.
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