Person: KHAN, MOHAMMAD ASİF
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- PublicationOpen AccessAvian Influenza H7N9 Virus Adaptation to Human Hosts(2021-05-01T00:00:00Z) Tan, Swan; Sjaugi, Muhammad Farhan; Fong, Siew Chinn; Chong, Li Chuin; Abd Raman, Hadia Syahirah; Nik Mohamed, Nik Elena; August, Joseph Thomas; Khan, Asif M.; KHAN, MOHAMMAD ASİFAvian influenza virus A (H7N9), after circulating in avian hosts for decades, was identified as a human pathogen in 2013. Herein, amino acid substitutions possibly essential for human adaptation were identified by comparing the 4706 aligned overlapping nonamer position sequences (1-9, 2-10, etc.) of the reported 2014 and 2017 avian and human H7N9 datasets. The initial set of virus sequences (as of year 2014) exhibited a total of 109 avian-to-human (A2H) signature amino acid substitutions. Each represented the most prevalent substitution at a given avian virus nonamer position that was selectively adapted as the corresponding index (most prevalent sequence) of the human viruses. The majority of these avian substitutions were long-standing in the evolution of H7N9, and only 17 were first detected in 2013 as possibly essential for the initial human adaptation. Strikingly, continued evolution of the avian H7N9 virus has resulted in avian and human protein sequences that are almost identical. This rapid and continued adaptation of the avian H7N9 virus to the human host, with near identity of the avian and human viruses, is associated with increased human infection and a predicted greater risk of human-to-human transmission.
- PublicationMetadata onlyComputational design and characterization of a multiepitope vaccine against carbapenemase-producing Klebsiella pneumoniae strains, derived from antigens identified through reverse vaccinology(2022-01-01T00:00:00Z) Cuscino, Nicola; Fatima, Ayesha; Di Pilato, Vincenzo; Bulati, Matteo; Alfano, Caterina; Monaca, Elisa; Di Mento, Giuseppina; Di Carlo, Daniele; Cardinale, Francesca; Monaco, Francesco; Rossolini, Gian Maria; KHAN, MOHAMMAD ASİF; Conaldi, Pier Giulio; Douradinha, Bruno; FATIMA, AYESHA; KHAN, MOHAMMAD ASİFKlebsiella pneumoniae is a Gram-negative pathogen of clinical relevance, which can provoke serious urinary and blood infections and pneumonia. This bacterium is a major public health threat due to its resistance to several antibiotic classes. Using a reverse vaccinology approach, 7 potential antigens were identified, of which 4 were present in most of the sequences of Italian carbapenem-resistant K. pneumoniae clinical isolates. Bioinformatics tools demonstrated the antigenic potential of these bacterial proteins and allowed for the identification of T and B cell epitopes. This led to a rational design and in silico characterization of a multiepitope vaccine against carbapenem-resistant K. pneumoniae strains. As adjuvant, the mycobacterial heparin-binding hemagglutinin adhesin (HBHA), which is a Toll-like receptor 4 (TLR-4) agonist, was included, to increase the immunogenicity of the construct. The multiepitope vaccine candidate was analyzed by bioinformatics tools to assess its antigenicity, solubility, allergenicity, toxicity, physical and chemical parameters, and secondary and tertiary structures. Molecular docking binding energies to TLR-2 and TLR-4, two important innate immunity receptors involved in the immune response against K. pneumoniae infections, and molecular dynamics simulations of such complexes supported active interactions. A codon optimized multiepitope sequence cloning strategy is proposed, for production of recombinant vaccine in classical bacterial vectors. Finally, a 3 dose-immunization simulation with the multiepitope construct induced both cellular and humoral immune responses. These results suggest that this multiepitope construct has potential as a vaccination strategy against carbapenem-resistant K. pneumoniae and deserves further validation.(c) 2022 The Author(s). Published by Elsevier B.V. on behalf of Research Network of Computational and Structural Biotechnology. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
- PublicationMetadata onlyCheminformatics-Based Drug Design Approach for Identification of Inhibitors Targeting the Characteristic Residues of MMP-13 Hemopexin Domain(2010-08-01T00:00:00Z) Kothapalli, Roopa; KHAN, MOHAMMAD ASİF; Basappa, Basappa; Gopalsamy, Anupriya; Chong, Yap Seng; Annamalai, Loganath; KHAN, MOHAMMAD ASİFBackground: MMP-13, a zinc dependent protease which catalyses the cleavage of type II collagen, is expressed in osteoarthritis (OA) and rheumatoid arthritis (RA) patients, but not in normal adult tissues. Therefore, the protease has been intensively studied as a target for the inhibition of progression of OA and RA. Recent reports suggest that selective inhibition of MMP-13 may be achieved by targeting the hemopexin (Hpx) domain of the protease, which is critical for substrate specificity. In this study, we applied a cheminformatics-based drug design approach for the identification and characterization of inhibitors targeting the amino acid residues characteristic to Hpx domain of MMP-13; these inhibitors may potentially be employed in the treatment of OA and RA.
- PublicationMetadata onlySTATdb: A Specialised Resource for the STATome(2014-08-01T00:00:00Z) Patro, C. Pawan K.; Khan, Asif M.; Tan, Tin Wee; Fu, Xin-Yuan; KHAN, MOHAMMAD ASİFSignal transducers and activators of transcription (STAT) proteins are key signalling molecules in metazoans, implicated in various cellular processes. Increased research in the field has resulted in the accumulation of STAT sequence and structure data, which are scattered across various public databases, missing extensive functional annotations, and prone to effort redundancy because of the dearth of community sharing. Therefore, there is a need to integrate the existing sequence, structure and functional data into a central repository, one that is enriched with annotations and provides a platform for community contributions. Herein, we present STATdb (publicly available at http://statdb.bic.nus.edu.sg/), the first integrated resource for STAT sequences comprising 1540 records representing the known STATome, enriched with existing structural and functional information from various databases and literature and including manual annotations. STATdb provides advanced features for data visualization, analysis and prediction, and community contributions. A key feature is a meta-predictor to characterise STAT sequences based on a novel classification that integrates STAT domain architecture, lineage and function. A curation policy workflow has been devised for regulated and structured community contributions, with an update policy for the seamless integration of new data and annotations.
- PublicationMetadata onlySimple re-instantiation of small databases using cloud computing(2013-10-01T00:00:00Z) Tan, Tin Wee; Xie, Chao; De Silva, Mark; Lim, Kuan Siong; Patro, C. Pawan K.; Lim, Shen Jean; Govindarajan, Kunde Ramamoorthy; Tong, Joo Chuan; Choo, Khar Heng; Ranganathan, Shoba; KHAN, MOHAMMAD ASİF; KHAN, MOHAMMAD ASİFBackground: Small bioinformatics databases, unlike institutionally funded large databases, are vulnerable to discontinuation and many reported in publications are no longer accessible. This leads to irreproducible scientific work and redundant effort, impeding the pace of scientific progress.
- PublicationMetadata onlyMapping HLA-A2,-A3 and-B7 supertype-restricted T-cell epitopes in the ebolavirus proteome(2018-01-01T00:00:00Z) Lim, Wan Ching; Khan, Asif M.; KHAN, MOHAMMAD ASİFBackground: Ebolavirus (EBOV) is responsible for one of the most fatal diseases encountered by mankind. Cellular T-cell responses have been implicated to be important in providing protection against the virus. Antigenic variation can result in viral escape from immune recognition. Mapping targets of immune responses among the sequence of viral proteins is, thus, an important first step towards understanding the immune responses to viral variants and can aid in the identification of vaccine targets. Herein, we performed a large-scale, proteome-wide mapping and diversity analyses of putative HLA supertype-restricted T-cell epitopes of Zaire ebolavirus (ZEBOV), the most pathogenic species among the EBOV family.
- PublicationMetadata onlyDendritic Cell Mediated Delivery of Plasmid DNA Encoding LAMP/HIV-1 Gag Fusion Immunogen Enhances T Cell Epitope Responses in HLA DR4 Transgenic Mice(2010-01-01T00:00:00Z) Simon, Gregory G.; Hu, Yongli; KHAN, MOHAMMAD ASİF; Zhou, Jingshi; Salmon, Jerome; Chikhlikar, Priya R.; Jung, Keun-Ok; Marques, Ernesto T. A.; August, J. Thomas; KHAN, MOHAMMAD ASİFThis report describes the identification and bioinformatics analysis of HLA-DR4-restricted HIV-1 Gag epitope peptides, and the application of dendritic cell mediated immunization of DNA plasmid constructs. BALB/c (H-2d) and HLA-DR4 (DRA1*0101, DRB1*0401) transgenic mice were immunized with immature dendritic cells transfected by a recombinant DNA plasmid encoding the lysosome-associated membrane protein-1/HIV-1 Gag (pLAMP/gag) chimera antigen. Three immunization protocols were compared: 1) primary subcutaneous immunization with 1x10(5) immature dendritic cells transfected by electroporation with the pLAMP/gag DNA plasmid, and a second subcutaneous immunization with the naked pLAMP/gag DNA plasmid; 2) primary immunization as above, and a second subcutaneous immunization with a pool of overlapping peptides spanning the HIV-1 Gag sequence; and 3) immunization twice by subcutaneous injection of the pLAMP/gag DNA plasmid. Primary immunization with pLAMP/gag-transfected dendritic cells elicited the greatest number of peptide specific T-cell responses, as measured by ex vivo IFN-gamma ELISpot assay, both in BALB/c and HLA-DR4 transgenic mice. The pLAMP/gag-transfected dendritic cells prime and naked DNA boost immunization protocol also resulted in an increased apparent avidity of peptide in the ELISpot assay. Strikingly, 20 of 25 peptide-specific T-cell responses in the HLA-DR4 transgenic mice contained sequences that corresponded, entirely or partially to 18 of the 19 human HLA-DR4 epitopes listed in the HIV molecular immunology database. Selection of the most conserved epitope peptides as vaccine targets was facilitated by analysis of their representation and variability in all reported sequences. These data provide a model system that demonstrates a) the superiority of immunization with dendritic cells transfected with LAMP/gag plasmid DNA, as compared to naked DNA, b) the value of HLA transgenic mice as a model system for the identification and evaluation of epitope-based vaccine strategies, and c) the application of variability analysis across reported sequences in public databases for selection of historically conserved HIV epitopes as vaccine targets.
- PublicationMetadata onlyAfrican Trypanosome-Induced Blood-Brain Barrier Dysfunction under Shear Stress May Not Require ERK Activation(2015-03-01T00:00:00Z) Sumpio, Brandon J.; Chitragari, Gautham; Moriguchi, Takeshi; Shalaby, Sherif; Pappas-Brown, Valeria; Khan, Asif M.; Sekaran, Shamala Devi; Sumpio, Bauer E.; Grab, Dennis J.; KHAN, MOHAMMAD ASİFAfrican trypanosomes are tsetse fly transmitted protozoan parasites responsible for human African trypanosomiasis, a disease characterized by a plethora of neurological symptoms and death. How the parasites under microvascular shear stress (SS) flow conditions in the brain cross the blood-brain barrier (BBB) is not known. In vitro studies using static models comprised of human brain microvascular endothelial cells (BMEC) show that BBB activation and crossing by trypanosomes requires the orchestration of parasite cysteine proteases and host calcium-mediated cell signaling. Here, we examine BMEC barrier function and the activation of extracellular signal-regulated kinase (ERK) 1/2 and ERK5, mitogen-activated protein kinase family regulators of microvascular permeability, under static and laminar SS flow and in the context of trypanosome infection. Confluent human BMEC were cultured in electric cell-substrate impedance sensing (ECIS) and parallel-plate glass slide chambers. The human BMEC were exposed to 2 or 14 dyn/cm(2) SS in the presence or absence of trypanosomes. Real-time changes in transendothelial electrical resistance (TEER) were monitored and phosphorylation of ERK1/2 and ERK5 analyzed by immunoblot assay. After reaching confluence under static conditions human BMEC TEER was found to rapidly increase when exposed to 2 dyn/cm2 SS, a condition that mimics SS in brain postcapillary venules. Addition of African trypanosomes caused a rapid drop in human BMEC TEER. Increasing SS to 14 dyn/cm2, a condition mimicking SS in brain capillaries, led to a transient increase in TEER in both control and infected human BMEC. However, no differences in ERK1/2 and ERK5 activation were found under any condition tested. African trypanosomiasis alters BBB permeability under low shear conditions through an ERK1/2 and ERK5 independent pathway.
- PublicationMetadata onlyHighly conserved influenza A sequences as T cell epitopes-based vaccine targets to address the viral variability(2011-04-01T00:00:00Z) Tan, Paul ThiamJoo; KHAN, MOHAMMAD ASİF; August, J. Thomas; KHAN, MOHAMMAD ASİFVaccines are the only proven effective method for prevention of human infectious diseases. Almost all traditional vaccines require activating immunological memory B cells to secrete neutralizing antibodies against invading pathogens. The complication with influenza viruses is the high viral mutation rate that results in immune escape through modification of the B cell epitopes. Studies of T cell immunity to influenza infection provide an alternative vaccine strategy based on highly conserved T cell epitopes. In this review, we discuss the importance of T cell-mediated immunity in influenza infection and the need for a targeted vaccine approach focused on highly conserved T cell epitopes to mitigate immune escape. We propose 15 highly conserved pan-influenza sequences as potential T cell epitopes-based vaccine targets for broad protection and lasting immunity against variant influenza strains.
- PublicationMetadata onlyCytokine Expression Profile of Dengue Patients at Different Phases of Illness(2012-12-01T00:00:00Z) Rathakrishnan, Anusyah; Wang, Seok Mui; Hu, Yongli; KHAN, MOHAMMAD ASİF; Ponnampalavanar, Sasheela; Lum, Lucy Chai See; Manikam, Rishya; Sekaran, Shamala Devi; KHAN, MOHAMMAD ASİFBackground: Dengue is an important medical problem, with symptoms ranging from mild dengue fever to severe forms of the disease, where vascular leakage leads to hypovolemic shock. Cytokines have been implicated to play a role in the progression of severe dengue disease; however, their profile in dengue patients and the synergy that leads to continued plasma leakage is not clearly understood. Herein, we investigated the cytokine kinetics and profiles of dengue patients at different phases of illness to further understand the role of cytokines in dengue disease.
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