16 results on '"Sirohi, Devika"'
Search Results
2. Chemical proteomics tracks virus entry and uncovers NCAM1 as Zika virus receptor
- Author
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Srivastava, Mayank, Zhang, Ying, Chen, Jian, Sirohi, Devika, Miller, Andrew, Zhang, Yang, Chen, Zhilu, Lu, Haojie, Xu, Jianqing, Kuhn, Richard J., and Andy Tao, W.
- Published
- 2020
- Full Text
- View/download PDF
3. The 3.8 Å resolution cryo-EM structure of Zika virus
- Author
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Sirohi, Devika, Chen, Zhenguo, Sun, Lei, Klose, Thomas, Pierson, Theodore C., Rossmann, Michael G., and Kuhn, Richard J.
- Published
- 2016
4. prM-reactive antibodies reveal a role for partially mature virions in dengue virus pathogenesis.
- Author
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Dowd, Kimberly A., Sirohi, Devika, Speer, Scott D., VanBlargan, Laura A., Chen, Rita E., Mukherjee, Swati, Whitener, Bradley M., Govero, Jennifer, Aleshnick, Maya, Larman, Bridget, Sukupolvi-Petty, Soila, Sevvana, Madhumati, Miller, Andrew S., Klose, Thomas, Aihua Zheng, Koenig, Scott, Kielian, Margaret, Kuhn, Richard J., Diamond, Michael S., and Pierson, Theodore C.
- Subjects
- *
DENGUE viruses , *VIRION , *CYTOSKELETAL proteins , *MONOCLONAL antibodies , *IMMUNOGLOBULINS - Abstract
Cleavage of the flavivirus premembrane (prM) structural protein during maturation can be inefficient. The contribution of partially mature flavivirus virions that retain uncleaved prM to pathogenesis during primary infection is unknown. To investigate this question, we characterized the functional properties of newly-generated dengue virus (DENV) prM-reactive monoclonal antibodies (mAbs) in vitro and using a mouse model of DENV disease. Anti-prM mAbs neutralized DENV infection in a virion maturation state--dependent manner. Alanine scanning mutagenesis and cryoelectron microscopy of anti-prM mAbs in complex with immature DENV defined two modes of attachment to a single antigenic site. In vivo, passive transfer of intact anti-prM mAbs resulted in an antibody-dependent enhancement of disease. However, protection against DENV- induced lethality was observed when the transferred mAbs were genetically modified to inhibit their ability to interact with Fcy receptors. These data establish that in addition to mature forms of the virus, partially mature infectious prM+ virions can also contribute to pathogenesis during primary DENV infections. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
5. STRUCTURAL BIOLOGY: The 3.8 Å resolution cryo-EM structure of Zika virus
- Author
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Sirohi, Devika, Chen, Zhenguo, Sun, Lei, Klose, Thomas, Pierson, Theodore C., Rossmann, Michael G., and Kuhn, Richard J.
- Published
- 2016
- Full Text
- View/download PDF
6. Zika Virus Can Strongly Infect and Disrupt Secondary Organizers in the Ventricular Zone of the Embryonic Chicken Brain.
- Author
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Thawani, Ankita, Sirohi, Devika, Kuhn, Richard J., and Fekete, Donna M.
- Abstract
Zika virus (ZIKV) is associated with severe neurodevelopmental impairments in human fetuses, including microencephaly. Previous reports examining neural progenitor tropism of ZIKV in organoid and animal models did not address whether the virus infects all neural progenitors uniformly. To explore this, ZIKV was injected into the neural tube of 2-day-old chicken embryos, resultinginnonuniformperiventricular infection 3 days later. Recurrent foci of intense infection were present at specific signaling centers that influence neuroepithelial patterning at a distance through secretion of morphogens. ZIKV infection reduced transcript levels for 3 morphogens, SHH, BMP7, and FGF8 expressed at themidbrain basal plate, hypothalamic floor plate, and isthmus, respectively. Levels of Patched1, a SHH-pathway downstream gene, were also reduced, and aSHH-dependent cell population in the ventral midbrain was shifted in position. Thus, the diminishment of signaling centers through ZIKV-mediated apoptosis may yield broader, noncell- autonomous changes in brain patterning. [ABSTRACT FROM AUTHOR]
- Published
- 2018
- Full Text
- View/download PDF
7. Enhancing dengue virus maturation using a stable furin over-expressing cell line.
- Author
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Mukherjee, Swati, Sirohi, Devika, Dowd, Kimberly A., Chen, Zhenguo, Diamond, Michael S., Kuhn, Richard J., and Pierson, Theodore C.
- Subjects
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FLAVIVIRUSES , *LIFE cycles (Biology) , *DEVELOPMENTAL biology , *TISSUE culture , *GENE expression - Abstract
Flaviviruses are positive-stranded RNA viruses that incorporate envelope (E) and premembrane (prM) proteins into the virion. Furin-mediated cleavage of prM defines a required maturation step in the flavivirus lifecycle. Inefficient prM cleavage results in structurally heterogeneous virions with unique antigenic and functional characteristics. Recent studies with dengue virus suggest that viruses produced in tissue culture cells are less mature than those produced in primary cells. In this study, we describe a Vero cell line that ectopically expresses high levels of human furin (Vero-furin) for use in the production of more homogenous mature flavivirus populations. Laboratory-adapted and clinical dengue virus isolates grow efficiently in Vero-furin cells. Biochemical and structural techniques demonstrate efficient prM cleavage in Vero-furin derived virus preparations. These virions also were less sensitive to neutralization by antibodies that bind efficiently to immature virions. This furin-expressing cell line will be of considerable utility for flavivirus neutralization and structural studies. [ABSTRACT FROM AUTHOR]
- Published
- 2016
- Full Text
- View/download PDF
8. Impact of Dengue Virus Infection on Global Metabolic Alterations in the Aedes aegypti Mosquito Vector
- Author
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Chotiwan, Nunya, Sanchez-Vargus, Irma, Grabowski, Jeffrey M., Hopf-jannasch, Amber, Hedrick, Victoria, Gough, Erik, Nakayasu, Ernesto, Sirohi, Devika, Hill, Catherine A., Kuhn, Richard J., and Perera, Rushika
- Published
- 2015
- Full Text
- View/download PDF
9. Characterization of the Proteome of Cytoplasmic Lipid Droplets in Mouse Enterocytes after a Dietary Fat Challenge.
- Author
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D’Aquila, Theresa, Sirohi, Devika, Grabowski, Jeffrey M., Hedrick, Victoria E., Paul, Lake N., Greenberg, Andrew S., Kuhn, Richard J., and Buhman, Kimberly K.
- Subjects
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CYTOPLASM , *ENTEROCYTES , *FAT content of food , *LABORATORY mice , *DIETARY supplements - Abstract
Dietary fat absorption by the small intestine is a multistep process that regulates the uptake and delivery of essential nutrients and energy. One step of this process is the temporary storage of dietary fat in cytoplasmic lipid droplets (CLDs). The storage and mobilization of dietary fat is thought to be regulated by proteins that associate with the CLD; however, mechanistic details of this process are currently unknown. In this study we analyzed the proteome of CLDs isolated from enterocytes harvested from the small intestine of mice following a dietary fat challenge. In this analysis we identified 181 proteins associated with the CLD fraction, of which 37 are associated with known lipid related metabolic pathways. We confirmed the localization of several of these proteins on or around the CLD through confocal and electron microscopy, including perilipin 3, apolipoprotein A-IV, and acyl-CoA synthetase long-chain family member 5. The identification of the enterocyte CLD proteome provides new insight into potential regulators of CLD metabolism and the process of dietary fat absorption. [ABSTRACT FROM AUTHOR]
- Published
- 2015
- Full Text
- View/download PDF
10. Coupling of replication and assembly in flaviviruses.
- Author
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Apte-Sengupta, Swapna, Sirohi, Devika, and Kuhn, Richard J
- Abstract
Flaviviruses affect hundreds of millions of people each year causing tremendous morbidity and mortality worldwide. This genus includes significant human pathogens such as dengue, West Nile, yellow fever, tick-borne encephalitis and Japanese encephalitis virus among many others. The disease caused by these viruses can range from febrile illness to hemorrhagic fever and encephalitis. A deeper understanding of the virus life cycle is required to foster development of antivirals and vaccines, which are an urgent need for many flaviviruses, especially dengue. The focus of this review is to summarize our current knowledge of flaviviral replication and assembly, the proteins and lipids involved therein, and how these processes are coordinated for efficient virus production. [ABSTRACT FROM AUTHOR]
- Published
- 2014
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11. Chloropyridinyl Esters of Nonsteroidal Anti-Inflammatory Agents and Related Derivatives as Potent SARS-CoV-2 3CL Protease Inhibitors.
- Author
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Ghosh, Arun K., Shahabi, Dana, Yadav, Monika, Kovela, Satish, Anson, Brandon J., Lendy, Emma K., Bonham, Connie, Sirohi, Devika, Brito-Sierra, Carlos A., Hattori, Shin-ichiro, Kuhn, Richard, Mitsuya, Hiroaki, and Mesecar, Andrew D.
- Subjects
NONSTEROIDAL anti-inflammatory agents ,SARS-CoV-2 ,PROTEASE inhibitors ,ENZYME inhibitors ,NORMAL-phase chromatography ,SALICYLIC acid ,ESTERS ,ESTER derivatives - Abstract
We report the design and synthesis of a series of new 5-chloropyridinyl esters of salicylic acid, ibuprofen, indomethacin, and related aromatic carboxylic acids for evaluation against SARS-CoV-2 3CL protease enzyme. These ester derivatives were synthesized using EDC in the presence of DMAP to provide various esters in good to excellent yields. Compounds are stable and purified by silica gel chromatography and characterized using
1 H-NMR,13 C-NMR, and mass spectral analysis. These synthetic derivatives were evaluated in our in vitro SARS-CoV-2 3CLpro inhibition assay using authentic SARS-CoV-2 3CLpro enzyme. Compounds were also evaluated in our in vitro antiviral assay using quantitative VeroE6 cell-based assay with RNAqPCR. A number of compounds exhibited potent SARS-CoV-2 3CLpro inhibitory activity and antiviral activity. Compound 9a was the most potent inhibitor, with an enzyme IC50 value of 160 nM. Compound 13b exhibited an enzyme IC50 value of 4.9 µM. However, it exhibited a potent antiviral EC50 value of 24 µM in VeroE6 cells. Remdesivir, an RdRp inhibitor, exhibited an antiviral EC50 value of 2.4 µM in the same assay. We assessed the mode of inhibition using mass spectral analysis which suggested the formation of a covalent bond with the enzyme. To obtain molecular insight, we have created a model of compound 9a bound to SARS-CoV-2 3CLpro in the active site. [ABSTRACT FROM AUTHOR]- Published
- 2021
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12. Complementary use of mass spectrometry and cryo-electron microscopy to assess the maturity of live attenuated dengue vaccine viruses.
- Author
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Trauchessec, Mathieu, Lambert, Olivier, Bonnafous, Pierre, Berard, Yves, Barriere, Fabienne, Huillet, Celine, Marco, Sergio, Sirohi, Devika, Hedrick, Victoria, Kuhn, Richard, Guy, Bruno, Ronzon, Frederic, and Manin, Catherine
- Abstract
• Sanofi Pasteur's tetravalent dengue vaccine is composed of four recombinant, live, attenuated vaccines (CYD 1–4). • Potential link between CYD vaccine virus maturity and clinical trial efficacy. • Maturity assessment of four CYD vaccine viruses by mass spectrometry. • Maturity assessment of four CYD vaccine viruses by cryo-electron microscopy. • CYD dengue vaccine viruses lots used in recent phase III efficacy trials, primarily display a mature phenotype. Dengue virus (DENV) infection is a global health threat with the potential to affect at least 3.6 billion people living in areas of risk. No specific curative treatments against dengue disease are available and vaccines are currently the only way to prevent the disease. The tetravalent dengue vaccine developed by Sanofi Pasteur has demonstrated significant efficacy in phase III studies and is now licensed in several countries for the prevention of disease in dengue-seropositives over 9 years of age. The vaccine is composed of four recombinant, live, attenuated vaccines (CYD 1–4) based on a yellow fever vaccine 17D (YFV 17D) backbone, each expressing the pre-membrane (prM) and envelope (E) genes of one of the four DENV serotypes. Virus maturity could impact the biological activity of the vaccine viruses. To address this question, the maturity of the four vaccine viruses used in phase III clinical studies was assessed by two complementary techniques: mass spectrometry (MS) and cryo-electron microscopy (cryoEM). MS assessed viral maturity at the molecular level by quantifying specifically the prM, and M proteins. CryoEM provided information at the particle level, allowing visualizing the different phenotypes of viral particles: spiky (immature), smooth/bumpy (mature), and mixed (partially mature). Results of the two assays used in this study show that all four CYD dengue vaccine viruses present in lots used in phase III efficacy trials, display in the majority a mature phenotype. [ABSTRACT FROM AUTHOR]
- Published
- 2019
- Full Text
- View/download PDF
13. Structural constraints link differences in neutralization potency of human anti-Eastern equine encephalitis virus monoclonal antibodies.
- Author
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Williamson LE, Bandyopadhyay A, Bailey K, Sirohi D, Klose T, Julander JG, Kuhn RJ, and Crowe JE Jr
- Subjects
- Humans, Horses, Animals, Antibodies, Neutralizing, Antibodies, Viral, Cryoelectron Microscopy, Epitopes, Antibodies, Monoclonal, Neutralization Tests, Encephalitis Virus, Eastern Equine, Encephalomyelitis, Equine
- Abstract
Selection and development of monoclonal antibody (mAb) therapeutics against pathogenic viruses depends on certain functional characteristics. Neutralization potency, or the half-maximal inhibitory concentration (IC
50 ) values, is an important characteristic of candidate therapeutic antibodies. Structural insights into the bases of neutralization potency differences between antiviral neutralizing mAbs are lacking. In this report, we present cryo-electron microscopy (EM) reconstructions of three anti-Eastern equine encephalitis virus (EEEV) neutralizing human mAbs targeting overlapping epitopes on the E2 protein, with greater than 20-fold differences in their respective IC50 values. From our structural and biophysical analyses, we identify several constraints that contribute to the observed differences in the neutralization potencies. Cryo-EM reconstructions of EEEV in complex with these Fab fragments reveal structural constraints that dictate intravirion or intervirion cross-linking of glycoprotein spikes by their IgG counterparts as a mechanism of neutralization. Additionally, we describe critical features for the recognition of EEEV by these mAbs including the epitope-paratope interaction surface, occupancy, and kinetic differences in on-rate for binding to the E2 protein. Each constraint contributes to the extent of EEEV inhibition for blockade of virus entry, fusion, and/or egress. These findings provide structural and biophysical insights into the differences in mechanism and neutralization potencies of these antibodies, which help inform rational design principles for candidate vaccines and therapeutic antibodies for all icosahedral viruses.- Published
- 2023
- Full Text
- View/download PDF
14. Can an FDA-Approved Alzheimer's Drug Be Repurposed for Alleviating Neuronal Symptoms of Zika Virus?
- Author
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Sirohi D and Kuhn RJ
- Subjects
- Cell Death, Humans, N-Methylaspartate, Alzheimer Disease, Zika Virus, Zika Virus Infection
- Abstract
Zika virus caught the world by surprise by its rapid spread and frightening disease outcomes. This major epidemic motivated many scientists to focus their attention on controlling this emerging pathogen. As many as 45 vaccine candidates are being developed, but progress in the antiviral arena has been slower. In a recent article (mBio 8:e00350-17, 2017, https://doi.org/10.1128/mBio.00350-17), Costa and colleagues showed that an FDA-approved drug used to treat Alzheimer's disease may moderate Zika virus-induced neuronal damage. This work is based on the premise that overstimulation of N -methyl-d-aspartate receptors (NMDARs) may drive neurodegeneration and that this may be responsible for neuronal cell death associated with Zika virus infection of the central nervous system (CNS). Thus, blockage of the NMDAR channel activity with FDA-approved memantine or other antagonists may reduce neurological complications associated with Zika virus infection. Repurposing a preapproved drug and targeting the host represent intriguing strategies and yet require more analysis prior to moving into clinical trials., (Copyright © 2017 Sirohi and Kuhn.)
- Published
- 2017
- Full Text
- View/download PDF
15. Structure of the immature Zika virus at 9 Å resolution.
- Author
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Prasad VM, Miller AS, Klose T, Sirohi D, Buda G, Jiang W, Kuhn RJ, and Rossmann MG
- Subjects
- Aedes, Animals, Capsid Proteins chemistry, Cell Line, Cryoelectron Microscopy, Glycosylation, Models, Molecular, Protein Processing, Post-Translational, Protein Structure, Quaternary, Virion ultrastructure, Capsid Proteins ultrastructure, Zika Virus ultrastructure
- Abstract
The current Zika virus (ZIKV) epidemic is characterized by severe pathogenicity in both children and adults. Sequence changes in ZIKV since its first isolation are apparent when pre-epidemic strains are compared with those causing the current epidemic. However, the residues that are responsible for ZIKV pathogenicity are largely unknown. Here we report the cryo-electron microscopy (cryo-EM) structure of the immature ZIKV at 9-Å resolution. The cryo-EM map was fitted with the crystal structures of the precursor membrane and envelope glycoproteins and was shown to be similar to the structures of other known immature flaviviruses. However, the immature ZIKV contains a partially ordered capsid protein shell that is less prominent in other immature flaviviruses. Furthermore, six amino acids near the interface between pr domains at the top of the spikes were found to be different between the pre-epidemic and epidemic ZIKV, possibly influencing the composition and structure of the resulting viruses.
- Published
- 2017
- Full Text
- View/download PDF
16. Characterization of the proteome of cytoplasmic lipid droplets in mouse enterocytes after a dietary fat challenge.
- Author
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D'Aquila T, Sirohi D, Grabowski JM, Hedrick VE, Paul LN, Greenberg AS, Kuhn RJ, and Buhman KK
- Subjects
- Animals, Apolipoproteins A metabolism, Carrier Proteins metabolism, Coenzyme A Ligases metabolism, Enterocytes ultrastructure, Lipid Droplets ultrastructure, Lipid Metabolism, Male, Metabolic Networks and Pathways, Mice, Mice, Inbred C57BL, Microscopy, Electron, Transmission, Models, Biological, Perilipin-3, Triglycerides metabolism, Dietary Fats administration & dosage, Enterocytes metabolism, Lipid Droplets metabolism, Proteome metabolism
- Abstract
Dietary fat absorption by the small intestine is a multistep process that regulates the uptake and delivery of essential nutrients and energy. One step of this process is the temporary storage of dietary fat in cytoplasmic lipid droplets (CLDs). The storage and mobilization of dietary fat is thought to be regulated by proteins that associate with the CLD; however, mechanistic details of this process are currently unknown. In this study we analyzed the proteome of CLDs isolated from enterocytes harvested from the small intestine of mice following a dietary fat challenge. In this analysis we identified 181 proteins associated with the CLD fraction, of which 37 are associated with known lipid related metabolic pathways. We confirmed the localization of several of these proteins on or around the CLD through confocal and electron microscopy, including perilipin 3, apolipoprotein A-IV, and acyl-CoA synthetase long-chain family member 5. The identification of the enterocyte CLD proteome provides new insight into potential regulators of CLD metabolism and the process of dietary fat absorption.
- Published
- 2015
- Full Text
- View/download PDF
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