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1. The NF-κB Transcriptional Footprint Is Essential for SARS-CoV-2 Replication

Author

Nilsson-Payant, Benjamin E., primary, Uhl, Skyler, additional, Grimont, Adrien, additional, Doane, Ashley S., additional, Cohen, Phillip, additional, Patel, Roosheel S., additional, Higgins, Christina A., additional, Acklin, Joshua A., additional, Bram, Yaron, additional, Chandar, Vasuretha, additional, Blanco-Melo, Daniel, additional, Panis, Maryline, additional, Lim, Jean K., additional, Elemento, Olivier, additional, Schwartz, Robert E., additional, Rosenberg, Brad R., additional, Chandwani, Rohit, additional, and tenOever, Benjamin R., additional

Published
2021
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2. Quantifying Absolute Neutralization Titers against SARS-CoV-2 by a Standardized Virus Neutralization Assay Allows for Cross-Cohort Comparisons of COVID-19 Sera

Author

Oguntuyo, Kasopefoluwa, Stevens, Christian S., Hung, Chuan Tien, Ikegame, Satoshi, Acklin, Joshua A., Kowdle, Shreyas S., Carmichael, Jillian C., Chiu, Hsin Ping, Azarm, Kristopher D., Haas, Griffin D., Amanat, Fatima, Klingler, Jéromine, Baine, Ian, Arinsburg, Suzanne, Bandres, Juan C., Siddiquey, Mohammed N. A., Schilke, Robert M., Woolard, Matthew D., Zhang, Hongbo, Duty, Andrew J., Kraus, Thomas A., Moran, Thomas M., Tortorella, Domenico, Lim, Jean K., Gamarnik, Andrea Vanesa, Hioe, Catarina E., Zolla Pazner, Susan, Ivanov, Stanimir S., Kamil, Jeremy, Krammer, Florian, Lee, Benhur, Ojeda, Diego Sebastian, González López Ledesma, María Mora, Costa Navarro, Guadalupe Soledad, Pallarés, H. M., Sanchez, Lautaro Nicolas, Perez, P., Ostrowsk, M., Villordo, S. M., Alvarez, D. E., Caramelo, J. J., Carradori, J., and Yanovsky, M. J.

Subjects
viral neutralization assay, medicine.drug_class, Enzyme-Linked Immunosorbent Assay, SARS-COV-2, Monoclonal antibody, Antibodies, Viral, Microbiology, Virus, Neutralization, Article, NEUTRALIZING ANTIBODIES, purl.org/becyt/ford/1 [https], 03 medical and health sciences, 0302 clinical medicine, Viral entry, Neutralization Tests, Virology, Biosafety level, Potency, Medicine, Humans, neutralizing antibodies, 030212 general & internal medicine, purl.org/becyt/ford/1.6 [https], Neutralizing antibody, 030304 developmental biology, convalescent-phase plasma, 0303 health sciences, biology, business.industry, SARS-CoV-2, fungi, COVID-19, VIRAL NEUTRALIZATION ASSAY, Gold standard (test), biology.organism_classification, Antibodies, Neutralizing, QR1-502, body regions, Titer, Vesicular stomatitis virus, biology.protein, Antibody, business, CONVALESCENT-PHASE PLASMA, Research Article
Abstract

The global coronavirus disease 2019 (COVID-19) pandemic has mobilized efforts to develop vaccines and antibody-based therapeutics, including convalescent-phase plasma therapy, that inhibit viral entry by inducing or transferring neutralizing antibodies (nAbs) against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike glycoprotein (CoV2-S). However, rigorous efficacy testing requires extensive screening with live virus under onerous biosafety level 3 (BSL3) conditions, which limits high-throughput screening of patient and vaccine sera. Myriad BSL2-compatible surrogate virus neutralization assays (VNAs) have been developed to overcome this barrier. Yet, there is marked variability between VNAs and how their results are presented, making intergroup comparisons difficult. To address these limitations, we developed a standardized VNA using CoV2-S pseudotyped particles (CoV2pp) based on vesicular stomatitis virus bearing the Renilla luciferase gene in place of its G glyco-protein (VSVDG); this assay can be robustly produced at scale and generate accurate neutralizing titers within 18 h postinfection. Our standardized CoV2pp VNA showed a strong positive correlation with CoV2-S enzyme-linked immunosorbent assay (ELISA) results and live-virus neutralizations in confirmed convalescent-patient sera. Three independent groups subsequently validated our standardized CoV2pp VNA (n . 120). Our data (i) show that absolute 50% inhibitory concentration (absIC50), absIC80, and absIC90 values can be legitimately compared across diverse cohorts, (ii) highlight the substantial but consistent variability in neutralization potency across these cohorts, and (iii) support the use of the absIC80 as a more meaningful metric for assessing the neutralization potency of a vaccine or convalescent-phase sera. Lastly, we used our CoV2pp in a screen to identify ultrapermissive 293T clones that stably express ACE2 or ACE2 plus TMPRSS2. When these are used in combination with our CoV2pp, we can produce CoV2pp sufficient for 150,000 standardized VNAs/week. IMPORTANCE Vaccines and antibody-based therapeutics like convalescent-phase plasma therapy are premised upon inducing or transferring neutralizing antibodies that inhibit SARS-CoV-2 entry into cells. Virus neutralization assays (VNAs) for measuring neutralizing antibody titers (NATs) are an essential part of determining vaccine or therapeutic efficacy. However, such efficacy testing is limited by the inherent dangers of working with the live virus, which requires specialized high-level biocontainment facilities. We there-fore developed a standardized replication-defective pseudotyped particle system that mimics the entry of live SARS-CoV-2. This tool allows for the safe and efficient measurement of NATs, determination of other forms of entry inhibition, and thorough investigation of virus entry mechanisms. Four independent labs across the globe validated our standardized VNA using diverse cohorts. We argue that a standardized and scalable assay is necessary for meaningful comparisons of the myriad of vaccines and antibody-based therapeutics becoming available. Our data provide generalizable metrics for assessing their efficacy. Fil: Oguntuyo, Kasopefoluwa. Icahn School of Medicine at Mount Sinai; Estados Unidos Fil: Stevens, Christian S.. Icahn School of Medicine at Mount Sinai; Estados Unidos Fil: Hung, Chuan Tien. Icahn School of Medicine at Mount Sinai; Estados Unidos Fil: Ikegame, Satoshi. Icahn School of Medicine at Mount Sinai; Estados Unidos Fil: Acklin, Joshua A.. Icahn School of Medicine at Mount Sinai; Estados Unidos Fil: Kowdle, Shreyas S.. Icahn School of Medicine at Mount Sinai; Estados Unidos Fil: Carmichael, Jillian C.. Icahn School of Medicine at Mount Sinai; Estados Unidos Fil: Chiu, Hsin Ping. Icahn School of Medicine at Mount Sinai; Estados Unidos Fil: Azarm, Kristopher D.. Icahn School of Medicine at Mount Sinai; Estados Unidos Fil: Haas, Griffin D.. Icahn School of Medicine at Mount Sinai; Estados Unidos Fil: Amanat, Fatima. Icahn School of Medicine at Mount Sinai; Estados Unidos Fil: Klingler, Jéromine. Icahn School of Medicine at Mount Sinai; Estados Unidos Fil: Baine, Ian. Icahn School of Medicine at Mount Sinai; Estados Unidos Fil: Arinsburg, Suzanne. Icahn School of Medicine at Mount Sinai; Estados Unidos Fil: Bandres, Juan C.. Icahn School of Medicine at Mount Sinai; Estados Unidos Fil: Siddiquey, Mohammed N. A.. Icahn School of Medicine at Mount Sinai; Estados Unidos Fil: Schilke, Robert M.. Icahn School of Medicine at Mount Sinai; Estados Unidos Fil: Woolard, Matthew D.. State University of Louisiana; Estados Unidos Fil: Zhang, Hongbo. State University of Louisiana; Estados Unidos Fil: Duty, Andrew J.. Icahn School of Medicine at Mount Sinai; Estados Unidos Fil: Kraus, Thomas A.. Icahn School of Medicine at Mount Sinai; Estados Unidos Fil: Moran, Thomas M.. Icahn School of Medicine at Mount Sinai; Estados Unidos Fil: Tortorella, Domenico. Icahn School of Medicine at Mount Sinai; Estados Unidos Fil: Lim, Jean K.. Icahn School of Medicine at Mount Sinai; Estados Unidos Fil: Gamarnik, Andrea Vanesa. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina. Icahn School of Medicine at Mount Sinai; Estados Unidos Fil: Hioe, Catarina E.. Icahn School of Medicine at Mount Sinai; Estados Unidos Fil: Zolla Pazner, Susan. Icahn School of Medicine at Mount Sinai; Estados Unidos Fil: Ivanov, Stanimir S.. State University of Louisiana; Estados Unidos Fil: Kamil, Jeremy. State University of Louisiana; Estados Unidos Fil: Krammer, Florian. Icahn School of Medicine at Mount Sinai; Estados Unidos Fil: Lee, Benhur. Icahn School of Medicine at Mount Sinai; Estados Unidos Fil: Ojeda, Diego Sebastian. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas en Retrovirus y Sida. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas en Retrovirus y Sida; Argentina Fil: González López Ledesma, María Mora. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina Fil: Costa Navarro, Guadalupe Soledad. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina Fil: Pallarés, H. M.. No especifíca; Fil: Sanchez, Lautaro Nicolas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina Fil: Perez, P.. No especifíca; Fil: Ostrowsk, M.. No especifíca; Fil: Villordo, S. M.. No especifíca; Fil: Alvarez, D. E.. No especifíca; Fil: Caramelo, J. J.. No especifíca; Fil: Carradori, J.. No especifíca; Fil: Yanovsky, M. J.. No especifíca

Published
2021
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3. Human Monoclonal Antibodies Potently Neutralize Zika Virus and Select for Escape Mutations on the Lateral Ridge of the Envelope Protein

Author

Bailey, Mark J., primary, Broecker, Felix, additional, Freyn, Alec W., additional, Choi, Angela, additional, Brown, Julia A., additional, Fedorova, Nadia, additional, Simon, Viviana, additional, Lim, Jean K., additional, Evans, Matthew J., additional, García-Sastre, Adolfo, additional, Palese, Peter, additional, and Tan, Gene S., additional

Published
2019
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5. P2X Antagonists Inhibit HIV-1 Productive Infection and Inflammatory Cytokines Interleukin-10 (IL-10) and IL-1β in a Human Tonsil Explant Model

Author

Soare, Alexandra Y., primary, Durham, Natasha D., additional, Gopal, Ramya, additional, Tweel, Benjamin, additional, Hoffman, Kevin W., additional, Brown, Julia A., additional, O’Brien, Megan, additional, Bhardwaj, Nina, additional, Lim, Jean K., additional, Chen, Benjamin K., additional, and Swartz, Talia H., additional

Published
2019
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6. Tick-Borne Encephalitis Virus Vaccine-Induced Human Antibodies Mediate Negligible Enhancement of Zika Virus Infection In Vitro and in a Mouse Model

Author

Duehr, James, primary, Lee, Silviana, additional, Singh, Gursewak, additional, Foster, Gregory A., additional, Krysztof, David, additional, Stramer, Susan L., additional, Bermúdez González, Maria C., additional, Menichetti, Eva, additional, Geretschläger, Robert, additional, Gabriel, Christian, additional, Simon, Viviana, additional, Lim, Jean K., additional, and Krammer, Florian, additional

Published
2018
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7. Disruption of the Opal Stop Codon Attenuates Chikungunya Virus-Induced Arthritis and Pathology

Author

Jones, Jennifer E., primary, Long, Kristin M., additional, Whitmore, Alan C., additional, Sanders, Wes, additional, Thurlow, Lance R., additional, Brown, Julia A., additional, Morrison, Clayton R., additional, Vincent, Heather, additional, Peck, Kayla M., additional, Browning, Christian, additional, Moorman, Nathaniel, additional, Lim, Jean K., additional, and Heise, Mark T., additional

Published
2017
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13. The NF-k B Transcriptional Footprint Is Essential for SARS-CoV-2 Replication.

Author

Nilsson-Payant, Benjamin E., Uhl, Skyler, Grimont, Adrien, Doane, Ashley S., Cohen, Phillip, Patel, Roosheel S., Higgins, Christina A., Acklin, Joshua A., Bram, Yaron, Chandar, Vasuretha, Blanco-Melo, Daniel, Panis, Maryline, Lim, Jean K., Elemento, Olivier, Schwartz, Robert E., Rosenberg, Brad R., Chandwani, Rohit, and tenOever, Benjamin R.

Subjects
*SARS-CoV-2, *TYPE I interferons, *COVID-19 pandemic, *VACCINE effectiveness, *COVID-19
Abstract

SARS-CoV-2, the etiological agent of COVID-19, is characterized by a delay in type I interferon (IFN-I)-mediated antiviral defenses alongside robust cytokine production. Here, we investigate the underlying molecular basis for this imbalance and implicate virus-mediated activation of NF-k B in the absence of other canonical IFN-I-related transcription factors. Epigenetic and single-cell transcriptomic analyses show a selective NF-k B signature that was most prominent in infected cells. Disruption of NF-k B signaling through the silencing of the NF-k B transcription factor p65 or p50 resulted in loss of virus replication that was rescued upon reconstitution. These findings could be further corroborated with the use of NF-k B inhibitors, which reduced SARS-CoV-2 replication in vitro. These data suggest that the robust cytokine production in response to SARS-CoV-2, despite a diminished IFN-I response, is the product of a dependency on NF-k B for viral replication. IMPORTANCE The COVID-19 pandemic has caused significant mortality and morbidity around the world. Although effective vaccines have been developed, large parts of the world remain unvaccinated while new SARS-CoV-2 variants keep emerging. Furthermore, despite extensive efforts and large-scale drug screenings, no fully effective antiviral treatment options have been discovered yet. Therefore, it is of the utmost importance to gain a better understanding of essential factors driving SARS-CoV-2 replication to be able to develop novel approaches to target SARS-CoV-2 biology. [ABSTRACT FROM AUTHOR]

Published
2021
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14. P2X Antagonists Inhibit HIV-1 Productive Infection and Inflammatory Cytokines Interleukin-10 (IL-10) and IL-1β in a Human Tonsil Explant Model.

Author

Soare AY, Durham ND, Gopal R, Tweel B, Hoffman KW, Brown JA, O'Brien M, Bhardwaj N, Lim JK, Chen BK, and Swartz TH

Subjects
Benzenesulfonates pharmacology, Down-Regulation, Gene Expression Regulation, HIV Infections drug therapy, HIV-1 drug effects, HIV-1 immunology, Humans, Models, Biological, Palatine Tonsil drug effects, Palatine Tonsil immunology, Palatine Tonsil virology, Pyridines pharmacology, Tetrazoles pharmacology, Tissue Culture Techniques, Virulence drug effects, Zidovudine pharmacology, HIV Infections immunology, HIV-1 pathogenicity, Interleukin-10 metabolism, Interleukin-1beta metabolism, Palatine Tonsil cytology, Purinergic P2X Receptor Antagonists pharmacology
Abstract

HIV-1 causes a persistent infection of the immune system that is associated with chronic comorbidities. The mechanisms that underlie this inflammation are poorly understood. Emerging literature has implicated proinflammatory purinergic receptors and downstream signaling mediators in HIV-1 infection. This study probed whether inhibitors of purinergic receptors would reduce HIV-1 infection and HIV-1-stimulated inflammation. An ex vivo human tonsil histoculture infection model was developed to support HIV-1 productive infection and stimulated the inflammatory cytokine interleukin-1 beta (IL-1β) and the immunosuppressive cytokine interleukin-10 (IL-10). This study tests whether inhibitors of purinergic receptors would reduce HIV-1 infection and HIV-1-stimulated inflammation. The purinergic P2X1 receptor antagonist NF449, the purinergic P2X7 receptor antagonist A438079, and azidothymidine (AZT) were tested in HIV-1-infected human tonsil explants to compare levels of inhibition of HIV-1 infection and HIV-stimulated inflammatory cytokine production. All drugs limited HIV-1 productive infection, but P2X-selective antagonists (NF449 and A438079) significantly lowered HIV-stimulated IL-10 and IL-1β. We further observed that P2X1- and P2X7-selective antagonists can act differentially as inhibitors of both HIV-1 infection and HIV-1-stimulated inflammation. Our findings highlight the differential effects of HIV-1 on inflammation in peripheral blood compared to those in lymphoid tissue. For the first time, we demonstrate that P2X-selective antagonists act differentially as inhibitors of both HIV-1 infection and HIV-1-stimulated inflammation. Drugs that block these pathways can have independent inhibitory activities against HIV-1 infection and HIV-induced inflammation. IMPORTANCE Patients who are chronically infected with HIV-1 experience sequelae related to chronic inflammation. The mechanisms of this inflammation have not been elucidated. Here, we describe a class of drugs that target the P2X proinflammatory signaling receptors in a human tonsil explant model. This model highlights differences in HIV-1 stimulation of lymphoid tissue inflammation and peripheral blood. These drugs serve to block both HIV-1 infection and production of IL-10 and IL-1β in lymphoid tissue, suggesting a novel approach to HIV-1 therapeutics in which both HIV-1 replication and inflammatory signaling are simultaneously targeted., (Copyright © 2018 American Society for Microbiology.)

Published
2018
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15. CX3CR1 is dispensable for control of mucosal Candida albicans infections in mice and humans.

Author

Break TJ, Jaeger M, Solis NV, Filler SG, Rodriguez CA, Lim JK, Lee CC, Sobel JD, Netea MG, and Lionakis MS

Subjects
Alleles, Animals, CX3C Chemokine Receptor 1, Candidiasis genetics, Candidiasis microbiology, Candidiasis, Vulvovaginal genetics, Candidiasis, Vulvovaginal microbiology, Disease Models, Animal, Female, Gastrointestinal Tract immunology, Gastrointestinal Tract microbiology, Gene Expression, Host-Pathogen Interactions, Humans, Interleukin-17 genetics, Interleukin-17 immunology, Interleukin-23 genetics, Interleukin-23 immunology, Interleukins genetics, Interleukins immunology, Mice, Mice, Inbred C57BL, Mice, Knockout, Opportunistic Infections genetics, Opportunistic Infections microbiology, Receptors, Chemokine deficiency, Receptors, Chemokine genetics, Tongue immunology, Tongue microbiology, Vagina immunology, Vagina microbiology, Interleukin-22, Candida albicans immunology, Candidiasis immunology, Candidiasis, Vulvovaginal immunology, Opportunistic Infections immunology, Receptors, Chemokine immunology
Abstract

Candida albicans is part of the normal commensal microbiota of mucosal surfaces in a large percentage of the human population. However, perturbations of the host's immune response or bacterial microbiota have been shown to predispose individuals to the development of opportunistic Candida infections. It was recently discovered that a defect in the chemokine receptor CX3CR1 increases susceptibility of mice and humans to systemic candidiasis. However, whether CX3CR1 confers protection against mucosal C. albicans infection has not been investigated. Using two different mouse models, we found that Cx3cr1 is dispensable for the induction of interleukin 17A (IL-17A), IL-22, and IL-23 in the tongue after infection, as well as for the clearance of mucosal candidiasis from the tongue or lower gastrointestinal (GI) tract colonization. Furthermore, the dysfunctional human CX3CR1 allele CX3CR1-M280 was not associated with development of recurrent vulvovaginal candidiasis (RVVC) in women. Taken together, these data indicate that CX3CR1 is not essential for protection of the host against mucosal candidiasis, underscoring the dependence on different mammalian immune factors for control of mucosal versus systemic Candida infections., (Copyright © 2015, American Society for Microbiology. All Rights Reserved.)

Published
2015
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