10 results on '"Herbert, Andrew S."'
Search Results
2. Antibodies targeting Crimean-Congo hemorrhagic fever virus GP38 limit vascular leak and viral spread
- Author
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Pahmeier, Felix, primary, Monticelli, Stephanie R., additional, Feng, Xinyi, additional, Hjorth, Christy K., additional, Wang, Albert, additional, Kuehne, Ana I., additional, Bakken, Russell R., additional, Batchelor, Thomas G., additional, Lee, Saeyoung E., additional, Middlecamp, Marissa, additional, Stuart, Lauren, additional, Abelson, Dafna M., additional, McLellan, Jason S., additional, Biering, Scott B., additional, Herbert, Andrew S., additional, Chandran, Kartik, additional, and Harris, Eva, additional
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- 2024
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3. Longitudinal proteome-wide antibody profiling in Marburg virus survivors identifies wing domain immunogen for vaccine design.
- Author
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Khurana, Surender, Grubbs, Gabrielle, Ravichandran, Supriya, Cluff, Emily, Kim, JungHyun, Kuehne, Ana I., Zak, Samantha, Dye, John M., Lutwama, Julius J., and Herbert, Andrew S.
- Subjects
MARBURG virus ,ANTIBODY formation ,VIRUS diseases ,IMMUNOGLOBULIN G ,IMMUNOGLOBULINS ,FC receptors - Abstract
Limited knowledge exists on the quality of polyclonal antibody responses generated following Marburg virus (MARV) infection and its evolution in survivors. In this study, we evaluate MARV proteome-wide antibody repertoire longitudinally in convalescent phase approximately every six months for five years following MARV infection in ten human survivors. Differential kinetics were observed for IgM vs IgG vs IgA epitope diversity, antibody binding, antibody affinity maturation and Fc-receptor interaction to MARV proteins. Durability of MARV-neutralizing antibodies is low in survivors. MARV infection induces a diverse epitope repertoire with predominance against GP, VP40, VP30 and VP24 that persisted up to 5 years post-exposure. However, the IgM and IgA repertoire declines over time. Within MARV-GP, IgG recognize antigenic sites predominantly in the amino-terminus, wing domain and GP2-heptad repeat. Interestingly, MARV infection generates robust durable FcɣRI, FcɣRIIA and FcɣRIIIA IgG-Fc receptor interactions. Immunization with immunodominant MARV epitopes reveals conserved wing region between GP1 and GP2, induces neutralizing antibodies against MARV. These findings demonstrate that MARV infection generates a diverse, long-lasting, non-neutralizing, IgG antibody repertoire that perturbs disease by FcɣR activity. This information, along with discovery of neutralizing immunogen in wing domain, could aid in development of effective therapeutics and vaccines against Marburg virus. One sentence summary: Longitudinal Marburg virus human antibody repertoire There is limited understanding of long-term antibody dynamics after Marburg virus infection. Here, Khurana et al report the antibody responses in Marburg virus disease survivors over five years and identify a conserved immunogen within the virus wing domain that could serve as a target for vaccine design. [ABSTRACT FROM AUTHOR]
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- 2024
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4. Design and characterization of protective pan-ebolavirus and pan-filovirus bispecific antibodies
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Wirchnianski, Ariel S., primary, Nyakatura, Elisabeth K., additional, Herbert, Andrew S., additional, Kuehne, Ana I., additional, Abbasi, Shawn A., additional, Florez, Catalina, additional, Storm, Nadia, additional, McKay, Lindsay G. A., additional, Dailey, Leandrew, additional, Kuang, Erin, additional, Abelson, Dafna M., additional, Wec, Anna Z., additional, Chakraborti, Srinjoy, additional, Holtsberg, Frederick W., additional, Shulenin, Sergey, additional, Bornholdt, Zachary A., additional, Aman, M. Javad, additional, Honko, Anna N., additional, Griffiths, Anthony, additional, Dye, John M., additional, Chandran, Kartik, additional, and Lai, Jonathan R., additional
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- 2024
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5. Crimean-Congo Hemorrhagic Fever Survivors Elicit Protective Non-Neutralizing Antibodies that Target 11 Overlapping Regions on Viral Glycoprotein GP38
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Shin, Olivia S, primary, Monticelli, Stephanie R, additional, Hjorth, Christy K, additional, Hornet, Vladlena, additional, Doyle, Michael, additional, Abelson, Dafna, additional, Kuehne, Ana I, additional, Wang, Albert, additional, Bakken, Russell R, additional, Mishra, Akaash K, additional, Middlecamp, Marissa, additional, Champney, Elizabeth, additional, Stuart, Lauren, additional, Maurer, Daniel P, additional, Li, Jiannan, additional, Berrigan, Jacob L, additional, Balinandi, Stephen, additional, Lutwama, Julius J, additional, Lobel, Leslie, additional, Zeitlin, Larry, additional, Walker, Laura M, additional, Dye, John M, additional, Chandran, Kartik, additional, Herbert, Andrew S, additional, Pauli, Noel T, additional, and McLellan, Jason S, additional
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- 2024
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6. Inflammation in the COVID-19 airway is due to inhibition of CFTR signaling by the SARS-CoV-2 spike protein.
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Caohuy, Hung, Eidelman, Ofer, Chen, Tinghua, Mungunsukh, Ognoon, Yang, Qingfeng, Walton, Nathan I., Pollard, Bette S., Khanal, Sara, Hentschel, Shannon, Florez, Catalina, Herbert, Andrew S., and Pollard, Harvey B.
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CYSTIC fibrosis transmembrane conductance regulator ,CHLORIDE channels ,POST-acute COVID-19 syndrome ,SODIUM channels ,SARS-CoV-2 ,CELL membranes ,AIRWAY (Anatomy) - Abstract
SARS-CoV-2-contributes to sickness and death in COVID-19 patients partly by inducing a hyper-proinflammatory immune response in the host airway. This hyper-proinflammatory state involves activation of signaling by NFκB, and unexpectedly, ENaC, the epithelial sodium channel. Post-infection inflammation may also contribute to "Long COVID"/PASC. Enhanced signaling by NFκB and ENaC also marks the airway of patients suffering from cystic fibrosis, a life-limiting proinflammatory genetic disease due to inactivating mutations in the CFTR gene. We therefore hypothesized that inflammation in the COVID-19 airway might similarly be due to inhibition of CFTR signaling by SARS-CoV-2 spike protein, and therefore activation of both NFκB and ENaC signaling. We used western blot and electrophysiological techniques, and an organoid model of normal airway epithelia, differentiated on an air–liquid-interface (ALI). We found that CFTR protein expression and CFTR cAMP-activated chloride channel activity were lost when the model epithelium was exposed to SARS-CoV-2 spike proteins. As hypothesized, the absence of CFTR led to activation of both TNFα/NFκB signaling and α and γ ENaC. We had previously shown that the cardiac glycoside drugs digoxin, digitoxin and ouabain blocked interaction of spike protein and ACE2. Consistently, addition of 30 nM concentrations of the cardiac glycoside drugs, prevented loss of both CFTR protein and CFTR channel activity. ACE2 and CFTR were found to co-immunoprecipitate in both basal cells and differentiated epithelia. Thus spike-dependent CFTR loss might involve ACE2 as a bridge between Spike and CFTR. In addition, spike exposure to the epithelia resulted in failure of endosomal recycling to return CFTR to the plasma membrane. Thus, failure of CFTR recovery from endosomal recycling might be a mechanism for spike-dependent loss of CFTR. Finally, we found that authentic SARS-CoV-2 virus infection induced loss of CFTR protein, which was rescued by the cardiac glycoside drugs digitoxin and ouabain. Based on experiments with this organoid model of small airway epithelia, and comparisons with 16HBE14o- and other cell types expressing normal CFTR, we predict that inflammation in the COVID-19 airway may be mediated by inhibition of CFTR signaling by the SARS-CoV-2 spike protein, thus inducing a cystic fibrosis-like clinical phenotype. To our knowledge this is the first time COVID-19 airway inflammation has been experimentally traced in normal subjects to a contribution from SARS-CoV-2 spike-dependent inhibition of CFTR signaling. [ABSTRACT FROM AUTHOR]
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- 2024
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7. A Longitudinal Analysis of Memory Immune Responses in Convalescent Crimean-Congo Hemorrhagic Fever Survivors in Uganda.
- Author
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Cohen CA, Balinandi S, Kuehne AI, Rock ML, Bonagofski LG, Ricks KM, Davis I, Abelson D, Stonier SW, Odongo M, Bornholdt ZA, Zeitlin L, Moyer C, Cose S, Dye JM, Lutwama JJ, and Herbert AS
- Abstract
Evaluating the adaptive immune responses to natural infection with Crimean-Congo hemorrhagic fever (CCHF) virus (CCHFV) in human survivors is critical to the development of medical countermeasures. However, the correlates of protection are unknown. As the most prevalent tick-borne human hemorrhagic fever virus with case fatality rates of 5%-30% and worldwide distribution, there is an urgent need to fill these knowledge gaps. Here, we describe adaptive immune responses in a cohort of Ugandan CCHF survivors via serial sampling over 6 years. We demonstrate persistent antibodies after infection and cross-neutralization against various clades of authentic CCHFV, as well as potent effector function. Moreover, we show for the first time persistent, polyfunctional antigen-specific memory T-cell responses to multiple CCHFV proteins up to 9 years after infection. Together, this data provides immunological benchmarks for evaluating CCHFV medical countermeasures and information that can be leveraged toward vaccine immunogen design and viral target identification for monoclonal antibody therapies., Competing Interests: Potential conflicts of interest. All authors: No reported conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (Published by Oxford University Press on behalf of Infectious Diseases Society of America 2024.)
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- 2024
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8. Antibodies targeting Crimean-Congo hemorrhagic fever virus GP38 limit vascular leak and viral spread.
- Author
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Pahmeier F, Monticelli SR, Feng X, Hjorth CK, Wang A, Kuehne AI, Bakken RR, Batchelor TG, Lee SE, Middlecamp M, Stuart L, Abelson DM, McLellan JS, Biering SB, Herbert AS, Chandran K, and Harris E
- Abstract
Crimean-Congo hemorrhagic fever virus (CCHFV) is a priority pathogen transmitted by tick bites, with no vaccines or specific therapeutics approved to date. Severe disease manifestations include hemorrhage, endothelial dysfunction, and multiorgan failure. Infected cells secrete the viral glycoprotein GP38, whose extracellular function is presently unknown. GP38 is considered an important target for vaccine and therapeutic design as GP38-specific antibodies can protect against severe disease in animal models, albeit through a currently unknown mechanism of action. Here, we show that GP38 induces endothelial barrier dysfunction in vitro , and that CCHFV infection, and GP38 alone, can trigger vascular leak in a mouse model. Protective antibodies that recognize specific antigenic sites on GP38, but not a protective neutralizing antibody binding the structural protein Gc, potently inhibit endothelial hyperpermeability in vitro and vascular leak in vivo during CCHFV infection. This work uncovers a function of the secreted viral protein GP38 as a viral toxin in CCHFV pathogenesis and elucidates the mode of action of non-neutralizing GP38-specific antibodies.
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- 2024
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9. Engineering, structure, and immunogenicity of a Crimean-Congo hemorrhagic fever virus pre-fusion heterotrimeric glycoprotein complex.
- Author
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McFadden E, Monticelli SR, Wang A, Ramamohan AR, Batchelor TG, Kuehne AI, Bakken RR, Tse AL, Chandran K, Herbert AS, and McLellan JS
- Abstract
Crimean-Congo hemorrhagic fever virus (CCHFV) is a tick-borne virus that can cause severe disease in humans with case fatality rates of 10-40%. Although structures of CCHFV glycoproteins GP38 and Gc have provided insights into viral entry and defined epitopes of neutralizing and protective antibodies, the structure of glycoprotein Gn and its interactions with GP38 and Gc have remained elusive. Here, we used structure-guided protein engineering to produce a stabilized GP38-Gn-Gc heterotrimeric glycoprotein complex (GP38-Gn
H-DS -Gc). A cryo-EM structure of this complex provides the molecular basis for GP38's association on the viral surface, reveals the structure of Gn, and demonstrates that GP38-Gn restrains the Gc fusion loops in the prefusion conformation, facilitated by an N-linked glycan attached to Gn. Immunization with GP38-GnH-DS -Gc conferred 40% protection against lethal IbAr10200 challenge in mice. These data define the architecture of a GP38-Gn-Gc protomer and provide a template for structure-guided vaccine antigen development., Competing Interests: COMPETING INTERESTS E.M. and J.S.M. are inventors on U.S. patent application no. 63/573,929 (Pre-fusion Stabilized CCHFV GP38-Gn-Gc Glycoprotein Complex). K.C. holds shares in Integrum Scientific, LLC and Eitr Biologics, Inc.- Published
- 2024
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10. Crimean-Congo Hemorrhagic Fever Survivors Elicit Protective Non-Neutralizing Antibodies that Target 11 Overlapping Regions on Viral Glycoprotein GP38.
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Shin OS, Monticelli SR, Hjorth CK, Hornet V, Doyle M, Abelson D, Kuehne AI, Wang A, Bakken RR, Mishra A, Middlecamp M, Champney E, Stuart L, Maurer DP, Li J, Berrigan J, Barajas J, Balinandi S, Lutwama JJ, Lobel L, Zeitlin L, Walker LM, Dye JM, Chandran K, Herbert AS, Pauli NT, and McLellan JS
- Abstract
Crimean-Congo hemorrhagic fever virus can cause lethal disease in humans yet there are no approved medical countermeasures. Viral glycoprotein GP38, unique to Nairoviridae , is a target of protective antibodies, but extensive mapping of the human antibody response to GP38 has not been previously performed. Here, we isolated 188 GP38-specific antibodies from human survivors of infection. Competition experiments showed that these antibodies bind across five distinct antigenic sites, encompassing eleven overlapping regions. Additionally, we reveal structures of GP38 bound with nine of these antibodies targeting different antigenic sites. Although GP38-specific antibodies were non-neutralizing, several antibodies were found to have protection equal to or better than murine antibody 13G8 in two highly stringent rodent models of infection. Together, these data expand our understanding regarding this important viral protein and inform the development of broadly effective CCHFV antibody therapeutics., Competing Interests: DECLARATION OF INTERESTS N.T.P., E.C., and J.L. are employees and shareholders of Adimab, LLC. D.P.M., L.M.W., O.S.S., V.H., and M.D. are shareholders of Adimab.
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- 2024
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