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Browsing by Author "Felgner, Philip L."
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Item Crystal structure of a conformational antibody that binds tau oligomers and inhibits pathological seeding by extracts from donors with Alzheimer's disease(American Society for Biochemistry and Molecular Biology, 2020-07-31) Abskharon, Romany; Seidler, Paul M.; Sawaya, Michael R.; Cascio, Duilio; Yang, Tianxiao P.; Philipp, Stephan; Williams, Christopher Kazu; Newell, Kathy L.; Ghetti, Bernardino; DeTure, Michael A.; Dickson, Dennis W.; Vinters, Harry V.; Felgner, Philip L.; Nakajima, Rie; Glabe, Charles G.; Eisenberg, David S.; Pathology and Laboratory Medicine, School of MedicineSoluble oligomers of aggregated tau accompany the accumulation of insoluble amyloid fibrils, a histological hallmark of Alzheimer disease (AD) and two dozen related neurodegenerative diseases. Both oligomers and fibrils seed the spread of Tau pathology, and by virtue of their low molecular weight and relative solubility, oligomers may be particularly pernicious seeds. Here, we report the formation of in vitro tau oligomers formed by an ionic liquid (IL15). Using IL15-induced recombinant tau oligomers and a dot blot assay, we discovered a mAb (M204) that binds oligomeric tau, but not tau monomers or fibrils. M204 and an engineered single-chain variable fragment (scFv) inhibited seeding by IL15-induced tau oligomers and pathological extracts from donors with AD and chronic traumatic encephalopathy. This finding suggests that M204-scFv targets pathological structures that are formed by tau in neurodegenerative diseases. We found that M204-scFv itself partitions into oligomeric forms that inhibit seeding differently, and crystal structures of the M204-scFv monomer, dimer, and trimer revealed conformational differences that explain differences among these forms in binding and inhibition. The efficiency of M204-scFv antibodies to inhibit the seeding by brain tissue extracts from different donors with tauopathies varied among individuals, indicating the possible existence of distinct amyloid polymorphs. We propose that by binding to oligomers, which are hypothesized to be the earliest seeding-competent species, M204-scFv may have potential as an early-stage diagnostic for AD and tauopathies, and also could guide the development of promising therapeutic antibodies.Item Protein-Specific Features Associated with Variability in Human Antibody Responses to Plasmodium falciparum Malaria Antigens(American Society of Tropical Medicine and Hygiene, 2018-01) Liu, Eugene W.; Skinner, Jeff; Tran, Tuan M.; Kumar, Krishan; Narum, David L.; Jain, Aarti; Ongoiba, Aissata ba; Traoré, Boubacar; Felgner, Philip L.; Crompton, Peter D.; Medicine, School of MedicineThe magnitude of antibody responses varies across the individual proteins that constitute any given microorganism, both in the context of natural infection and vaccination with attenuated or inactivated pathogens. The protein-specific factors underlying this variability are poorly understood. In 267 individuals exposed to intense seasonal malaria, we examined the relationship between immunoglobulin G (IgG) responses to 861 Plasmodium falciparum proteins and specific features of these proteins, including their subcellular location, relative abundance, degree of polymorphism, and whether they are predicted to have human orthologs. We found that IgG reactivity was significantly higher to extracellular and plasma membrane proteins and also correlated positively with both protein abundance and degree of protein polymorphism. Conversely, IgG reactivity was significantly lower to proteins predicted to have human orthologs. These findings provide insight into protein-specific factors that are associated with variability in the magnitude of antibody responses to natural P. falciparum infection-data that could inform vaccine strategies to optimize antibody-mediated immunity as well as the selection of antigens for sero-diagnostic purposes.Item Treatment of Chronic Asymptomatic Plasmodium falciparum Infection Does Not Increase the Risk of Clinical Malaria Upon Reinfection(Oxford, 2017-03) Portugal, Silvia; Tran, Tuan M.; Ongoiba, Aissata; Bathily, Abroudramane; Li, Shanping; Doumbo, Safiatou; Skinner, Jeff; Doumtabe, Didier; Kone, Younoussou; Sangala, Jules; Jain, Aarti; Davies, D. Huw; Hung, Christopher; Liang, Li; Ricklefs, Stacy; Homann, Manijeh Vafa; Felgner, Philip L.; Porcella, Stephen F.; Färnert, Anna; Doumbo, Ogobara K.; Kayentao, Kassoum; Greenwood, Brian M.; Traore, Boubacar; Crompton, Peter D.; Medicine, School of MedicineBackground. Chronic asymptomatic Plasmodium falciparum infections are common in endemic areas and are thought to contribute to the maintenance of malaria immunity. Whether treatment of these infections increases the subsequent risk of clinical episodes of malaria is unclear. Methods. In a 3-year study in Mali, asymptomatic individuals with or without P. falciparum infection at the end of the 6-month dry season were identified by polymerase chain reaction (PCR), and clinical malaria risk was compared during the ensuing 6-month malaria transmission season. At the end of the second dry season, 3 groups of asymptomatic children were identified: (1) children infected with P. falciparum as detected by rapid diagnostic testing (RDT) who were treated with antimalarials (n = 104), (2) RDT-negative children whose untreated P. falciparum infections were detected retrospectively by PCR (n = 55), and (3) uninfected children (RDT/PCR negative) (n = 434). Clinical malaria risk during 2 subsequent malaria seasons was compared. Plasmodium falciparum–specific antibody kinetics during the dry season were compared in children who did or did not harbor asymptomatic P. falciparum infections. Results. Chronic asymptomatic P. falciparum infection predicted decreased clinical malaria risk during the subsequent malaria season(s); treatment of these infections did not alter this reduced risk. Plasmodium falciparum–specific antibodies declined similarly in children who did or did not harbor chronic asymptomatic P. falciparum infection during the dry season. Conclusions. These findings challenge the notion that chronic asymptomatic P. falciparum infection maintains malaria immunity and suggest that mass drug administration during the dry season should not increase the subsequent risk of clinical malaria.