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Principal Investigator: Michael S Diamond
Organization: WASHINGTON UNIVERSITY
Fiscal Year: 2022
Award: $950,300
Funding agency: National Institute of Allergy and Infectious Diseases
PROJET SUMMARY/ABSTRACT
Globally, the four serotypes of DENV cause an estimated 390 million new cases of dengue fever and 500,000
cases of dengue hemorrhagic fever (DHF) per year. Zika virus (ZIKV) is a related emerging virus linked to
Guillain-Barre syndrome in adults, and microcephaly, congenital malformations, and spontaneous abortion of
the fetus during pregnancy. Currently, no antiviral therapy is available for either virus. In the first two cycles of
this collaborative and inter-disciplinary R01, we developed panels of monoclonal antibodies (Abs) against the E
proteins of all four DENV serotypes and analyzed their structural, biophysical, and cellular mechanisms of
neutralization. These studies defined novel epitopes on DENV E proteins recognized by inhibitory Abs, some
of which are not solvent-accessible according to existing atomic models of the virus particle. We also defined
the dynamic state of DENV and related flaviviruses, determined the atomic structure of mature and immature
ZIKV, characterized atomic interactions between DENV and ZIKV virions, E protein, and new highly
neutralizing mouse and human Abs, and identified how different maturation states influence epitope
accessibility and Ab neutralization. Our studies revealed that flavivirus structure is more complex than
anticipated and is likely a heterogeneous and dynamic ensemble of different states, each of which may interact
differentially with Abs. In this renewal, our collaborative and inter-disciplinary team hopes to gain insight into
questions about the antigenicity of flavivirus virions and subviral particles (SVPs) as well as the cross-reactivity
that limits vaccine and diagnostic development and may affect pathogenesis. Our group will define new states
of DENV and ZIKV particle structure and determine how these states influence epitope exposure and
interaction with specific neutralizing Abs available in our laboratories. We also will compare the atomic
structure of SVPs with infectious virions, determine how these differences affect binding and induction of
neutralization Abs, and characterize further the structural basis of cross-reactivity of DENV and ZIKV. Our
studies may facilitate the generation of novel antigens and immunogens with improved capacity to detect and
elicit specific protective Ab responses against DENV, ZIKV, and likely other emerging flaviviruses.
Terms: <21+ years old><AIDP><Acute Autoimmune Neuropathy><Acute Infective Polyneuritis><Acute Inflammatory Demyelinating Polyradiculoneuropathy><Acute Inflammatory Polyneuropathy><Acute Inflammatory Polyradiculoneuropathy><Adult><Adult Human><Affect><Amino Acids><Antibodies><Antibody Response><Antigenic Determinants><Antigens><Antiviral Therapy><Binding><Binding Determinants><Biophysics><Birth Defects><Breakbone Fever Virus><Circulatory Collapse><Clinical Treatment Moab><Complex><Congenital Abnormality><Congenital Anatomic Abnormality><Congenital Anatomical Abnormality><Congenital Defects><Congenital Deformity><Congenital Malformation><Country><Cryo-electron Microscopy><Cryo-electron tomography><Cryoelectron Microscopy><DENV infection><DENV vaccine><Dengue Fever><Dengue Hemorrhagic Fever><Dengue Infection><Dengue Vaccine><Dengue Virus><Dengue disease><Dengue fever virus><Dengue virus infection><Dengue virus vaccine><Dengvaxia><Development><Diagnosis><Diagnostic><Diagnostic Reagent><Diamond><E protein><Electron Cryomicroscopy><Encapsulated><Engineering><Epitopes><Exposure to><Fetus><Flavivirus><Gene variant><Generations><Genes><Genetic Alteration><Genetic Change><Genetic defect><Genetics-Mutagenesis><Gestation><Goals><Group B Arbovirus><Guillain Barré Syndrome><Guillaine-Barre Syndrome><Hu-mABs><Human><Immune><Immunes><Immunization><Immunize><Immunologic Sensitization><Immunologic Stimulation><Immunological Sensitization><Immunological Stimulation><Immunostimulation><Individual><Infection><Laboratories><Landry's paralysis><Landry-Guillain-Barre Syndrome><Life><Link><M protein><Mediating><Messenger RNA><Mice><Mice Mammals><Microcephaly><Miscarriage><Modeling><Modern Man><Molecular Configuration><Molecular Conformation><Molecular Interaction><Molecular Stereochemistry><Monitor><Monoclonal Antibodies><Murine><Mus><Mutagenesis><Mutagenesis Molecular Biology><Mutate><Mutation><Paper><Pathogenesis><Pathogenicity><Pregnancy><Publishing><Role><Sampling><Serology><Serotyping><Shock><Spontaneous abortion><Structural Protein><Structure><Syndrome><Temperature><Therapeutic antibodies><Translating><Vaccination><Vaccines><Variant><Variation><Viral><Viral Genetics><Virion><Virus><Virus Particle><ZIKV><ZIKV vaccine><Zika Virus><Zika vaccine><Zika virus vaccine><acute idiopathic polyneuritis><acute post-infectious polyneuropathy><acute postinfectious polyneuropathy><adulthood><allele variant><allelic variant><aminoacid><anti-viral therapy><atomic interactions><base><biophysical approaches><biophysical foundation><biophysical methodology><biophysical methods><biophysical principles><biophysical sciences><biophysical techniques><breakbone fever><circulatory shock><conformation><conformational state><cross reactivity><cryo-EM><cryo-EM tomography><cryoEM><cryoEM tomography><cryoelectron tomography><dengue viral infection><develop a vaccine><develop vaccines><development of a vaccine><developmental><electron cryo-tomography><genetic variant><genome mutation><genomic variant><humAbs><human mAbs><human monoclonal antibodies><human monoclonals><immunogen><immunogenicity><improved><in vivo><insight><lipid based nanoparticle><lipid nanoparticle><mAbs><mRNA><micrencephaly><microencephaly><multiple myeloma M Protein><mutant><neutralizing antibody><novel><particle><polyclonal antibody><response><social role><vaccine antibodies><vaccine candidate><vaccine development><vaccine induced antibodies><vaccine-induced antibodies><viral infectious disease treatment><virus genetics><zikav>