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Principal Investigator: Gabriel D Victora
Organization: ROCKEFELLER UNIVERSITY
Fiscal Year: 2024
Award: $812,354
Funding agency: National Institute of Allergy and Infectious Diseases
PROJECT SUMMARY
Germinal centers (GCs) are the site of affinity maturation, a prototypical Darwinian process that is required to
generate the potent antibodies that protect against infectious disease. Over the past decades, work by several
groups, including our own, has led to a comprehensive general understanding of the cellular and molecular
mechanisms that drive evolution in the GC. However, this mechanistic understanding has yet to reach sufficient
granularity to allow for accurate prediction of the outcomes of GC evolution and efficient guidance of GC B cells
along predetermined mutational trajectories. Several population-level phenomena observed in GCs remain
poorly understood, including the apparent stochasticity of “clonal bursts,” proliferative sprees in which the entire
GC is taken over by the descendants of a single cell in a matter of a few days, the continuous presence of B
cells with low affinities in GCs even at late stages of the reaction, and the apparent inability of GCs to find certain
somatic mutations despite their benefit in terms of affinity. Greater understanding of these apparently aberrant
evolutionary pathways may improve our ability to predict and potentially control the output of the GC reaction. In
this application, we develop a full toolset consisting of a mouse monoclonal for Ig genes encoding an antibody
to a classic protein antigen, a deep mutational scan (DMS) experiment in which the effects on affinity of every
possible mutation in both chains of this Ig are measured experimentally, and a computational framework that
allows us to assign affinities to any Ig sequence that we recover from these monoclonal GC B cells. We will use
these tools to conduct replicated evolution experiments on hundreds of GCs, reconstructing the evolutionary
paths and affinities of thousands of B cells in the course of GC maturation. We propose to use this approach to
gain insight into how B cell evolution plays out within GCs in vivo, focusing on the interplay between
reproducibility and stochasticity in evolution. Understanding such evolutionary aspects will be important for the
field’s efforts to guide B cell clones through defined affinity maturation trajectories through vaccination.
Terms: <AICDA><AICDA protein><AID gene><AID protein><AIDS Virus><Ab-mediated immunity><Ab-mediated protection><Acquired Immune Deficiency Syndrome Virus><Acquired Immunodeficiency Syndrome Virus><Affinity><Allergy><Amino Acid Substitution><Antibodies><Antibody immunity><Antibody protection><Antibody-mediated protection><Antigenic Determinants><Antigens><Autoimmune Diseases><B blood cells><B cell><B cell receptor><B cells><B-Cell Antigen Receptor><B-Cells><B-Lymphocytes><B-cell><Basic Research><Basic Science><Binding Determinants><Biological><CDA2 protein><COVID-19 vaccination><Cell Body><Cell Lineage><Cells><Chickens><Clone Cells><Communicable Diseases><Complex><Coupling><DNA><Deoxyribonucleic Acid><Elements><Enzyme Activation><Epitopes><Evolution><Feedback><GC1><GW112><Gallus domesticus><Gallus gallus><Gallus gallus domesticus><Genetic Alteration><Genetic Change><Genetic defect><Germinal Center><Goals><Grippe><HIV><Hand><Human Immunodeficiency Viruses><Hypersensitivity><Ig Genes><Ig Somatic Hypermutation><IgY><Immune Globulins><Immunoglobulin Genes><Immunoglobulin Somatic Hypermutation><Immunoglobulins><Individual><Infection Control><Infectious Disease Pathway><Infectious Diseases><Infectious Disorder><Influenza><Influenza HA><Influenza Hemagglutinin><Knowledge><LAV-HTLV-III><Laboratories><Lesion><Lymphadenopathy-Associated Virus><Measures><Methodology><Methods><Mice><Mice Mammals><Modeling><Modification><Molecular><Murine><Mus><Mutation><OLFM4><OLFM4 gene><Olfactomedin 4><Outcome><Output><Pathway interactions><Pattern><Play><Population><Position><Positioning Attribute><Process><Property><Proteins><Reaction><Reproducibility><SARS-CoV-2 vaccination><Severe acute respiratory syndrome coronavirus 2 vaccination><Shapes><Site><Somatic Mutation><Structure of germinal center of lymph node><System><Techniques><Time><Vaccination><Virus-HIV><Work><Yeasts><activation-induced cytidine deaminase><activation-induced deaminase><antibody-mediated immunity><antigen binding><antigen bound><autoimmune condition><autoimmune disorder><autoimmunity disease><biologic><computational framework><computer framework><coronavirus disease 2019 vaccination><experiment><experimental research><experimental study><experiments><fitness><flu HA><flu hemagglutinin><genome mutation><hands><immunogen><immunoglobulin Y><improved><in vivo><influenza viral HA><influenza viral hemagglutinin><influenza virus HA><influenza virus hemagglutinin><insight><mutation scanning><mutation screening><outcome prediction><pathogen><pathway><permissiveness><repair><repaired><somatic hypermutation><somatic variant><tool><vaccinate against COVID-19><vaccinate against SARS-CoV-2><vaccinate against coronavirus disease 2019><vaccinate against severe acute respiratory syndrome coronavirus 2><vaccination against COVID-19><vaccination against SARS-CoV-2><vaccination against Severe acute respiratory syndrome coronavirus 2><vaccination against coronavirus disease 2019>