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Principal Investigator: GEORGE Georgiou GEORGIOU
Organization: WASHINGTON UNIVERSITY
Fiscal Year: 2024
Award: $359,802
Funding agency: National Institute of Allergy and Infectious Diseases
ABSTRACT – CORE C
Core C will be responsible for the in-depth determination of the molecular composition, temporal dynamics and
functional properties of the antibodies that comprise the polyclonal response to influenza HA or to SARS-CoV2
S in peripheral blood and in the respiratory track, following infection or vaccination. Core C will also perform the
comprehensive sequencing and functional analyses of the natively paired VH:VL BCR repertoire encoded by B
cell subsets of interest from peripheral blood, lymph node FNA, bone marrow aspirates and from respiratory
track specimens. Both the IgG and the IgA serological and BCR repertoires will be determined and compared.
Furthermore, we will analyze the immunoglobulin subclass repertoires. The studies by Core C will be enabled
by a set of technologies developed by the UT Austin team, namely Ig-Seq: bottom-up high resolution LC-MS/MS
based identification and quantification of antigen-specific circulating antibodies: BCR-Seq:very high throughput
sequencing of natively paired VH and VL cDNA from single B cells and HuRep: extensive functional analysis of
the B cell encoded repertoire displayed on yeast. Core C, together with Projects 1 and 2, will seek to address
a plethora of key questions on the humoral responses to infection by respiratory pathogens and also following
vaccination, including: (i) How does the sequence and functional diversity of the peripheral blood antibody
repertoire compares to those of respiratory track antibodies? (ii) What fraction of the mucosal antibodies develop
locally and are produced by tissue resident plasma cells versus being produced at other anatomical locations
and then exported to the respiratory track following transcytosis from peripheral blood? (iii) What is the temporal
persistence of individual IgG/IgA antibody clones in the respiratory track? (iv) To what extent does the
concentration of individual IgG antibodies in peripheral blood correlates with their level in the mucosa following
transcytosis via FcRn? Also, a related question is whether there exist abundant centrally produced antibodies
that are not found in the respiratory track, either because of poor transepithelial export or enhanced mucosal
elimination (e.g. due to proteolysis). (v) How do B cell clonal expansions in peripheral blood, lymph node
aspirates and in the bone marrow correlate with the concentration of the respective antibody in circulation and
in BALF? Finally, (iv) very importantly, together with Project 1 we will delineate the binding and neutralization
breadth of the dominant anti-HA or anti-SARS-CoV2 antibodies in circulation and in the respiratory track.
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substance><Location><Lung Lavage><Lymph Node Reticuloendothelial System><Lymph node proper><Lymphatic nodes><Maps><Memory B Cell><Memory B-Lymphocyte><Methodology><Modern Man><Molecular><Molecular Interaction><Mucosa><Mucosal Tissue><Mucous Membrane><Peptide/Protein Chemistry><Peptides><Photoradiation><Physiologic><Physiological><Plasma><Plasma Cells><Plasma Serum><Plasmablast><Plasmacytes><Population><Property><Protein Chemistry><Protein Cleavage><Protein Engineering><Proteins><Proteolysis><Proteomics><Pulmonary Body System><Pulmonary Organ System><Recombinants><Research Specimen><Resolution><Respiratory Infections><Respiratory System><Respiratory Tract Infections><Respiratory Tracts><Respiratory tract structure><Reticuloendothelial System, Serum, Plasma><Role><SARS-CoV-2 S><SARS-CoV-2 S protein><SARS-CoV-2 antibody><SARS-CoV-2 spike><SARS-CoV-2 spike glycoprotein><SARS-CoV-2 spike protein><SARS-CoV-2 vaccination><Serology><Severe acute respiratory syndrome coronavirus 2 S 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region><tool><transcytosis><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>