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Principal Investigator: Taia Wang
Organization: STANFORD UNIVERSITY
Fiscal Year: 2024
Award: $347,463
Funding agency: National Institute of Allergy and Infectious Diseases
PROJECT SUMMARY
lgG perform immunomodulatory signaling via lgG Fe-Fey receptor (FcyR) interactions that trigger different
effector functions according to the balance of activating to inhibitory (A/I) signals. Non-neutralizing, FcyR-
mediated effector functions can be critical for optimal protection in many infectious diseases, including both
influenza viruses and SARS-CoV-2. Studies over the past decade have shown tremendous heterogeneity in
lgG Fe domains across individuals, with Fe domain structure (both protein and glycan components) being
one key determinant of effector functions that are engaged during an infection. Yet, it is clear from clinical
studies showing variable efficacy of monoclonal antibody (mAb) therapeutics with homogenous Fe
domains that Fe domain
structure is not the sole determinant of antibody effector function in vivo. The functional capacity of effector
cells is almost certainly a critical determinant of lgG activity in vivo, but this has not been defined. This
proposal addresses key unanswered questions in immunity mediated by broad, FcyR-dependent antibodies
against influenza viruses and SARS-CoV-2: 1) how much heterogeneity exists in the functional capacity
of human
effector cells and is function altered by influenza virus or SARS-CoV-2 vaccination or infection, 2) how do
obesity and diabetes - states that confer high risk during influenza virus or SARS-CoV-2 infections - impact
effector cell function 3) can the functional capacity of hypo- or hyperresponsive effector cells be "tuned" using
lgG engineering strategies. We will address these questions in experiments that include key collaborations
with Project 2 (Barnes), Project 3 (Khatri) and the Technology Project (Davis). Designed immunogen baits via
Project 2 will be used to pull out broadly reactive, anti-influenza and SARS-CoV-2 lgG from polyclonal
antisera to study the effector functions recruited by these antibodies. Effector cells will furthermore be
subject to transcriptomics before and after treatment with lgG immune complexes to define correlates for
responses through collaboration with Project 3. In collaboration with the Technology Project we will use
spleen, tonsil, and lung organoids to test the hypothesis that effector cell functions can be "tuned" using
engineered lgG immune complexes. Finally, to follow up on our observation from humans that effector cell
function is heterogeneous across individuals, we will use different collaborative cross mouse strains to test
the hypothesis that the ability of broad, non-neutralizing anti-influenza mAbs to protect is correlated with the
functional capacity of their effector cells (collaboration between Dr. Taia Wang and Dr. David Schneider).
Collectively, this work, alongside the other projects proposed, helps to establish a rigorous immunological
foundation for factors underlying protection against influenza virus and SARS-CoV-2.
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disease><SARS-CO-V2><SARS-COVID-2><SARS-CoV disease><SARS-CoV-2><SARS-CoV-2 S><SARS-CoV-2 S protein><SARS-CoV-2 infection><SARS-CoV-2 spike><SARS-CoV-2 spike glycoprotein><SARS-CoV-2 spike protein><SARS-CoV-2 vaccination><SARS-CoV-2 vaccine><SARS-CoV2><SARS-CoV2 infection><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-coronavirus-2 vaccine><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><SIS cytokines><Severe Acute Respiratory Coronavirus 2><Severe Acute Respiratory Distress Syndrome CoV 2><Severe Acute Respiratory Distress Syndrome Corona Virus 2><Severe Acute Respiratory Distress Syndrome Coronavirus 2><Severe Acute Respiratory Syndrome><Severe Acute Respiratory Syndrome CoV 2><Severe Acute Respiratory Syndrome CoV 2 vaccine><Severe Acute Respiratory Syndrome CoV disease><Severe Acute Respiratory Syndrome coronavirus disease><Severe Acute Respiratory Syndrome-associated coronavirus 2><Severe Acute Respiratory Syndrome-related coronavirus 2><Severe acute respiratory syndrome associated corona virus 2><Severe acute respiratory syndrome coronavirus 2><Severe acute respiratory syndrome coronavirus 2 S protein><Severe acute respiratory syndrome coronavirus 2 infection><Severe acute respiratory syndrome coronavirus 2 spike glycoprotein><Severe acute respiratory syndrome coronavirus 2 spike protein><Severe acute respiratory syndrome coronavirus 2 vaccination><Severe acute respiratory syndrome coronavirus 2 vaccine><Severe acute respiratory syndrome related corona virus 2><Signal Transduction><Signal Transduction Systems><Signaling><Spleen><Spleen Reticuloendothelial System><Structure><Subcellular Process><Technology><Testing><Therapeutic Monoclonal Antibodies><Tonsil><Vaccination><Variant><Variation><Work><Wuhan coronavirus><active followup><adiposity><adulthood><anti-flu><anti-influenza><antibody dependent cell mediated cytotoxicity><antibody dependent cytotoxicity><antibody mediated cellular 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2><vaccination against COVID-19><vaccination against SARS-CoV-2><vaccination against Severe acute respiratory syndrome coronavirus 2><vaccination against coronavirus disease 2019><vaccine against 2019-nCov><vaccine against COVID-19><vaccine against SARS-CoV-2><vaccine against SARS-coronavirus-2><vaccine against Severe Acute Respiratory Syndrome CoV 2><vaccine against Severe acute respiratory syndrome coronavirus 2><vaccine candidates against SARS-CoV-2><vaccine for novel coronavirus><vaccine response><vaccine responsiveness><vaccine-induced response><vaccines preventing COVID><vaccines to prevent COVID>