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Principal Investigator: JUN WANG
Organization: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
Fiscal Year: 2022
Award: $211,875
Funding agency: National Institute of Allergy and Infectious Diseases
Project Summary
The rapid spread of SARS-CoV-2 and the resulting Coronavirus Disease 2019 (COVID-19) pose a global
pandemic. SARS-CoV-2 and its family members share some puzzling, unique pathological features, most
notably acute respiratory distress syndrome (ARDS), cytokine release syndrome (CRS), and lymphopenia,
despite excessive myeloid cell–dominant inflammation, which has been correlated with COVID-19 severity. How
the virus engages and dysregulates the immune system is currently unknown; although angiotensin-converting
enzyme 2 (ACE2) is the canonical SARS-CoV-2 receptor, immune cells, particularly myeloid cells, express little,
if any, levels of ACE2 despite evidence for direct viral engagement.
Based on our extensive experience in the discovery and characterization of immune-modulatory receptor-ligand
interactions, we sought to address how SARS-CoV-2 interacts with myeloid cells, which play essential roles in
both virus innate sensing and the modulation of host immunity, by developing a myeloid cell receptor-focused
ectopic expression screen. In ongoing experiments, we have identified several novel glycan-dependent host
interaction partners for SARS-CoV-2 Spike (S) protein, including several C-type lectins and Tweety Family
Member 2 (TTYH2). Pulmonary single-cell RNA sequencing (scRNA-seq) analysis in COVID-19 patients
indicates a myeloid cell-dominant expression of these receptors as opposed to ACE2. In the preliminary studies,
we have shown that these molecules interact mostly through regions outside of the ACE2 receptor-binding
domain (RBD), suggesting that they may provide a novel function outside of virus entry. Although these receptors
do not support the active replication of authentic SARS-CoV-2, the direct virus-myeloid cell engagement induces
a robust pro-inflammatory response, which is blocked by receptor-decoy proteins and a picomolar-affinity anti-
spike bispecific nanobody that also blocks virus infection through ACE2. Together, our findings provide the first
evidence for direct immune modulation by SARS-CoV-2, potentially targeted for therapeutic benefit.
Given these findings, we hypothesize that novel SARS-CoV-2 virus-receptor interactions in myeloid cells
constitute a pathogenic pathway for COVID-19, serving as signaling receptors that directly drive myeloid cell
dysregulation. These new direct virus-immune interactions may also have heretofore unexplored functions to
affect other cells indirectly. These hypotheses will be addressed within the following Specific Aims: (1) to
determine the functional contribution of each myeloid cell receptor in the induction of pro-inflammatory responses
upon SARS-CoV-2 engagement, and (2) to determine the role of these interactions in the dysregulation of
adaptive immunity and SARS-CoV-2 trans-infection through ACE2 receptor. Our study on novel virus myeloid
cell receptors that govern aberrant immune responses would greatly contribute to our understanding of COVID-
19 pathogenesis, revealing new therapeutic targets against COVID-19 for the benefit of humanity at large.
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