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Principal Investigator: Noam A Cohen
Organization: PHILADELPHIA VA MEDICAL CENTER
Fiscal Year: 2023
Funding agency: Veterans Affairs
ABSTRACT
Severe acute respiratory syndrome coronavirus SARS-CoV-2, the causative agent of coronavirus
disease 2019 (COVID-19) has led to a pandemic with a mortality of approximately 3.5% and a wide range of
morbidity outcomes negatively impacted by pre-existing conditions. Given the prevalence of pre-existing
comorbid conditions in Veterans, it is imperative to understand the mechanisms of how SARS-CoV-2 invades
and replicates within the barrier defense cells of the nose, which is the primary portal for viral entry. Furthermore,
current data suggests that the nasal carriage functions as a potential reservoir for viral persistence and
transmission (i.e., shedding) at times that are both prior to and during the manifestation of severe respiratory
symptoms. This project utilizes a unique biobank of cryopreserved nasal cells collected from over 1000
individuals over 15 years to understand the critical issues surrounding SARS-CoV-2 interaction with the human
nasal epithelia.
Paradoxically, while SARS-CoV-2 can be detected in nasal swabs prior to its detection in sputum, there
is a paucity of rhinologic symptoms (<5% with nasal congestion) associated with COVID-19, with the exception
of reversible anosmia in 30-70% of patients. This is particularly problematic because up to 25% of infected
individuals remain asymptomatic, but can continue to spread SARS-CoV-2 through airborne droplets. This work
seeks to elucidate both the mechanisms controlling which epithelial cell lineages become infected with virus and
the type of immune response generated within infected or neighboring epithelia. Through this approach, we will
shed light on the issue of why certain individuals never develop symptoms while others progress to severe
respiratory failure and death.
We will focus on the SARS-CoV-2 receptor Angiotensin Converting Enzyme 2 (ACE2), which is essential
and sufficient for the virus to enter cells. Our preliminary data generated from single cell RNA analysis of primary
human sinonasal tissue demonstrates that ACE2 is expressed in discrete clusters of nasal epithelia. ACE2-
specific immunostaining of human nasal epithelial cells ex vivo and primary ciliated air liquid interface (ALI)
cultures corroborates the sc-RNAseq data. Furthermore, our data show that inoculation of primary ALI cultures
with SARS-CoV-2 results in approximately 1%-25% of cells becoming infected, suggesting a selective process.
These data indicate that we are uniquely poised to test the hypothesis that ACE2 expressing cells constitute a
unique reservoir of viral replication and are likely to mount an inflammatory cytokine response that is distinct
from non-infected epithelia. Using our established team of experts in nasal epithelial cell biology, viral
pathogenesis, inflammatory cytokine biology and genetics we will determine the following: A) which types of
epithelia are virally infected, B) what are the local inflammatory cascades in infected vs. non-infected cells, and
C) will pharmacologic manipulation of the epithelial innate defense pathways significantly alter SARS-CoV-2
ability to infect, replicate and be released from human nasal epithelia. Successful completion of this work is likely
to have a major impact on development of novel strategies to combat COVID19 disease progression within the
general population and especially in the U.S. Veteran population.
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