Epithelial Barriers and Viral Infection
ACE2, the receptor for the SARS-CoV-2, is expressed at low levels
throughout the trachea, large, and small airways.26ACE2 is expressed in multiple epithelial type cells throughout the
respiratory tract including alveolar type II cells with the highest
expression occurring in clusters of goblet cells and ciliated cells of
the nasal epithelium.27,28 With the high expression of
ACE II in the nasal epithelium, this location is not only accessible but
welcoming to this destructive pathogen.
The older adult population is inarguably becoming sicker from SARS-CoV-2
infection, and differential expression of ACE2 receptor in adult
epithelial cells to mediate viral entry could be a plausible
explanation. Surprisingly, recent studies have shown no significant
difference in ACE2 gene expression with age, with some studies showing
reduced ACE2 gene expression in the older
population.26,29 In contrast to ACE2 receptors,
TMPRSS2, the serine protease “sidekick” for viral entry, has been
shown to have an increased expression with age.30,31Of note, CD147 and GRP78 are identified as other candidate receptors to
allow entry of this viral invader.26 Expression of
CD147 has actually been shown to increase with age though more
investigation is needed to elucidate the significance of this early
finding; if the virus uses this back door for attack, this important
vulnerability could help explain age differences.32 Of
note, CD147 is a glycosylated transmembrane protein of the
immunoglobulin super family that acts as the main upstream stimulator of
matrix metalloproteinases (MMPs).33 Activation of
CD147 could have important implications for disease progression.
Likewise, GRP78 may be central to the disease process as it is a member
of the heat-shock protein-70 (HSP70) family and involved in the folding
and assembly of proteins in the endoplasmic
reticulum.34
Paradoxically, infection with SARS-CoV-2 stimulates an
interferon-mediated innate immune response upregulating ACE2, enabling
more viral entry sites.30 After SARS-CoV-2 has
breached the upper airway through nasal epithelium, a systemic response
with both cytokines and interferons may cascade to lower airway leading
to increased expression ACE2 portals of entry that allow attack of the
lower respiratory tract. An understanding of the gene expression of
epithelial cells under stress are necessary to better understand how
this invader breaches defenses. If a child’s immune system fails to
induce ACE2 receptors in the lower airway, then the virus may stay
contained within the upper airway or have a delayed progression to
pneumonia. Epithelial binding alone does not convincingly explain the
stark age difference.