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.