Roles of steroid receptors in the lung and COVID-19

Abstract

COVID-19 symptoms and mortality are largely due to its devastating effects in the lungs. The disease is caused by the SARS (Severe Acute Respiratory Syndrome)-CoV-2 coronavirus, which requires host cell proteins such as ACE2 (angiotensin-converting enzyme 2) and TMPRSS2 (transmembrane serine protease 2) for infection of lung epithelia. The expression and function of the steroid hormone receptor family is important in many aspects that impact on COVID-19 effects in the lung - notably lung development and function, the immune system, and expression of TMPRSS2 and ACE2. This review provides a brief summary of current knowledge on the roles of the steroid hormone receptors [androgen receptor (AR), glucocorticoid receptor (GR), progesterone receptor (PR), mineralocorticoid receptor (MR) and oestrogen receptor (ER)] in the lung, their effects on host cell proteins that facilitate SARS-CoV-2 uptake, and provides a snapshot of current clinical trials investigating the use of steroid receptor (SR) ligands to treat COVID-19.

Keywords: COVID-19; androgen; estrogens; nuclear receptors; sars-cov-2; steroids.

Figure 1. Lung architecture

The lung is composed of branching tubes (bronchi and bronchioles) descending from the central trachea, leading to alveolar sacs. The tubules and alveolar sacs are composed of specialised cells which allow for gaseous exchange. AT1 - alveolar type 1, AT2 - alveolar type 2.

Figure 2. SARS-CoV-2 lung entry

(A) Representative image of basic COVID-19 structure. (B) Lung damage caused by COVID. COVID infects epithelial cells in the alveolar sac, increasing viral load within infected cell, leads to cell damage/death causing immune activation, cytokine release, fibrotic responses.

Figure 3. Steroid receptor regulation of host genes affecting COVID infection

(A) Role of SRs in COVID infection of cells. SRs regulate ACE2 and TMPRSS2 expression, allowing for SARS-CoV-2 interaction with ACE2, activation of S-proteins by TMPRSS2, and viral entry. (B) Data from www.signalingpathways.org indicating binding scores (x-axis) of the androgen (AR), glucocorticoid (GR), progesterone (PGR), and estrogen (ESR1), receptors within an area of 10 kb up- or downstream from the transcription start site (TSS) of the ACE2 (green) and TMPRSS2 (blue) genes in multiple human cell types. Binding scores for the pioneer factor, FOXA1, are also provided.