Androgen drives the expression of SARS-CoV-2 entry proteins in sinonasal tissue
image: (a) Representative images of TMPRSS2 IHC of murine prostate glands (n = 18; 9 young and 9 old) treated with vehicle, enzalutamide for 1 week, or enzalutamide for 2 weeks (n = 3 each), respectively. (b) Representative images of TMPRSS2 IHC of murine prostate glands (n = 8) treated with vehicle (n = 4), enzalutamide (n = 2), or abiraterone (n = 2), respectively. (c) Western blots of LNCaP and 16D cells treated with castration, enzalutamide (Enza), or Apalutamide (Apa), demonstrating the expression of TMPRSS2, PSA, and the loading control vinculin. (d) Quantification of RNA sequencing data (TPM) demonstrated reduced mRNA levels of KLK3 (PSA) and TMPRSS2 in 16D cells treated with vehicle or enzalutamide for 48 h. Data represent the unpaired t test with Welch’s correction. ***p < 0.001, **p < 0.01. (e, f) Representative images of TMPRSS2 IHC of LNCaP xenografts (e) (n = 2 each) and a patient-derived xenograft (f) at precastration, 7 days post castration, or 7 days post castration + enzalutamide treatment, respectively (n = 2 each). IHC, immunohistochemistry; KLK3, kallikrein 3; PSA, prostate-specific antigen; TMPRSS2, transmembrane serine protease 2.
Credit: Huihui Ye, Rong Rong Huang
Background and objectives
Men have higher morbidity and mortality from COVID-19 than women, possibly due to androgen receptor-regulated viral entry protein expression. This led to a clinical trial of androgen deprivation therapy (ADT), which has not shown a significant benefit in the outcomes among hospitalized male COVID-19 patients. The aim of this study was to explore biological explanations for the failure of ADT to mitigate clinical outcomes in men with severe COVID-19 by assessing the role of androgen in regulating viral entry protein expression in the upper and lower respiratory tract.
Methods
Immunohistochemistry was used to assess the expression of transmembrane serine protease 2 (TMPRSS2) and angiotensin-converting enzyme 2 (ACE2) and how it correlated to androgen receptor expression in the sinonasal epithelium, minor salivary glands of the sinus, lacrimal glands, and lungs from mice pretreated with and without castration and ADT as well as the sinonasal epithelium obtained from healthy human donors and hospitalized COVID-19 patients.
Results
In murine models, castration and ADT treatment downregulated the expression of TMPRSS2 and ACE2 in the sinonasal epithelium, minor salivary glands of the sinus, and lacrimal glands, but not in the lungs. Correlative analyses using human tissue also showed a potential role of ADT in men during the early sinonasal phase but not in the later lung phase of SARS-CoV-2 infection.
Conclusions
Our study suggests a potential benefit of ADT in male patients with early COVID-19 when the virus enters the nasopharynx, but not in those with advanced disease. The downregulation of viral entry proteins in the upper respiratory system following androgen blockade may be a key mechanism for this effect.
Full text
https://www.xiahepublishing.com/2771-165X/JCTP-2022-00031
The study was recently published in the Journal of Clinical and Translational Pathology.
Journal of Clinical and Translational Pathology (JCTP) is the official scientific journal of the Chinese American Pathologists Association (CAPA). It publishes high quality peer-reviewed original research, reviews, perspectives, commentaries, and letters that are pertinent to clinical and translational pathology, including but not limited to anatomic pathology and clinical pathology. Basic scientific research on pathogenesis of diseases as well as application of pathology-related diagnostic techniques or methodologies also fit the scope of the JCTP.
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