SARS-CoV-2 Viral Entry Proteins in Hyperandrogenemic Female Mice: Implications for Women with PCOS and COVID-19

Abstract

SARS-CoV-2, the causative agent of COVID-19, infects host cells using the angiotensin I converting enzyme 2 (ACE2) as its receptor after priming by host proteases, including TMPRSS2. COVID-19 affects multiple organ systems, and male patients suffer increased severity and mortality. Polycystic Ovary Syndrome (PCOS) is the most common endocrine disorder in reproductive-age women and is characterized by hyperandrogenism, ovulatory dysfunction, and polycystic ovarian morphology. PCOS is associated with obesity and cardiometabolic comorbidities, both being risk factors associated with severe COVID-19 pathology. We hypothesize that elevated androgens in PCOS regulate SARS-CoV-2 entry proteins in multiple tissues increasing the risk for this population. Female mice were treated with dihydrotestosterone (DHT) for 90 days. Body composition was measured by EchoMRI. Fasting glucose was determined by an enzymatic method. mRNA and protein levels of ACE2, Tmprss2, Cathepsin L, Furin, Tmprss4, and Adam17 were quantified by RT-qPCR, Western-blot, or ELISA in tissues, serum, and urine. DHT treatment increased body weight, fat and lean mass, and fasting glucose. Ace2 mRNA was upregulated in the lung, cecum, heart, and kidney, while downregulated in the brain by DHT. ACE2 protein was upregulated by DHT in the small intestine, heart, and kidney. The SARS-CoV-2 priming proteases Tmprss2, Cathepsin L, and Furin mRNA were upregulated by DHT in the kidney. ACE2 sheddase Adam17 mRNA was upregulated by DHT in the kidney, which corresponded with increased urinary ACE2 in DHT treated mice. Our results highlight the potential for increased cardiac, renal, and gastrointestinal dysfunction in PCOS women with COVID-19.

Pannexin-1 channel opening is critical for COVID-19 pathogenesis

“…In addition, Panx-1 blockers also reduce the secretion of proteases into the extracellular space, such as cathepsins (Swayne et al, 2020). Extracellular proteases, such as furin and cathepsins, promote SARS-CoV-2 infection over other coronaviruses, as demonstrated by others (Bestle et al, 2020;Dessie and Malik, 2021;Huffman et al, 2021;Murgolo et al, 2021;Raghav et al, 2021;Rossi et al, 2020;Watzky et al, 2021;Zhang et al, 2021), and our current data support these findings by identifying a novel mechanism of virus-mediated inflammation. Our data that ATP, PGE 2 , and IL1b are highly concentrated in the BAL obtained from COVID-19 individuals is exciting but needs to be considered carefully due to the fact that during the evolution of the disease, significant apoptosis of lung cells occurs (Liu et al, 2021).…”

Cardiac and Renal SARS-CoV-2 Viral Entry Protein Regulation by Androgens and Diet: Implications for Polycystic Ovary Syndrome and COVID-19

“…Total kidney and LV RNA were extracted, DNAse treated, quantified, and reverse transcribed (5 µg), as previously described [ 37 , 99 ]. Quantitative RT-PCR was performed using TaqMan gene expression assays (Applied Biosystems, Foster City, CA, USA) for Ace2 (Mm01159006_m1), Tmprss2 (Mm00443687_m1), Tmprss4 (Mm00520486_m1), Furin (Mm00440646_m1), Ctsl (Mm00515597_m1), Adam17 (Mm00456428_m1), Gapdh (Mm99999915_g1), B2m (Mm00437762_m1), Actb (Mm02619580_g1), and 18S rRNA (Hs99999901_s1).…”

“…We previously reported that excess androgens in a rodent model of PCOS upregulate ACE2 protein expression in the heart, kidney, and small intestine [ 37 ]. Whether obesity, a comorbidity of both PCOS and COVID-19, modulates SARS-CoV-2 viral entry factors in cardiovascular and renal systems in PCOS is unknown.…”

Polycystic ovary syndrome and risks for COVID-19 infection: A comprehensive review

“…As previously stated, androgens favor SARS-CoV-2 infection [ 52 , 56 – 58 , 126 – 130 ]. Studies of these phenomena in humans are supported by animal models [ 123 ]. In addition to higher susceptibility to the SARS-CoV-2 virus, women with hyperandrogenic PCOS phenotype have more pronounced symptoms than women with PCOS and normal androgen levels [ 131 ].…”

“…In PCOS, elevated androgens upregulate the SARS-CoV-2 receptor ACE2 and modify host proteases to increase SARS-CoV-2 viral entry into tissues. The Up arrow signifies increase(s); the lightning bolt represents injury (from Lizneva et al [ 122 , 123 ], with permission of CC-Creative Commons License Deed) …”