Possible protective role of 17β-estradiol against COVID-19

Severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) is the virus that causes coronavirus disease 2019 (COVID-19); a worldwide pandemic as declared by the World Health Organization (WHO). SARS-CoV-2 appears to infect cells by first binding and priming its viral-spike proteins with membrane-associated angiotensin-converting enzyme 2 (ACE2) and transmembrane protease serine 2 (TMPRSS2). Through the coordinated actions of ACE2 and TMPRSS2, SARS-CoV-2 spike proteins fuse with plasma membranes and ultimately the virus enters cells. ACE2 is integral to the renin-angiotensin-aldosterone system (RAAS), and SARS-CoV-2 down-regulates protein expression levels of ACE2. Once infected, patients typically develop acute respiratory distress syndrome (ARDS) and a number of other severe complications that result in a high rate of fatality, especially in older (>60 years) adults and in people with pre-existing medical conditions. Data now indicate clearly that among people of all age groups, COVID-19 fatalities are higher in men than women. Here, attention is focused on these sex differences and posit a role of estrogen in these differences as well as possible therapeutic and protective actions of 17β-estradiol against COVID-19.


Introduction
Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is a novel virus in the coronaviridae family that causes the disease now termed coronavirus 2019 (COVID-19) [1,2]. SARS-CoV-2 is a large single-stranded RNA enveloped virus [3] that reportedly originated in China [3] and that has now spread quickly worldwide leaving behind severe medical complications, high levels of fatality, and serious disruptions in normal daily living and global economies [4]. Accordingly, the WHO declared COVID-19 to be a pandemic.
SARS-CoV-2 infects cells by binding viral-spike proteins with membrane-associated angiotensin-converting enzyme 2 (ACE2) and priming of spike proteins by transmembrane protease serine 2 (TMPRSS2). Together ACE2 and TMPRSS2 facilitate the entry of SARS-CoV2 into cells by promoting the fusion of viral proteins with host plasma membranes [5,6].

The ACE2 receptor is expressed on different types of cells and tissues including human
This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. considered to be nuclear steroid receptors, but are in fact associated with plasma membranes, cytoplasm as well as the nucleus. Both ER-α and ER-β are involved in both cellular signaling and the regulation of gene expression through induction of ligandactivated transcription factors and direct binding to promoter-associated estrogen response elements (ERE) of target genes [57][58][59]. 17β-estradiol protects against multiple pathological complications including ARDS [60-64], hypertension [65,66], atherosclerosis [67], vasoconstriction [68,69], fibrosis [70,71], inflammation [72][73][74], autoimmune diseases [75][76][77], viral infections [53, [78][79][80], and neurological disorders [81][82][83]. Because of such wideranging effects, it is important to consider the extent to which 17β-estradiol might control SARS-CoV-2 and the expression of this virus's associated disease COVID-19 [84][85][86][87][88] through its ability to affect the RAAS system, anti-inflammatory and anti-viral responses, and upregulation of endolysosomal degradation pathways.
Levels of 17β-estradiol's are higher in women during reproduction and pre-menopause age [140], and this correlates with robust innate immune responses and enhanced ability to clear viruses [52,141]. Lower levels of 17β-estradiol are observed during menopause and this corresponds to decreased immune responses and increased levels of the pro-inflammatory cytokines IL-6, IL-1β, and TNF-α [73,140]. The involvement of 17β-estradiol in these responses is supported by findings that 17β-estradiol supplementation suppresses the production of pro-inflammatory cytokines and boosts immune responses [47,73,[142][143][144]. In contrast, high testosterone levels can reduce immune responses in response of the influenza vaccine [46,128]. Women as well as men with lower levels of testosterone both exhibit higher immune responses and more protection against infections [46]. Although different mechanisms are involved, 17β-estradiol suppresses infection of multiple viruses including influenza [51], HCV [80], Rubella virus [79], HIV-1 [78,133], HSV-1 [141], and SARS-CoV [54]. Experimentally in mice, greater levels of SARS-CoV infection were found in male mice [54] by a mechanism involving estrogen receptor-associated signaling [54], higher accumulation of inflammatory cells, and increased levels of some specific cytokines [IL-6,TNF-α,IL-1β], and chemokines (CXCL-1, CCL2). SARS-CoV2 induces an inflammatory storm in patients with severe symptoms [145], and multiple anti-inflammatory strategies are being tested for their ability to suppress virus-induced severe acute respiratory distress syndromes, including tocilizumab and anti-TNF-α therapy. IL-6 and TNF-α both play important roles in inflammatory storms and ARDS development [146,147]. Tocilizumab, a humanized anti-human IL-6 receptor monoclonal antibody, has been used against COVID-19 and results show improvement in clinical symptoms and suppression of IL-6-mediated inflammation [148,149]. Similarly, anti-TNF therapies are being tested clinically to protect people at high risk for COVID-19 [149,150]. The antiinflammatory effects of 17β-estradiol [73,74,[151][152][153] include its ability to decrease ARDS by reducing inflammation and infiltration of immune cells in lungs [154], suppress LPS and burn trauma-induced acute lung injury [61], and attenuate NF-kB-mediated inflammation [63,155]. These might help explain results that women have fewer fatalities in COVID-19 and similarly with SARS-CoV and MERS-CoV.
Viral infection typically requires the involvement of endolysosomes [183,184] and SARS-CoV-2 is endocytosed following fusion with cell membranes in a pH-dependent manner [5,185]. Unclear, however, are mechanisms by which endocytosed virus is released from endolysosomes. Regardless, 17β-estradiol may stimulate endolysosomes to promote the degradation of cellular or extracellular materials [186]. Recently, it has been proved that SARS-CoV-2 blocks the autophagy pathway; however, spermidine reduce SARS-COV-2 infection by alleviating the lysosomal degradation pathway [187]. Hence, it needs to validate further that 17β-estradiol may restrict the SARS-CoV-2 infection by promoting the endolysosomal degradation pathway? SARS-CoV-2 infects men and women at the same rate, but men have a higher risk of developing severe complications and death. SARS-CoV-2 infects men and women at the same rate, but men have a higher risk of developing severe complications and death. Immune-compromised patients with hypertension, diabetes, cancer, and HIV-1 are at higher risk of being infected with the virus and developing severe symptoms including ARDS and death. 17β-estradiol might decrease SARS-CoV-2 infection by controlling RAAS, suppressing inflammatory storms, inducing anti-viral immune responses, and enhancing the virus' degradation in endolysosomes by promoting the fusion of endosomes and lysosomes. High-risk patients may benefit from strategies designed to increase levels of 17β-estradiol by consuming estrogen pills and 17β-estradiol-enriched herbs [188,189].
Finally, it is important to address albeit briefly why postmenopausal women who have low levels of estradiol are still exhibiting lower death rates than are men from COVID-19. One reason might be the presence of catalytically-active mature natural killer (NK) cells (CD56dim); these cells are more plentiful in women than in men at ages greater than age 70 [37,190] and these cells may participate in suppression of SARS-CoV-2 infection. Other possible mechanisms may too be involved in protection of women from COVID-19.    SARS-CoV-2 may activate the ACE/AT1 axis by down-regulating ACE2 and thereby promoting the development of ARDS by inducing an inflammatory storm and increasing oxidative stress. 17β-estradiol may enhance expression levels of ACE2 (ACE2/Mas axis) and reduce ARDS. Activation of estrogen receptors regulates 17β-estradiol-mediated cellular signaling and gene expression. ACE catalyzes the conversion of Ang I to Ang II, which activates AT1 receptors. ACE2 catalyzes the conversion of Ang II to Ang I-7, which activates the Mas receptor. (SARS-CoV-2, severe acute respiratory syndrome-coronavirus 2; ER-α, estrogen receptor-α; ER-β, estrogen receptor-β; AT1R, angiotensin II type 1 (AT1) receptor; ACE, angiotensin-converting enzyme; ACE2, angiotensin-converting enzyme 2; MasR, Mas receptor; Ang II, angiotensin II; Ang 1-7, angiotensin 1-7).