Front Pharmacol. 2020; 11: 1085. Published online 2020 Jul 15. doi: 10.3389/fphar.2020.01085
Selective Estrogen Receptor Modulators in COVID-19: A Possible Therapeutic Option?
Alba Calderone, 1 Francesco Menichetti, 2 Ferruccio Santini, 1 , 2 Luciano Colangelo, 2 , 3 Ersilia Lucenteforte, 2 and Vincenzo Calderone 4 , *
Male and female genders exhibit significant differences in the outcome of infective diseases caused by several viral pathogens. Along with behavioral or social factors which can affect the exposure to infection and the availability of therapies, it is widely accepted that genetic and physiological factors can markedly influence sex-related differences in immune responses. In particular, receptors for gonadal hormones are expressed in many immune cell types and, consistently, sex-related differences in immune function are likely to be strongly influenced by circulating sex steroid hormones (Klein and Huber, 2010).
Concerning coronaviruses, epidemiological data from SARS epidemic (severe acute respiratory syndrome caused by SARS-CoV in 2002–2003) and MERS epidemic (Middle East respiratory syndrome, caused by MERS-CoV in 2012–2013) showed evident sex-dependent differences in disease outcome (Karlberg et al., 2004). Notably, such a sex-dependent difference is presently observed in the new SARS pandemic, broken out in 2019 and caused by SARS-CoV-2 (COVID-19). In particular, susceptibility to SARS-CoV-2 infection is almost similar in both genders, but higher severity and mortality are observed in male patients (Wenham et al., 2020).
FASEB J. 2020 Nov;34(11):14103-14119. doi: 10.1096/fj.202001394RR. Epub 2020 Sep 23.
SARS-CoV-2 and the possible connection to ERs, ACE2, and RAGE: Focus on susceptibility factors
Roberta Sessa Stilhano 1, Angelica Jardim Costa 2, Michelle Sayuri Nishino 3 4, Shahin Shams 5, Cynthia Silva Bartolomeo 1 6, Ana Cristina Breithaupt-Faloppa 7, Eduardo Alexandre Silva 5, Ana Lopez Ramirez 8, Carla Maximo Prado 6, Rodrigo Portes Ureshino 3 4
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has provoked major stresses on the health-care systems of several countries, and caused the death of more than a quarter of a million people globally, mainly in the elderly population with preexisting pathologies. Previous studies with coronavirus (SARS-CoV) point to gender differences in infection and disease progression with increased susceptibility in male patients, indicating that estrogens may be associated with physiological protection against the coronavirus. Therefore, the objectives of this work are threefold. First, we aim to summarize the SARS-CoV-2 infection pathway and the roles both the virus and patient play in COVID-19 (Coronavirus disease 2019) progression, clinical symptomatology, and mortality. Second, we detail the effect estrogen has on viral infection and host infection response, including its role in both the regulation of key viral receptor expression and the mediation of inflammatory activity. Finally, we describe how ERs (estrogen receptors) and RAGE (receptor for advanced glycation end-products) play a critical role in metabolic pathways, which we envisage could maintain a close interplay with SARS-CoV and COVID-19 mortality rates, despite a current lack of research directly determining how. Taken together, we present the current state of the field regarding SARS-CoV-2 research and illuminate where research is needed to better define the role both estrogen and metabolic comorbidities have in the COVID-19 disease state, which can be key in screening potential therapeutic options as the search for effective treatments continue.
BMC Med. 2020 Nov 25;18(1):369. doi: 10.1186/s12916-020-01851-z.
Evidence for treatment with estradiol for women with SARS-CoV-2 infection
Ute Seeland 1, Flaminia Coluzzi 2 3, Maurizio Simmaco 4 5, Cameron Mura 6, Philip E Bourne 6, Max Heiland 7, Robert Preissner 1, Saskia Preissner 8
Background: Given that an individual’s age and gender are strongly predictive of coronavirus disease 2019 (COVID-19) outcomes, do such factors imply anything about preferable therapeutic options?
Methods: An analysis of electronic health records for a large (68,466-case), international COVID-19 cohort, in 5-year age strata, revealed age-dependent sex differences. In particular, we surveyed the effects of systemic hormone administration in women. The primary outcome for estradiol therapy was death. Odds ratios (ORs) and Kaplan-Meier survival curves were analyzed for 37,086 COVID-19 women in two age groups: pre- (15-49 years) and peri-/post-menopausal (> 50 years).
Results: The incidence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is higher in women than men (by about + 15%) and, in contrast, the fatality rate is higher in men (about + 50%). Interestingly, the relationships between these quantities are linked to age: pre-adolescent girls and boys had the same risk of infection and fatality rate, while adult premenopausal women had a significantly higher risk of infection than men in the same 5-year age stratum (about 16,000 vs. 12,000 cases). This ratio changed again in peri- and postmenopausal women, with infection susceptibility converging with men. While fatality rates increased continuously with age for both sexes, at 50 years, there was a steeper increase for men. Thus far, these types of intricacies have been largely neglected. Because the hormone 17ß-estradiol influences expression of the human angiotensin-converting enzyme 2 (ACE2) protein, which plays a role in SARS-CoV-2 cellular entry, propensity score matching was performed for the women’s sub-cohort, comparing users vs. non-users of estradiol. This retrospective study of hormone therapy in female COVID-19 patients shows that the fatality risk for women > 50 years receiving estradiol therapy (user group) is reduced by more than 50%; the OR was 0.33, 95% CI [0.18, 0.62] and the hazard ratio (HR) was 0.29, 95% CI [0.11,0.76]. For younger, pre-menopausal women (15-49 years), the risk of COVID-19 fatality is the same irrespective of estradiol treatment, probably because of higher endogenous estradiol levels.
Conclusions: As of this writing, still no effective drug treatment is available for COVID-19; since estradiol shows such a strong improvement regarding fatality in COVID-19, we suggest prospective studies on the potentially more broadly protective roles of this naturally occurring hormone.
Front. Mol. Biosci., 16 October 2020 | https://doi.org/10.3389/fmolb.2020.568954
Identifying Pathways and Networks Associated With the SARS-CoV-2 Cell Receptor ACE2 Based on Gene Expression Profiles in Normal and SARS-CoV-2-Infected Human Tissues
Qiushi Feng1,2, Lin Li1,2 and Xiaosheng Wang1,2*
Because ACE2 is a host cell receptor of the SARS-CoV-2, an investigation of ACE2 expression in normal and virus-infected human tissues is crucial for understanding the mechanism of SARS-CoV-2 infection. We identified pathways associated with ACE2 expression and gene co-expression networks of ACE2 in pan-tissue based on the gene expression profiles in normal human tissues. We found that the pathways significantly associated with ACE2 upregulation were mainly involved in immune, stromal signature, metabolism, cell growth and proliferation, and cancer and other diseases. The number of genes having a significant positive expression correlation with ACE2 in females far exceeded that in males. The estrogen receptors (ESR1 and ESR2) and androgen receptor (AR) genes had a significant positive expression correlation with ACE2. Meanwhile, the enrichment levels of immune cells were positively associated with the expression levels of ESR1 and ESR2, while they were inversely associated with the expression levels of AR in pan-tissue and multiple individual tissues. It suggests that females are likely to have a more robust immune defense system against SARS-CoV-2 than males. ACE2 was upregulated in SARS-CoV-2-infected tissues relative to normal tissues and in SARS-CoV-2-infected males relative to females, while its expression levels had no significant difference between healthy females and males. Numerous immune-related pathways were highly enriched in SARS-CoV-2-infected males relative to females. These data indicate that males are more susceptible and more likely to have an excessive immune response to SARS-CoV-2 infection than females. This study furnishes potentially cues explaining why females have better clinical outcomes of SARS-CoV-2 infections than males and warrant further investigation for understanding the mechanism of SARS-CoV-2 infection.
J Infect Dis. 2007 May 1;195(9):1294-302. doi: 10.1086/513434. Epub 2007 Mar 23.
Progesterone inhibits HIV-1 replication in human trophoblast cells through inhibition of autocrine tumor necrosis factor secretion
Laura Diaz Muñoz 1, Maria Jesús Serramía, Manuel Fresno, Maria Angeles Muñoz-Fernández
Background: Progesterone levels are higher in placental barriers during pregnancy, but the effect of progesterone on human immunodeficiency virus type 1 (HIV-1) infection in placental cells has not been addressed. We hypothesize that progesterone may affect HIV infection.
Methods: Purified trophoblastic cells and trophoblastic cell lines were infected or transfected with HIV-1, and the effect of progesterone was analyzed. Viral replication was measured by viral p24 or viral load quantification. Nuclear factor kappa -B (NF- kappa B) or long terminal repeat (LTR)-dependent transcription was measured by luciferase assays. Expression of chemokine receptors was analyzed by flow cytometry. Tumor necrosis factor (TNF) messenger RNA was assessed by reverse-transcription polymerase chain reaction (RT-PCR) and quantitative RT-PCR.
Results: Progesterone inhibits HIV-1 replication in placental cells at the concentration found in the placental interface, at a postentry step, and does not affect cell surface expression of chemokine receptors. Progesterone did not inhibit basal or induced LTR transcription or NF- kappa B activation. TNF synthesis in placental cells is induced by HIV-1 infection that, in an autocrine manner, activates viral replication, because neutralizing anti-TNF antibodies block it. Progesterone inhibits the induction of TNF synthesis by viral infection and virus or gp-120-induced TNF transcription.
Conclusion: Our results demonstrate that progesterone inhibits HIV-1 replication in placental cells by reducing TNF levels, which are required for optimal viral replication.
Biomedical and Biotechnology Research Journal (BBRJ). DOI:10.4103/bbrj.bbrj_53_20Corpus ID: 219958422.
Tamoxifen from chemotherapy to antiviral drug: Possible activity against COVID-19
Huda Almosawey, Falah Al-Khikani, +3 authors Atyaf Al-Asadi
Tamoxifen (TAM) is the oldest and the most-prescribed selective estrogen receptor modulator (SERM). It is a member of the triphenylethylene group. TAM has been used to treat breast cancer that spreads to other parts of the human body; it is also utilized to decreasing the chances of breast cancer developing in high-risk patients. Recently, some studies focused on the potential antimicrobial action of TAM. Coronaviruses are enveloped positive-sense RNA nucleic acid viruses that have club-like spikes, characterized by a distinctive replication strategy; they are round and sometimes pleomorphic in shape. Coronavirus disease 2019 (COVID-19) is regarding the new genera of coronaviredia that appeared for the first time in Wuhan, China, in early December 2019. Due to the continuous spread of the novel COVID-19 with the exponential rise in death numbers, new therapeutic development is urgent; in general, there are no specific antiviral drugs or vaccines for 2019-nCoV. Hence, this review will discuss the most recent information about the antiviral action of TAM against COVID-19 infection by trying to give a deep understanding of major properties, mechanisms of action, immune system responses, and antimicrobial efficiency of TAM that is regarding the promising way to treat COVID-19 novel infection. The current review may serve as an impetus for researchers working in the field of medical microbiology, vaccination, and antiviral drug design. The review also rationally reports and critically analyzes the available knowledge by focusing and mentioning future steps and strategies trying to find appropriate solutions regarding challenges in COVID-19 management by TAM utilization.
Minireview | Therapeutics and Prevention. DOI: 10.1128/mBio.02272-18
Repurposing Estrogen Receptor Antagonists for the Treatment of Infectious Disease
Marhiah C. Montoya, Damian J. Krysan
The studies exploring the antiviral activity of triphenylethylene-based SERMs have mainly focused on three infections: human immunodeficiency virus (HIV), hepatitis C virus (HCV), and Ebola virus (EBOV). TAM is active against HIV, HCV, and herpes simplex virus 1 (HSV-1), while CLM and TOR are active against EBOV.
As part of the initial search for anti-HIV drugs in the early 1990s, TAM was identified as a disruptor of viral replication during chronic infection based on the 4B-phorbol-12-myristate-13-acetate-mediated model and as a disruptor of HIV-associated transactivation in cells of monocytic and T-cell lineages at half-maximal inhibitory concentrations (IC50) of ≤10 µM (32). TAM also inhibited HIV replication in nonstimulated, HIV-infected lymphocytes through pathways independent of its antiestrogen activity (33). As with other off-target effects in human cells, the mechanism of action was attributed to inhibition of PKC and interaction with other targets in the NF-κB pathway (32). TAM’s activity was not better than the HIV treatment option available at the time, AZT (33). Thus, these in vitro data did not lead to in vivo or clinical studies.
TAM (1 µM) inhibits HCV replication by interfering with the association of estrogen receptor alpha with RNA-dependent RNA polymerase NS5B (34). As a result, TAM interferes with the formation of the replication complex and ultimately prevents viral genome replication (34). Further studies have shown that TAM protects cells from HCV-induced cytopathic effects at ≤8 µM and blocks HCV core protein expression if given at or before infection (35). The activity of TAM against both HIV and HCV is increased when cells are exposed to the drug prior to infection. More recent characterization of the activity of SERMS against HCV by Murakami et al. indicates that TAM inhibits viral attachment, entry, replication, and exit (36, 37). Interestingly, this multiple-step inhibitory activity of TAM was also observed in a single study of its activity against HSV-1 replication (38). Specifically, a chloride channel-inhibitory activity of TAM is thought to prevent viral fusion, cell penetration, and translocation (38). Additionally, TAM inhibits viral production in both wild-type and acyclovir-resistant strains (38).
The activity of SERMs against EBOV was discovered through a dedicated repurposing screen of FDA-approved drugs in 2013. Although this screen identified only CLM and TOR, subsequent targeted assays found that TAM, raloxifene (RLX), and the CLM stereoisomers enclomiphene and zuclomiphene are also active against EBOV (39 – 43). CLM and TOR have in vitro antiviral activity against a variety of EBOV strains with IC50 values ranging from 2.42 to 11.1 µM and 0.162 to 6.17 µM, respectively (41, 44). In a murine EBOV infection model, male and female mice were treated with CLM or TOR at 60 mg/kg/day with dosing on day 0, day 1, and alternating days thereafter for 10 days. At 28 days postinfection, 90% of CLM-treated mice survived (P < 0.0001) while 50% of TOR-treated mice survived (P = 0.0441) (41). A follow-up in vivo study of CLM using an alternative dosing strategy did not observe a survival benefit, suggesting that a balance between activity and toxicity was quite important for efficacy (42). In vitro mechanistic experiments suggest that CLM and TOR inhibit viral entry into the host cell in a dose-dependent manner with specificity to virus-like particles containing EBOV GP1,2 (41). Further studies of the crystal structure suggest that TOR binds in the pocket between GP1 and GP2 and, consequently, may decrease stability of the complex. In this way, TOR may prevent the conformational changes necessary for GP1,2-promoted viral fusion with the endolysosomal membrane (45). Finally, these promising results have led to a series of studies evaluating the combination of TOR/CLM with a variety of other molecules (46 – 48). Since some of these combinations have shown synergistic activity, it will be interesting to see whether more effective therapies based on the SERMs can be developed.
Cell Cycle. 2020; 19(24): 3632–3638.
Clinical stage molecule PT150 is a modulator of glucocorticoid and androgen receptors with antiviral activity against SARS-CoV-2.
Neil D. Theise,a,b Anthony R. Arment,c Dimple Chakravarty,d John M. H. Gregg,b Ira M. Jacobson,e Kie Hoon Jung,f Sujit S. Nair,d Ashutosh K. Tewari,d Archie W. Thurston,g John Van Drie,h and Jonna B. Westoverf
PT150 is a clinical-stage molecule, taken orally, with a strong safety profile having completed Phase 1 and Phase 2 clinical trials for its original use as an antidepressant. It has an active IND for COVID-19. Antiviral activities have been found for PT150 and other members of its class in a variety of virus families; thus, it was now tested against SARS-CoV-2 in human bronchial epithelial lining cells and showed effective 90% inhibitory antiviral concentration (EC90) of 5.55 µM. PT150 is a member of an extended platform of novel glucocorticoid receptor (GR) and androgen receptor (AR) modulating molecules. In vivo, their predominant net effect is one of systemic glucocorticoid antagonism, but they also show direct downregulation of AR and minor GR agonism at the cellular level. We hypothesize that anti-SARS-CoV-2 activity depends in part on this AR downregulation through diminished TMPRSS2 expression and modulation of ACE2 activity. Given that hypercortisolemia is now suggested to be a significant co-factor for COVID-19 progression, we also postulate an additive role for its potent immunomodulatory effects through systemic antagonism of cortisol.
Front Immunol. 2020 Aug 28;11:2145. doi: 10.3389/fimmu.2020.02145. eCollection 2020.
Re-analysis of Single Cell Transcriptome Reveals That the NR3C1-CXCL8-Neutrophil Axis Determines the Severity of COVID-19
Jang Hyun Park 1, Heung Kyu Lee 1 2
SARS-CoV-2 infection has recently been declared a pandemic. Some patients showing severe symptoms exhibit drastic inflammation and airway damage. In this study, we re-analyzed published scRNA-seq data of COVID-19 patient bronchoalveolar lavage fluid to further classify and compare immunological features according to the patient’s disease severity. Patients with severe symptoms showed DNA damage and apoptotic features of epithelial cells. Our results suggested that epithelial damage was associated with neutrophil infiltration. Myeloid cells of severe patients showed higher expression of proinflammatory cytokines and chemokines such as CXCL8. As a result, neutrophils were abundant in lungs of patients from the severe group. Furthermore, recruited neutrophils highly expressed genes related to neutrophil extracellular traps. Neutrophil-mediated inflammation was regulated by glucocorticoid receptor expression and activity. Based on these results, we suggest that severe COVID-19 symptoms may be determined by differential expression of glucocorticoid receptors and neutrophils.