SARS-CoV-2 Spike Protein Binds And Modulates Estrogen Receptors – Increasing Risk Of Thrombosis

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A new study funded by the U.S. NIH has found that the spike proteins of the SARS-CoV-2 virus also binds to estrogen receptors (Erα and Erβ) and modulates them.

The study findings suggest that, given the role of ERα in the coagulation cascade, S-protein could increase the pro-coagulation activity of endothelial cells leading to an enhanced risk of thrombosis.

The study findings were published in the peer reviewed journal: Science Advances
https://www.science.org/doi/10.1126/sciadv.add4150
 

E2 is the most potent endogenous estrogen and is highly selective for ER. In the absence of E2, ERs exist within target cells in a transcriptionally inactive form. Upon ligand activation, ERs undergo homodimerization and binding to discrete DNA regions present at enhancers of specific target genes.

Gene regulation occurs when the ER homodimer builds a transcriptional complex with NRC proteins, which can either activate or inactivate transcriptional activity (32, 33). Our results, together with prior observations (34), suggest that S-ERα interactions are involved in SARS-CoV-2 infection and COVID-19 pathology via modulation of ERα signaling, transcriptional regulation of ACE2, and potentially of other genes with roles in inflammation and immunity.

Our collective findings indicate that S exhibits structural and functional properties consistent with a role as an NRC at ERα, and it is plausible that this function may extend to other NRs as well. Furthermore, given its conserved LXD motif, it is possible that these properties may also extend to S proteins from other coronavirus strains.

Alveolar macrophages are abundant in the lungs where they play a central role as a first-line defense against various pathogens (35) including SARS-CoV-2 (36, 37). Estrogens are not only responsible for the maturation and proper functioning of the female reproductive system but also play important roles in immunity (32, 38–41).

In particular, ERα signaling in alveolar macrophages is considered a key component of the immune response to infection (42–44). We observed ER-dependent biological effects of S in the RAW264.7 macrophage cell line. Whereas ERα is mainly localized to the cell nucleus in MCF-7 cells (45), we found that ERα showed cytoplasmic localization in MCF-7 cells transfected with S DNA.

We observed a similar ectopic localization pattern in lung cells, especially in alveolar macrophages from SARS-CoV-2–infected hamsters and humans. More specifically, we found that cytoplasmic ERα colocalized at the surface of SARS-CoV-2 virions within alveolar macrophages, confirming that direct S-ERα interactions occur in the context of SARS-CoV-2 infection in this cell type.

Our results, together with prior findings, suggest that S-ERα interactions in alveolar macrophages may play a critical role in SARS-CoV-2 infection and COVID-19 pathology.
We observed an apparent discrepancy between the effect of S on ERα cytosolic localization and E2-mediated biological effects such as E2-induced ER transcription, MCF-7 cell proliferation, and osteoclast differentiation. ER signaling is complex and can have contrasting biological effects across different cell types.

For this reason, we interpret here the effect of S-ERα cytosolic colocalization as a modulator and not necessarily an inhibitor of ER signaling. In regard to the effects of S on MCF-7 cell proliferation specifically, we believe that the most plausible explanation for this effect is that S-ERα cytosolic localization may result in a potentiation of membrane-bound ERα signaling either by a direct S/membrane-bound ERα or, more likely, as an indirect consequence of an imbalance in the finely tuned ER-mediated hormone response.

In line with this hypothesis, although membrane ERs have lost the capacity to bind to specific response elements or transcription initiation complexes onto DNA, the rapid membrane activation of these receptors stimulates DNA synthesis and cell proliferation (46). In addition, the membrane-bound ER structures maintain the AF-2 transcriptional activation domain (47) that we proposed to be the S binding site on ERs. Last, membrane ER activation is inhibited by the same synthetic ER antagonists that block transcriptional activation by the classically described ERs (48).

One of the most frequently reported COVID-19 epidemiologic findings is sex-related mortality and specifically male-related susceptibility. The evidence to date supports a higher predominance of men in several countries; thus, the male sex has been considered a poor prognostic factor (49). In line with these reports, male laboratory animals are more susceptible to SARS-CoV and SARS-CoV-2 infection and related pathology as compared to females (31, 50, 51).

ER signaling contributes to these sex differences (45, 51), and the potential protective effects of estrogens in COVID-19 have been widely debated in the literature (52), although a recent study showed that E2 treatment did not alleviate lung complications in SARS-CoV-2–infected male hamsters (51).

Accordingly, here, we focused our efforts on male hamsters due to their known higher susceptibility to SARS-CoV-2 infection compared to females. Nevertheless, future studies will aim to address this limitation by examining whether SARS-CoV-2 infection leads to similar effects in female hamsters as those observed here in males.

Notably, sex-based differences have been reported in various chronic inflammatory responses associated with lung disease (53) and, specifically, as a function of ER signaling in activated macrophages (42). Whereas circulating estrogens play a protective role by regulating both the innate and adaptive immune response to infection (54), it may be possible that the modulation of ER signaling in SARS-CoV-2–infected lung tissue may stimulate proinflammatory signals leading to hypertrophy, vasoconstriction, and vessel obstruction.

As compared to female patients, hyperactivation of ER signaling in pulmonary tissue in males has been associated with lower frequency but more severe progression of vascular obliteration in pulmonary arterial hypertension (53). This model could also potentially explain the widely discussed effect of ER modulation in SARS-CoV-2 infection and the reported protective effect of antiestrogenic treatment on COVID-19 prevalence in women with ovarian and breast cancer (4).

In conclusion, we report novel interactions between the SARS-CoV-2 S and ERα that may have important therapeutic implications for COVID-19. Our results also highlight the use of multimodal PET/CT imaging and the Food and Drug Administration–approved [18F]FES radiopharmaceutical as a translational approach and biomarker for the longitudinal assessment of COVID-19 lung pathology.

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