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The SARS-CoV-2 spike protein binds and modulates estrogen receptors


Oscar Solis et al., 2022, Science Advances


Coronavirus disease 2019 (COVID-19) is an infectious disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The most frequent symptom of severe COVID-19 is pneumonia, accompanied by fever, cough, and dyspnea commonly associated with cytokine storm, systemic inflammatory response, and coagulopathy. The elderly and those with underlying comorbidities are more likely to develop severe illness and mortality.
SARS-CoV-2 is characterized by four structural proteins: spike (S), envelope (E), membrane (M), and nucleocapsid (N) proteins. Currently, most COVID-19 vaccines use S as the target antigen, as it is an important determinant capable of inducing a robust protective immune response. Furthermore, it is a critical component for cell infection via direct interaction with angiotensin-converting enzyme 2 (ACE2). S is composed of 1273 amino acids. It consists of a signal peptide located at the N terminus (amino acids 1 to 13), the S1 subunit (14 to 685 residues), and the S2 subunit (686 to 1273 residues). The S1 subunit contains the ACE2 receptor binding domain (RBD), whereas the S2 subunit is responsible for viral and host cell membrane fusion that requires other proteins. Cells are still susceptible to infection and show S-dependent biological responses independent of ACE2, suggesting that S may promote pathology independent from its capacity to bind ACE2. Given the multitude and complex array of systemic symptoms associated with COVID-19, it is possible that other molecular targets of S may exist. Identification of additional S targets would be critical for advancing our understanding of SARS-CoV-2 infection and COVID-19 pathobiology.

Results from the nanoScan PET/CT

Hamsters were imaged inside in-house developed, sealed biocontainment devices compliant with ABSL-3. A cohort of male noncastrated hamsters was imaged longitudinally 1 day before SARS-CoV-2 infection and 7 days after infection using [18F]FES (n = 4 to 5). A second cohort of SARS-CoV-2–infected male hamsters was intravenously coinjected with [18F]FES and E2 (0.3 mg/kg; 3% dimethyl sulfoxide; Sigma-Aldrich) on day 7 after infection (n = 4). Each animal was injected 16.1 ± 1.5 MBq of [18F]FES intravenously via the penile vein. A 90-min PET acquisition and subsequent CT were performed using the nanoScan PET/CT. For each animal, 8 to 13 volumes of interest (VOIs) were manually selected using CT as a guide and applied to the PET dataset using VivoQuantTM 2020 (Invicro, Boston, MA) for visualization and quantification. A VOI was placed on the left ventricle of the heart to measure the blood uptake. [18F]FES PET activity was calculated for each hamster (n = 4 to 5 hamsters per group) as the average activity of all VOIs normalized by the mean standardized uptake value (SUVmean). All animals were euthanized 110 min after injection, and the lung was harvested to quantify associated radioactivity using an automated γ-counter. Heatmap overlays were implemented using RStudio version 1.2.1335 (R Foundation) as previously described. Multiple comparisons were performed using two-way repeated-measures analysis of variance, followed by Bonferroni’s multiple-comparison test.

Figure 4. shows the PET/CT imaging workflow with the corresponding results. Syrian golden hamsters (male, 6 to 8 weeks old; Envigo, Indianapolis, IN) were exposed to a 1.5 × 105 median tissue culture infective dose (TCID50) in 100 μl of Dulbecco’s modified Eagle’s medium (DMEM) by the intranasal route as previously described. Male hamsters were imaged longitudinally inside in-house developed and sealed BSL-3–compliant biocontainment devices at 1 day before (day −1) and at 7 days (day 7) after infection using the positron emission tomography (PET) radiopharmaceutical [18F]fluoroestradiol [[18F]FES; 20 megabecquerels (MBq) per animal, n = 5] and computed tomography (CT; Fig. 4A). A 90-min dynamic PET acquisition was performed immediately after intravenous [18F]FES injection to visualize the hamster body from the eyes to thighs (starting at the skull vertex). Following PET, a CT scan was immediately performed as previously described. SARS-CoV-2 infection in hamsters produced marked pathology in the lung (as detected by CT and an established image algorithm and analysis pipeline) at day 7 after infection compared to day −1 (before infection) (Fig. 4, B to D). No distinguishable [18F]FES uptake was present in the lungs at day −1 (Fig. 4B). In contrast, the pattern of lung lesions detected via CT overlapped with the lung [18F]FES uptake at day 7 (Fig. 4B). Specifically, lung [18F]FES uptake at day 7 was significantly higher in infected lung regions compared to these same sites at day −1 and at unaffected areas at day 7 (Fig. 4, C and D). Furthermore, [18F]FES lung uptake at day 7 was significantly decreased after pretreatment with a pharmacological dose (1 mg/kg, intravenously) of E2, indicating that it reflected specific ERα binding (Fig. 4, C and D).

  • In conclusion, the authors report novel interactions between the SARS-CoV-2 S and ERα that may have important therapeutic implications for COVID-19.
  • Their 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.

Full article on science.org

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