Spike Protein Subunits of SARS-CoV-2 Alter Mitochondrial Metabolism in Human Pulmonary Microvascular Endothelial Cells: Involvement of Factor Xa.

Background: Mitochondria have been involved in host defense upon viral infections. Factor Xa (FXa), a coagulating factor, may also have influence on mitochondrial functionalities. The aim was to analyze if in human pulmonary microvascular endothelial cells (HPMEC), the SARS-CoV-2 (COVID-19) spike protein subunits, S1 and S2 (S1+S2), could alter mitochondrial metabolism and what is the role of FXA. Methods: HPMEC were incubated with and without recombinants S1+S2 (10 nmol/L each). Results: In control conditions, S1+S2 failed to modify FXa expression. However, in LPS (1 µg/mL)-incubated HPMEC, S1+S2 significantly increased FXa production. LPS tended to reduce mitochondrial membrane potential with respect to control, but in higher and significant degree, it was reduced when S1+S2 were present. LPS did not significantly modify cytochrome c oxidase activity as compared with control. Addition of S1+S2 spike subunits to LPS-incubated HPMEC significantly increased cytochrome c oxidase activity with respect to control. Lactate dehydrogenase activity was also increased by S1+S2 with respect to control and LPS alone. Protein expression level of uncoupled protein-2 (UCP-2) was markedly expressed when S1+S2 were added together to LPS. Rivaroxaban (50 nmol/L), a specific FXa inhibitor, significantly reduced all the above-mentioned alterations induced by S1+S2 including UCP-2 expression. Conclusions: In HPMEC undergoing to preinflammatory condition, COVID-19 S1+S2 spike subunits promoted alterations in mitochondria metabolism suggesting a shift from aerobic towards anaerobic metabolism that was accompanied of high FXa production. Rivaroxaban prevented all the mitochondrial metabolic changes mediated by the present COVID-19 S1 and S2 spike subunits suggesting the involvement of endogenous FXa.

Albumin Binds COVID-19 Spike 1 Subunit and Predicts In-Hospital Survival of Infected Patients-Possible Alteration by Glucose.

(1) Background: This study aimed to analyze if the serum albumin levels of hospitalized SARS-CoV-2 (COVID-19) patients on admission could predict <30 days in-hospital all-cause mortality, and if glucose levels on admission affected this predictive ability. (2) Methods: A multicenter retrospective cohort of 1555 COVID-19-infected adult patients from public hospitals of the Madrid community were analyzed. (3) Results: Logistic regression analysis showed increased mortality for ages higher than 49 y. After adjusting for age, comorbidities and on-admission glucose levels, it was found that on-admission serum albumin ≥3.5 g/dL was significantly associated with reduced mortality (OR 0.48; 95%CI:0.36-0.62). There was an inverse concentration-dependent association between on-admission albumin levels and <30 days in-hospital all-cause mortality. However, when on-admission glucose levels were above 125 mg/dL, higher levels of serum albumin were needed to reach an association with survival. In vitro experiments showed that the spike protein S1 subunit of SARS-CoV-2 binds to native albumin. The binding ability of native albumin to the spike protein S1 subunit was decreased in the presence of an increasing concentration of glycated albumin. (4) Conclusions: On-admission serum albumin levels were inversely associated with <30 days in-hospital all-cause mortality. Native albumin binds the spike protein S1 subunit, suggesting that native albumin may act as a scavenger of the SARS-CoV-2 virus.