RESUMO
The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remains an important health threat. Syncytial formation by infected cells mediated by the SARS-CoV-2 spike protein (SARS-2-S) is a hallmark of COVID-19-associated pathology. Although SARS-CoV-2 infection evokes cellular senescence, as in other viruses, the direct link between SARS-2-S-induced syncytia with senescence in the absence of viral infection and their senescence fate determinants remain unknown. Here, we show that syncytia formed by cells expressing exogenously delivered SARS-2-S exhibited a senescence-like phenotype in vitro and that SARS-2-S mRNA induced senescence phenotype in vivo. Extracellular vesicles (EVs) containing SARS-2-S also induced senescent syncytium formation independent of the de novo synthesis of SARS-2-S. Mechanistically, we show that the accumulation of endogenous dsRNA, partially that whose formation is induced by activation of the unfolded protein response (UPR), in SARS-2-S syncytia triggers RIG-I-MAVS signalling to drive the TNF--dependent survival and senescence fate of SARS-2-S syncytia. Our findings suggest that the fusogenic ability of SARS-2-S might contribute to the side effects of particular COVID-19 vaccines or perhaps long COVID-19 syndrome and provide insight into how these effects can be prevented.
RESUMO
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection induces new-onset diabetes and severe metabolic complications of pre-existing diabetes. The pathogenic mechanism underlying this is incompletely understood. Here, we provided evidence linking circulating GP73 with the exaggerated gluconeogenesis triggered by SARS-CoV-2 infection. We found that SARS-CoV-2 infection or glucotoxic condition increased the cellular secretion of GP73. Secreted GP73 trafficked to the liver and kidney to stimulate gluconeogenesis through cAMP/PKA pathway. By using global phosphoproteomics, we found a drastic remodeling of PKA kinase hub exerted by GP73. Notably, COVID-19 patients showed pathologically elevated plasma GP73, and neutralization of the secreted GP73 inhibited enhanced PKA signaling and glucose production associated with SARS-CoV-2 infection. GP73 blockade also reduced gluconeogenesis and lowered hyperglycemia in type 2 (T2D) diabetic mice. Therefore, our findings provide novel insight into the roles of GP73 as a key glucogenic hormone and mechanistic clues underlying the development of SARS-CoV-induced glucose abnormalities.
RESUMO
The recently emerged pathogenic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread rapidly, leading to a global COVID-19 pandemic. Binding of the viral spike protein (SARS-2-S) to cell surface receptor angiotensin-converting enzyme 2 (ACE2) mediates host cell infection. In the present study, we demonstrate that in addition to ACE2, the S1 subunit of SARS-2-S binds to HDL and that SARS-CoV-2 hijacks the SR-B1-mediated HDL uptake pathway to facilitate its entry. SR-B1 facilitates SARS-CoV-2 entry into permissive cells by augmenting virus attachment. MAb (monoclonal antibody)-mediated blocking of SARS-2-S-HDL binding and SR-B1 antagonists strongly inhibit HDL-enhanced SARS-CoV-2 infection. Notably, SR-B1 is co-expressed with ACE2 in human pulmonary and extrapulmonary tissues. These findings revealed a novel mechanism for SARS-CoV-2 entry and could provide a new target to treat SARS-CoV-2 infection.
RESUMO
In this study, we specifically addressed the connection between the SARS-CoV-2 virus with host cholesterol metabolism. Plasma lipid profile was measured in 861 COVID-19 patients classified as mild (n=215), moderate (n=364), severe (n=217) or critical (n=65) and 1108 age- and sex-matched healthy individuals. We showed that the levels of both TG and HDL-C were significantly lower in patients with severe disease than in patients with moderate or mild disease. After successful treatment, cholesterol metabolism was reestablished in patients with SARS-CoV-2 infection. The serum concentrations of TC and HDL-C can be used as indicators of disease severity and prognosis in COVID-19 patients.
