RESUMO
Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the virus that causes coronavirus disease-19 (COVID-19), emerged in late 2019 in Wuhan, China and its rapid global spread has resulted in millions of deaths. An important public health consideration is the potential for SARS-CoV-2 to establish endemicity in a secondary animal reservoir outside of Asia or acquire adaptations that result in new variants with the ability to evade the immune response and reinfect the human population. Previous work has shown that North American deer mice (Peromyscus maniculatus) are susceptible and can transmit SARS-CoV-2 to naive conspecifics, indicating its potential to serve as a wildlife reservoir for SARS-CoV-2 in North America. In this study, we report experimental SARS-CoV-2 susceptibility of two additional subspecies of the North American deer mouse and two additional deer mouse species, with infectious virus and viral RNA present in oral swabs and lung tissue of infected deer mice and neutralizing antibodies present at 15 days post-challenge. Moreover, some of one species, the California mouse (P. californicus) developed clinical disease, including one that required humane euthanasia. California mice often develop spontaneous liver disease, which may serve as a comorbidity for SARS-CoV-2 severity. The results of this study suggest broad susceptibility of rodents in the genus Peromyscus and further emphasize the potential of SARS-CoV-2 to infect a wide array of North American rodents. ImportanceA significant concern is the spillback of SARS-CoV-2 into North American wildlife species. We have determined that several species of peromyscine rodents, the most abundant mammals in North America, are susceptible to SARS-CoV-2 and that infection is likely long enough that the virus may be able to establish persistence in local rodent populations. Strikingly, some California mice developed clinical disease that suggests this species may be useful for the study of human co-morbidities often associated with severe and fatal COVID-19 disease.
RESUMO
Background/objectivesCoronavirus disease 2019 (COVID-19) patients exhibit lipid metabolic alterations, but the mechanism remains unknown. In this study, we aimed to investigate whether the Spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) impairs lipid metabolism in host cells. MethodsA Spike cell line in HEK293 was generated using the pcDNA vector carrying the Spike gene expression cassette. A control cell line was generated using the empty pcDNA vector. Gene expression profiles related to lipid metabolic, autophagic, and ferroptotic pathways were investigated. Palmitic acid (PA)-overload was used to assess lipotoxicity-induced necrosis. ResultsAs compared with controls, the Spike cells showed a significant increase in lipid depositions on cell membranes as well as dysregulation of expression of a panel of molecules involved lipid metabolism, autophagy, and ferroptosis. The Spike cells showed an upregulation of nuclear factor erythroid 2-related factor 2 (Nrf2), a multifunctional transcriptional factor, in response to PA. Furthermore, the Spike cells exhibited increased necrosis in response to PA-induced lipotoxicity compared to control cells in a time- and dose-dependent manner via ferroptosis, which could be attenuated by the Nrf2 inhibitor trigonelline. ConclusionsThe Spike protein impairs lipid metabolic and autophagic pathways in host cells, leading to increased susceptibility to lipotoxicity via ferroptosis which can be suppressed by a Nrf2 inhibitor. This data also suggests a central role of Nrf2 in Spike-induced lipid metabolic impairments. HighlightsO_LIThe Spike protein increases lipid deposition in host cell membranes C_LIO_LIThe Spike protein impairs lipid metabolic and autophagic pathways C_LIO_LIThe Spike protein exaggerates PA-induced lipotoxicity in host cells via ferroptosis C_LIO_LINrf2 inhibitor Trigonelline can mitigate the Spike protein-induced necrosis C_LI
