Impact of SARS-CoV-2 ORF6 and its variant polymorphisms on host responses and viral pathogenesis

: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) encodes several proteins that inhibit host interferon responses. Among these, ORF6 antagonizes interferon signaling by disrupting nucleocytoplasmic trafficking through interactions with the nuclear pore complex components Nup98-Rae1. However, the roles and contributions of ORF6 during physiological infection remain unexplored. We assessed the role of ORF6 during infection using recombinant viruses carrying a deletion or loss-of-function (LoF) mutation in ORF6. ORF6 plays key roles in interferon antagonism and viral pathogenesis by interfering with nuclear import and specifically the translocation of IRF and STAT transcription factors. Additionally, ORF6 inhibits cellular mRNA export, resulting in the remodeling of the host cell proteome, and regulates viral protein expression. Interestingly, the ORF6:D61L mutation that emerged in the Omicron BA.2 and BA.4 variants exhibits reduced interactions with Nup98-Rae1 and consequently impairs immune evasion. Our findings highlight the role of ORF6 in antagonizing innate immunity and emphasize the importance of studying the immune evasion strategies of SARS-CoV-2

Modeling Morality

Unlike any other field, the science of morality has drawn attention from an extraordinarily diverse set of disciplines. An interdisciplinary research program has formed in which economists, biologists, neuroscientists, psychologists, and even philosophers have been eager to provide answers to puzzling questions raised by the existence of human morality. Models and simulations, for a variety of reasons, have played various important roles in this endeavor. Their use, however, has sometimes been deemed as useless, trivial and inadequate. The role of models in the science of morality has been vastly underappreciated. This omission shall be remedied here, offering a much more positive picture on the contributions modelers made to our understanding of morality