Lind Bradshaw (hallmark09)

We discover how the glycan shield contributes to the stability of these conformations along the minimum free-energy pathway. A local analysis of seven key binding pockets reveals that six out them, including those for engaging ACE2, therapeutic mini-proteins, linoleic acid, two different kinds of antibodies, and protein-glycan interaction sites, switch conformations between their known apo- and holo-conformations, even when the global spike conformation is 1RBD-up. This is reminiscent of a conformational pre-equilibrium. We found only one binding pocket, namely antibody AB-C135 to remain closed along the entire minimum free energy path, suggesting an induced fit mechanism for this enzyme.Although SARS-CoV-2 severe infection is associated with a hyperinflammatory state, lymphopenia is an immunological hallmark, and correlates with poor prognosis in COVID-19. However, it remains unknown if circulating human lymphocytes and monocytes are susceptible to SARS-CoV-2 infection. In this study, SARS-CoV-2 infection of human peripheral blood mononuclear cells (PBMCs) was investigated both in vitro and in vivo . We found that in vitro infection of whole PBMCs from healthy donors was productive of virus progeny. Results revealed that monocytes, as well as B and T lymphocytes, are susceptible to SARS-CoV-2 active infection and viral replication was indicated by detection of double-stranded RNA. Moreover, flow cytometry and immunofluorescence analysis revealed that SARS-CoV-2 was frequently detected in monocytes and B lymphocytes from COVID-19 patients, and less frequently in CD4 + T lymphocytes. The rates of SARS-CoV-2-infected monocytes in PBMCs from COVID-19 patients increased over time from symptom onset. Additionally, SARS-CoV-2-positive monocytes and B and CD4+T lymphocytes were detected by immunohistochemistry in post mortem lung tissue. SARS-CoV-2 infection of blood circulating leukocytes in COVID-19 patients may have important implications for disease pathogenesis, immune dysfunction, and virus spread within the host.The introduction of vaccines has inspired new hope in the battle against SARS-CoV-2. However, the emergence of viral variants, in the absence of potent antivirals, has left the world struggling with the uncertain nature of this disease. Antibodies currently represent the strongest correlate of immunity against COVID-19, thus we profiled the earliest humoral signatures in a large cohort of severe and asymptomatic COVID-19 individuals. While a SARS-CoV-2-specific immune response evolved rapidly in survivors of COVID-19, non-survivors exhibited blunted and delayed humoral immune evolution, particularly with respect to S2-specific antibody evolution. Given the conservation of S2 across β-coronaviruses, we found the early development of SARS-CoV-2-specific immunity occurred in tandem with pre-existing common β-coronavirus OC43 humoral immunity in survivors, which was selectively also expanded in individuals that develop paucisymptomatic infection. These data point to the importance of cross-coronavirus immunity as a correlate of protection against COVID-19.RNA viruses use CpG reduction to evade the host cell defense, but the driving mechanisms are still largely unknown. In an attempt to address this we used a rapidly growing genomic dataset of SARS-CoV-2 with relevant metadata information. Remarkably, by simply ordering SARS-CoV-2 genomes by their date of collection, we find a progressive increase of C-to-U substitutions resulting in 5'-UCG-3' motif reduction that in turn have reduced the CpG frequency over just a few months of observation. This is consistent with APOBEC-mediated RNA editing resulting in CpG reduction, thus allowing the virus to escape ZAP-mediated RNA degradation. Our results thus link the dynamics of target sequences in the viral genome for two known host molecular defense mechanisms, mediated by the APOBEC and ZAP proteins.Sarbecovirus (CoV) infections, including Severe Acute Respiratory CoV (SARS-CoV)