Patterns of Volatility Across the Spike Protein Accurately Predict the Emergence of Mutations within SARS-CoV-2 Lineages (preprint)

New lineages of SARS-CoV-2 are constantly emerging. They contain mutations in the spike glycoprotein that can affect virus infectivity, transmissibility, or sensitivity to vaccine-elicited antibodies. Here we show that the emergence of new spike variants is accurately predicted by patterns of amino acid variability (volatility) in small virus clusters that phylogenetically-precede or chronologically-predate such events. For each spike position, volatility within the virus clusters, volatility at adjacent positions on the three-dimensional structure of the protein, and volatility across the network of co-volatile sites describe its likelihood for mutations. By combining these variables, early-pandemic sequences accurately forecasted mutations in lineages that appeared 6-13 months later. The patterns of mutations in variants Alpha and Delta, as well as the recently-appearing variant Omicron were also predicted remarkably well. Importantly, probabilities assigned to spike positions for within-lineage mutations were lineage-specific, and accurately forecasted the observed changes. Sufficient antecedent warning of the imminent changes in SARS-CoV-2 lineages will allow design of immunogens that address their specific antigenic properties.

Phosphatidylserine Receptors Enhance SARS-CoV-2 Infection: AXL as a Therapeutic Target for COVID-19 (preprint)

Phosphatidylserine (PS) receptors are PS binding proteins that mediate uptake of apoptotic bodies. Many enveloped viruses utilize this PS/PS receptor mechanism to adhere to and internalize into the endosomal compartment of cells and this is termed apoptotic mimicry. For viruses that have a mechanism(s) of endosomal escape, apoptotic mimicry is a productive route of virus entry. We evaluated if PS receptors serve as cell surface receptors for SARS-CoV-2 and found that the PS receptors, AXL, TIM-1 and TIM-4, facilitated virus infection when low concentrations of the SARS-CoV-2 cognate receptor, ACE2, was present. Consistent with the established mechanism of PS receptor utilization by other viruses, PS liposomes competed with SARS-CoV-2 for binding and entry. We demonstrated that this PS receptor enhances SARS-CoV-2 binding to and infection of an array of human lung cell lines and is an under-appreciated but potentially important host factor facilitating SARS-CoV-2 entry.