COVID-19 Virtual Symposium #18

Today was the eighteenth Columbia COVID-19 Virtual Symposium.

Presentation Summaries and Video Recordings

Written summaries were kindly provided by the Presenters or the Columbia Researchers Against COVID-19 (CRAC) Team.

If you are having trouble viewing the embedded videos, try refreshing the page. If that doesn't work, visit the Herbert Irving Comprehensive Cancer Center's YouTube page. 

Jesse Bloom, PhD  - The Evolutionary Potential of the SARS-CoV-2 receptor binding domain (RBD)

The presentation introduced the mechanism of receptor-binding domain (RBD). With the use of deep mutational scanning to map functional constraints on SARS-CoV-2 RBD, the research group was able to identify the structure-function relationship, analyze SARS-CoV-2 genetic variation, and understand the functional diversity in scarbecovirus RBDs. DMS measurement has been applied to assess the affinity and stability of the RBDs. In general, research shows that mutations that increase ACE2 binding enhance infectivity by spike-pseudotyped lentivirus. Also, there are single mutations that dramatically improve RBD expression and stability, which might be helpful for vaccines. RBD variation is shaped by purifying selection. To summarize, the research group can map the effects of all mutations on ACE 2binding and RBD expression. It is useful for understanding viral evolution and is interesting to apply more broadly to scarbecoviruses and ACE2 homologs. The research group can completely map antibody escape mutations. Also, it is useful for designing antibody cocktails and understanding the antigenic consequences of mutations.

Bette Korber, PhD - The D614G Mutation in Spike: Increased infectivity and neutralizing antibody sensitivity and the underlying mechanism

The talk started with the introduction of G614, which is a part of the G clade that came out of Europe and has been followed by GISAID since early spring. Epidemiological evidence showed that G514 is more transmissible, especially, the recurring increases in frequency are not consistent with founder effects. The research study showed that RBD antibodies can be more potent against G614 than D614. The D614G mutant Spike prefers the “one up” conformation which allows ACE2 interactions and exposes the RBD epitope regions. The research followed the procedure that systematically extracted all GISAID regional data where both forms were co-circulating, there was enough time to see a change, and there were enough sequences for statistical assessment. A comprehensive and global search of all geographic regions in GISAD continued to show that the G form almost always became dominant at every level, continent, country, state, city. If random founder effects were driving shifts in population, these founder effects would not always go towards the G form. To summarize, more research needs to understand the biology of this virus. The virus is different and more transmissible than it was when the world began to shelter in place mid-March. Specifically, G614 is in itself an inspiration for greater caution, which could help inform epidemiological models. Finally, more research is needed to know the impact of G614 on vaccines and therapeutics. G614 is sensitive to polyclonal antibodies from sera, more sensitive to D614 vaccine raised Nabs than is D614. G614’s greater infectivity makes it easier to use in a pseudovirus assay than D614. G614 may be useful as a vaccine antigen because the RBD, a key neutralizing target, is more exposed. 

Craig Wilen, MD, PhD - Genome-wide CRISPR screen identifies host genes essential for SARS-CoV-2 infection

Dr. Wilen discussed the significance of host-virus interactions on prognostics and therapeutics because it can inform why clinical presentation is so variable as well as develop therapeutics against host targets. SARS-CoV-2 uses ACE2 receptors to enter the cell, and then CTSL or TMPRSS2 for proteolytic activity. Using a CRISPR forward screen on Vero E6 cells, they strikingly found that chromatin and histone remodelers such as SWI/SNF gene SMARCA4 were important to viral entry. Pathway analysis found the SWI/SNF complex to be pro-viral. Others include Smad3 and Smad4. HMGB1 is a pleiotropic protein that is pro-viral for SARS-CoV2, is regulated by ACE2 and CTSL, and it is critical for viral entry. Some small molecules targeting Smad3 and the SWI/SNF complex were found to inhibit viral replication.

A. David Paltiel, PhD and Rachel Walensky, MD, MPH - COVID-19 and higher education: What is the test we need to open college campuses?

University re-opening has been a contentious issue recently, and Drs. Paltiel and Walensky discussed statistical modeling they had done to anticipate how coronavirus may spread around college campuses. The most optimistic scenario is that exogenous infection entering a campus have an R₀ of 1.5 over the course of one semester. The input parameters assume that students will largely adhere to mask-wearing and social distancing rules, but that violations will nonetheless occur. The single most powerful tool in combating spread is testing frequency. In the best case scenario, weekly screenings and isolation pools for infected students reduce the R₀ to 1.5. The preferred strategy is the one that confers the greatest benefit without exceeding the maximum willingness to pay to avert an infection.

Jason McLellan, PhD - Structure-based Design of Prefusion-stabilized SARS-CoV-2 Spikes

Dr. McLellan reported the results of his efforts to produce a protein similar to the CoV S-2P spike protein to be used in research and as a possible vaccine with for these purpose enhanced properties. His work focused on the five substitute types salt bridges, prolines, disulfides, cavity filling and hydration bonds. Both single substitutes as well as pure and mixed multi-substitutes were examined, leading to a way more improved protein with very similar properties. Additionally it shows similar properties as in CoV-1, which sparks the hope of a universal Corona vaccine.

Jingyue Ju, PhD - Nucleotide Analogues as Inhibitors of SARS-CoV-2 Polymerase, a Key Drug Target for COVID-19

Dr. Ju in his talk presented in detail the CoV-2 Polymerase cycle, which step-wise replicates the virus RNA. The Polymerase is a very well defined drug target, favourable for possible vaccines. This is very similar to the Hepatitis C virus and indeed drugs developed for this virus showed promising results as a possible treatment of COVID-19.