Covid19 Symposium Summary
Wednesday, April 1, 2020
8:30 am to 1:30 pm
David Ho: Characterizing and isolating antibodies from convalescent patients
Dr. Ho is using three parallel strategies to find a neutralizing antibody for a therapeutic treatment.
The first approach is to isolate neutralizing antibodies from B cells using a yeast library for screening (with Brandon Dekosky).
The second strategy is to sort plasmablasts based on cell surface markers to look for the correct antibody. This is in collaboration with Victor Guo, Chuck Drake and Peter Sims.
His final strategy is to take patient serum with high neutralizing titers absorbed with SARS-CoV-2 spike trimer protein in order to elute the bound antibody. This bound antibody can then be identified via mass spectrometry (this is done in collaboration with Trixi Ueberheide from NYU).
His team is also amassing a cohort of convalescent cases (most from New Rochelle) and they will systematically study and characterize the virology as well as look for the ability of the serum to neutralize a pseudotyped virus that carries the SARS-CoV-2 protein.
Ian Lipkin: Diagnostics, therapeutics and social engagement at MSPH
Dr. Lipkin is looking for testing assays that are more efficient to provide increased diagnostic capability and capacity. Some of these include developing more sensitive triplex assays that can also detect the flu. His laboratory is supporting four collaborative projects for Phase II clinical trials:
Randomized Phase II Open label trial of severely ill patients (PI: Max O’Donnell)
Phase II trial on healthcare workers
Randomized Double-Blinded Phase II trial of subjects who have been in close contact with patients who are positive but are unaffected (no or mild symptoms) (PI: Jessica Justman)
Randomized double-blinded Phase II trial of CP in hospital workers (needs a new PI but currently Elizabeth Oelsner)
Also, MSPH is focusing on creating public service announcements.
Donna Farber: In vitro and In vivo models to study SARS-Cov2 infection
Immune responses do not always result in protective immunity and the peak of the adaptive response typically occurs well after the virus is cleared. Determining the dynamics of immune response to respiratory infections, including its association with age, sex, and co-morbidities, may be critical to understanding COVID pathology and inform containment and convalescent plasma transfer strategies.
In Dr. Farber’s study of mouse models, she has found that regardless of infectious dose, viral clearance generally occurs with the same kinetics. However, infectious dose has a strong impact on morbidity, oxygen saturation, and mortality, suggesting that some immunopathology results not from the virus itself, but from the immune response that is triggered.
Using pediatric ICU samples to study the human respiratory tract, Dr. Farber has identified key T-cell populations that can contribute to or protect against these lung injuries and immunopathologies. Dr. Farber is now studying respiratory samples from COVID-19 patients to study how these populations interplay in COVID and whether particular molecular signatures may be associated with injury-free clearance.
Andrea Califano: Targeting Master Regulators of coronavirus infection
Andrea Califano has generated algorithms to identify master regulators that ultimately determine a cell’s transcriptional profile and undergo dynamic changes in the context of disease. With the use of these algorithms, drug targets and therapeutics have been evaluated in various diseases for their ability to these reverse pathogenic changes in master regulators.
Using computational analysis, Dr. Califano has found that infection of cells with the SARS-CoV virus results in transcriptional changes similar to what is seen in cancer cells undergoing transformation.
Based on these profiles, several drugs either approved or late-stage in the approval process have been identified that can reverse the SARS-CoV infection signature, potentially inhibiting pathogenesis.
Magda Sobieszczyk and Michael Yin: Update on COVID-19 related clinical trials
CUIMC is currently focusing on two types of clinical trials: large, randomized NIH-initiated or multi-center national studies to achieve rapid, clinically and virologically relevant endpoints; and smaller, scientifically important studies which may be nimbler and more relevant for our patient populations.
One major focus is the trial of Remdesivir, an antiviral that targets the viral polymerase, in participants with moderate or severe COVID-19. The study, led by Max O’Donnoll, was launched at our center a few days ago, and is being replicated elsewhere.
Sarilumab, a monoclonal antibody against the IL-6 receptor, is also being studied in a randomized, double-blinded, placebo-controlled study assessing safety and efficacy. Prior studies in China suggest immunomodulatory IL-6 inhibitors may be beneficial, but did not have a placebo arm; a critical need exists to investigate this in a systemic fashion.
Other antivirals, immunomodulators and convalescent plasma are also potential future studies.
Raul Rabadan: Recombination and lineage-specific mutations led to the emergence of SARS-CoV-2
The SARS-CoV-2 virus is continually mutating, with about one amino acid substitution occurring every week. Additionally, recombination that occurs when there is co-infection of two different viruses is also a significant contributor to the evolution of the virus.
Work by Dr. Rabadan suggests that, although SARS-CoV and SARS-CoV-2 appear only distantly related based on overall sequence, about 10-15 years ago, there was recombination of two viruses that created the ancestor of SARS-CoV-2. The SARS-CoV-2 ancestor likely took part of the receptor binding domain from SARS, enabling it to bind to human ACE2 receptor. Further mutation then allowed for higher binding affinity and refined interactions with the receptor.
This two-hit model helps explain the ability of SARS-CoV-2 to cause COVID disease, and emphasizes the important role animal reservoirs of these viruses can play in facilitating the development of human pathogenesis.
Jingyue Ju: Nucleotide Analogues as Inhibitors of SARS-CoV-2 Polymerase
The SARS-CoV-2 virus uses an RNA-dependent RNA polymerase to replicate and Dr. Ju has experimentally identified five nucleotide analogues as inhibitors of the SARS-CoV-2 polymerase, four of which are FDA approved. He is hoping to determine whether these analogs could terminate the polymerase reaction. Remdesivir, with similar structure to drugs for hepatitis C and HIV, may be a candidate drug.
Eldad Hod, Kevin Roth, Krzysztof Kiryluk, Wendy Chung: Building Biorepositories from Scratch in the Midst of a Crisis
The CALM (Center for Advanced Laboratory Medicine) has been instrumental in organizing residual patient samples for research purposes.
They are collecting EDTA whole blood, serum, urine, NP swabs (live virus), stool/rectal (live virus)
These samples are useful for downstream applications: DNA, RNA (viral vs human), antibodies, flow cytometry, transcriptomics, metabolomics and proteomics
The COVID Biobank is part of a larger effort (by many entities across campus) to build a common Columbia repository (Columbia University Biobank) that would have specimens as well as data (such as genomic).
The Biobank will help in understanding the degree to which host genetics contribute to variability and disease complications, and may explain severe familial aggregation.
Jahar Battacharya: Effects of SARS-CoV-2 on Alveolar Epithelial Cells and Macrophages
Dr. Battacharya, in collaboration with Ira Tabas and Christine Garcia, is interested in understanding the basic mechanisms that the virus uses to infect critical cells in the pulmonary alveoli and cause acute respiratory distress syndrome.
They plan to infect mice with a pseudovirus or the spike protein to evaluate the immunologic response, as well as the mechanistic processes that occur, such as the binding of ACE2 to enter the lung and disruption of macrophage and type 2 cell communication.
Sagi Shapira: Experimental and computational interrogation of CoV protein functions
Dr. Shipira developed an algorithm, called P-HIPSTer, that allows him to use protein structure to identify interactions between pathogens and host.
Viruses may manipulate the host through structural mimicry of the host proteins. Coronaviruses seem to use the mimicry strategy far more than other viruses.
Even though viruses have a small proteome (less than 30 proteins) many of them mimic human proteins (7-8 found in Coronavirus). One such protein, C2 (complement), is implicated in coagulation and may explain enhanced susceptibility in older patients.
George Hripcsak: International observational research on COVID-19
OHDSI is a world-wide network that has combined databases of retrospective patient data from several countries. Columbia is the organizing center.
When Dr. Hripcsak compares the age distribution data for those that test SARS-CoV-2 in Korea and CUIMC, he sees that age group with the highest positive test results in Korea is from individuals that are aged 20-44, where CUIMC is between 60-80 yo. Both sites see an equal split in terms of gender. This may be indicative of Korea’s widespread testing strategy. This data also suggests that it is an infection of the young and a disease of the old.
By using the EHR, DBMI and others can begin to look at risk (Does already being on an ACE inhibitor help or harm your outcome if you contract SARS-CoV-2?) and clinical outcomes.
We can get demographics, number of visits, labs, and medications now and soon we will be able to pull information on diagnoses, procedures, and vitals notes.
Sarah Rossetti and Kenrick Cato: Scaling up for Surge Capacity and COVID-19 Patient tracking in the EHR: Leveraging Healthcare process modeling
Sarah Rossetti and Kenrick Cato from the School of Nursing are working on using applied operational/clinical informatics approaches to dynamically classify the level of care needed, and other characteristics for hospital beds, during a surge of patients.
Their model has several use cases: to foundationally map beds, identify bed changes (i.e. surgical suites to patient beds) during a surge, and to track new beds (i.e. have become ICU beds or influx of ventilators).
They hope to use the CONCERN model to help hospital decision makes understand the risk of patient deterioration by location
Xinchen Wang and David Goldstein: Transcriptional inhibition of viral entry proteins as a therapeutic strategy SARS CoV 2
TMPRSS2 could be another target, besides ACE2 for transcriptional inhibition. TMPRSS2 expression is affected by estradiol and there has been some indication that this observation may also be occurring in the lung. The regulation of TMPRSS2 expression by estradiol is interesting given the reported severity of COVID 19 effect on men and the elderly, those that have gone through puberty, more.
Drs. Wang and Goldstein are interested in determining whether TMPRSS2 gene expression causally affects COVID-19 severity. Their hypotheses will be: TMPRSS2 expression in lung at the time of infection correlates with disease severity, and that COVID 19 patients with severe symptoms have higher TMPRSS2 expression than patients with mild symptoms.
Matteo Porotto and Anne Moscona: Entry inhibitor peptides for SARS-CoV-2
Drs. Porotto and Moscona are pursuing an anti-viral strategy geared at targeting the virus’ ability to fuse with the host cell’s membrane. In particular, she wants to use peptides fused with lipids to interfere with the fusion process for the viral and host membranes.
This could potentially be administered as an aerosol spray. They will use ferrets for live infection.
Hans Snoeck: Viral modeling using hPSC-derived lung organoids
Dr. Snoeck is generating human lung organoids from embryonic stem cells or iPSCs as a resource to model COVID 19. There are two methods he uses: lung bud organoids that are grown on kidneys in culture and growing the organoids in Matrigel.
While there are limitations, he is collaborating with Michael Shen to model the effects of TMPRSS2 and with investigators at Sinai to infect the organoids with live virus. He is also collaborating with the Moscana group.
Noemie Elhadad: CovidWatcher: a citizen-science platform for tracking impact of the pandemic
Dr. Elhadad has developed CovidWatcher, which is a citizen-science platform for tracking the impact of the pandemic. It works as a crowd sourcing research platform to gather longitudinal information rather than a decision tool to advise patients if they should seek help.
The goal is to provide information to different stake holders (such as the health department, hospitalists, etc) to help them obtain live statistics to predict hot spots and prevent future spread. The platform and IRB can accommodate up to 1 million participants and obtain information on symptoms and their environment.
Alex Chavez and Rodney Rothstein: Multiplexed antiviral drug discovery
Drs Chavez and Rothstein are collaborating to find a broad acting drug that can be applicable to many corona viruses, which will be useful if there is another outbreak of a corona virus.
Typically, drug discovery is applied to a single cell line/protein target and they are using a yeast screening model ,with DNA barcoding, to look at the effect that various drugs have on many viral proteases, including the 3CL, at one time.
Vincent Racaniello: Fecal shedding in COVID-19 patients and function of SARS-CoV-2 nsp4 and ORF8 proteins
Dr. Racaniello has two projects, one more clinical and one more basic.
The clinical project is to determine the role of fecal shedding and transmission since during the CoV1 outbreak transmission occurred due to a building’s plumbing issue.
The second project will determine the role that two viral proteins, nsp4 and orf8, play within the cell and its role within pathogenesis. This will be done in collaboration with Rodney Rothstein to use yeast to identify pathways that regulate lipid metabolism and vesicle trafficking.
Written summaries provided by the Columbia University Irving Medical Center’s Office of Research.
By Drs. Danielle Matsushima, John Seeley and John Smerdon