Mini-Lungs In A Dish, Airway Stem Cells, Evolution of Virus Mutations: COVID-19 Updates

October 30, 2020 I Neutrons chart atomic map of COVID-19’s viral replication, Organs-on-Chips technology, coronaviruses mimic proteins that control blood coagulation and inflammation, therapeutic effects of Chinese herbal medicine, crystal structure identified on SARS-CoV-2 papain-like protease, and potent antibody isolated. Plus: NIH researchers discover key pathway in lysosomes for coronaviruses exit, deep learning models to target SARS-CoV-2 main protease, RBD nanoparticles may be effective vaccine, predicting outbreaks, virus may ‘hide’ in asymptomatic people, and NYC outbreak linked to Europe.

Research News 

Michigan State University researchers have repurposed their deep learning models to help drug developers target SARS-CoV-2 main protease. The main protease is crucial in how the virus replicates itself, and the team has used its models to predict the effectiveness of 100 known protease inhibitors to fight COVID-19 and ranked those inhibitors to highlight the most promising ones. This research, published in the journal Chemical Science, has the potential to save drug developers time and money but the authors note that this machine learning is not a replacement for preclinical and clinical trials. DOI:10.1039/D0SC04641H

Turning the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein into a nanoparticle may be the answer for an effective COVID-19 vaccine, say a team of researchers led at the University of Buffalo. The team hypothesized that by converting the RBD into a nanoparticle, similar in size to the virus, would induce higher levels of neutralizing antibodies and greater immune system response against the COVID-19 virus. They tested this theory and when the RBD was converted to nanoparticles, it maintained its original shape and structure and remained stable in an environment that is similar to the human body. When tested in mice and rabbits, high antibody levels were generated when immunized with RBD particles that were converted through the use of liposomes. This work is published in Advanced Materials. DOI:10.1002/adma.202005637

A new study, published in EMBO Reports, sought out an understanding of why some SARS-CoV-2 infected people show no symptoms. The research team, led at Aarhus University in Denmark, isolated alveolar macrophages from lung lavage and looked at the immune system activation in these cells when exposed to the virus. Their findings suggest that the SARS-CoV-2 virus may hide its genomic material from being recognized in the alveolar macrophages, thus no production of interferons or activation of the immune system in the early stages of COVID-19 infection. The team states that more research is needed to understand how the virus avoids immune system recognition in some individuals. DOI:10.15252/embr.202051252

More than 90% of people with mild to moderate COVID-19 produce a strong antibody response and maintain those antibodies for at least five months, according to new research from the Icahn School of Medicine at Mount Sinai. These findings were based on over 30,000 participants who were screened at Mount Sinai between March and October using an enzyme-linked immunosorbent assay (ELISA). The research team then recalled 121 plasma donors at a variety of titer levels (with the vast majority having moderate to high titers of anti-spike antibodies) for repeat testing at three and five months after symptom onset. These follow-up tests revealed that a moderate level of antibody was retained by most people at 5 months post-symptom onset. This study is published in Science. DOI:10.1126/science.abd7728

National Institutes of Health (NIH) researchers have discovered that coronaviruses use lysosomes to exit infected cells, and that they stay completely intact. This research, published in Cell, shows that coronavirus de-acidifies lysosomes which significantly weakens the activity of their destructive enzymes. With this discovery, the team aims to find ways to disrupt this pathway to prevent lysosomes from delivering viruses to the outside of the cell, or in other terms, re-acidify lysosomes to restore their normal function so they can fight SARS-CoV-2. They have already identified one enzyme inhibitor that may block coronaviruses from leaving the infected cell. DOI:10.1016/j.cell.2020.10.039

Researchers from the Department of Energy’s Oak Ridge National Laboratory (ORNL) have used neutron scattering to map key information on SARS-CoV-2 viral replication mechanism. Scientists from this study, published in the Journal of Biological Chemistry, created a 3D map that shows the location of every atom in an enzyme molecule critical to SARS-CoV-2 reproduction. The neutron scattering experiments were performed at the High Flux Isotope Reactor and the Spallation Neutron Source at ORNL and researchers hope this new information will improve the degree of specificity of drug inhibitors for COVID-19. DOI:10.1074/jbc.AC120.016154

Coronaviruses were found to mimic over 150 proteins, including many that control blood coagulation or activate immune proteins that increase inflammation, a new study has found. This research, led at Columbia University Irving Medical Center and published in Cell Systems, used supercomputers to search for viral mimics with a program resembling 3D facial recognition software. More than 7,000 viruses and over 4,000 hosts across Earth’s ecosystems were scanned and 6 million instances of viral mimicry were uncovered, including coronaviruses—which were particularly good at it. DOI:10.1016/j.cels.2020.09.006

Lianhuaqingwen (LHQW) capsule, an herbal medicine, has been clinically proven to be an effective therapy for COVID-19 pneumonia, and researchers have aimed to determine human exposure to LHQW components. The study, published in Acta Pharmaceutica Sinica B, analyzed these effects of LHQW components on human exposure and found that several of its components may play a role in inhibiting SARS-CoV-2 by affecting binding between ACE2 and S protein. This research demonstrates molecular mechanisms of clinical use for LHQW for prevention and treatment of COVID-19 and demonstrates the utility of the human exposure-based approach to identify pharmacologically active components in herbal medicines with approved therapeutic effects. DOI:10.1016/j.apsb.2020.10.002

Researchers have identified two important structures of SARS-CoV-2 papain-like protease (PLpro). The first has a novel crystal packing, high solvent content and reasonable resolution, offering a good foundation for fragment-based screening targeting the enzyme. The second GRL0617 bound structure provides valuable insight into the inhibition mechanism at atomic level. The authors of this paper, published in Acta Pharmaceutica Sinica B, believe these findings will contribute to therapeutic advancements for SARS-CoV-2. DOI:10.1016/j.apsb.2020.08.014

Scientists from Fred Hutchinson Cancer Research Center have isolated a potent antibody, named CV30, from a blood sample of recovered COVID-19 patient. The team found this antibody was 530 times more potent than the dozens of other antibodies naturally produced by the patient, and this particular antibody neutralized SARS-CoV-2 with two mechanisms. It overlaps the virus’s target site on human cells and induces shedding of part of the spike, S1, from the virus. The authors of this study, published in Nature Communications, hope that this discovery may be useful in the prevention and treatment of COVID-19. DOI:10.1038/s41467-020-19231-9

New research led at NYU Grossman School of Medicine traces the origins of New York City’s SARS-CoV-2 outbreak and shows that the virus first appeared in late February and closely matches strains from Europe or other states in the U.S. rather than those from China. The study, published in Genome Research, collected viral genetic information on 864 nasal swabs from COVID-19 positive individuals in New York between March 12 and May 10. The researchers then compared the gene sequences of the virus from those samples to the original strain isolated last winter from Wuhan, China patients. This revealed not only that these strains did not closely match those from China, but that the virus stemmed from at least 109 different sources rather than from a single infected person. Authors of the study also noted that 95 percent of New Yorkers with COVID-19 had a strain with a mutation, making it easier to transmit to others. DOI:10.1101/gr.266676.120

COVID-19 case load and severity will depend on degree of immunity, reinfection rates, vaccine efficacy and willingness to accept a vaccine, based on an interactive model published in Science. The model found that, when looking at several scenarios, a vaccine that produces a strong immune response would significantly decrease future caseload. However, the effect of “vaccine hesitancy” would slow containment of SARS-CoV-2 regardless of an effective vaccine. As expected, the model demonstrated that if immune responses are weak against reinfection, then larger and more frequent outbreaks will occur. DOI:10.1126/science.abd7343

A team of scientists from the New York Genome Center, NYU, and the Icahn School of Medicine at Mount Sinai performed a CRISPR screen to identify which gene modifications made human lungs cells more resistant to SARS-CoV-2 infection and studied the effects of amlodipine on blocking the virus. Researchers discovered a large array of genes that have not previously been considered as therapeutic targets for COVID-19. Additionally, they found that amlodipine, a calcium-channel blocker, effectively blocks SARS-CoV-2 infection. This research is published in Cell. DOI:10.1016/j.cell.2020.10.030

University of Illinois researchers and students have tracked the evolution of the SARS-CoV-2 virus starting in January, when the first SARS-CoV-2 genome was published, up until late May with more than 15,300 genomes. The team found that in some regions, the virus is still actively producing new mutations, while in other regions the mutation rate has slowed down. Overall, the study documented a generalized slowdown of mutation rate in April and stabilization within the spike protein. Of particular interest, they identified the 614 mutation that occurred over the entire virus population prior to the slowing in April. The 614 mutation was associated with higher infectivity, increased viral loads and higher case fatality rates in previous studies. They also identified evolving mutations that may indicate what is to come next with COVID-19. This research is published in Evolutionary Bioinformatics. DOI:10.1177/1176934320965149

A new study, published in Cell, details proviral and antiviral genes identified in a genome-wide screen of a line of green monkey cells that have a higher risk of death from SARS-CoV-2 exposure than human cell lines. The researchers from Yale University and the Broad Institute of MIT and Harvard aim to guide further research on the development of new COVID-19 therapies through this work. The screens identified two new pro-viral protein complexes, SWI/SNF complex and HMGB1, that were both linked to increased infection and cell death. A third protein complex, histone H3 complex, was found to provide a protective effect by inhibiting the virus to infect cells. DOI:10.1016/j.cell.2020.10.028

Researchers have successfully created human airway stem cells by reprogramming patients’ blood cells. The study, led at Boston Medical Center and published in Cell Stem Cell, details how to generate and purify large quantities of patient-specific airway basal cells by using a blood sample. These advances could lead to new treatments for airway diseases and patients with lung damage from COVID-19, with the end goal being to regenerate the airway in these patients. DOI:10.1016/j.stem.2020.09.017

Diabetic kidney cells behave similarly to kidney cells in COVID-19 patients with kidney damage, potentially making diabetes and SARS-CoV-2 a deadly combination. A new study, published in Kidney International, looked at molecular processes in biopsies from healthy kidney donors and patients with diabetic kidney disease, as well as kidney cells in urine samples from COVID-19 patients with kidney damage. Machine learning was used to identify biological connections between genes and functionally related groups of genes (or modules). Several modules were present in both the COVID-19 patients’ kidney cells and the cells from diabetic kidney disease patients. This finding suggests that cells from diabetic kidney patients may be more vulnerable to COVID-19 and the two together may exacerbate each other’s effects. The study did not, however, look at gene expression in kidney cells from patients with both diabetes and COVID-19 and the researchers suggest further investigation. DOI:10.1016/j.kint.2020.09.015

New research suggests that diabetes and low albumin levels may reduce the effectiveness of dexamethasone. The team of scientists determined how serum albumin transports dexamethasone and that low levels of albumin, a result of diabetes and high blood sugar levels or other drug interactions, can decrease the drugs ability to calm a hyperactive immune system in severe COVID-19 patients. To get a better understanding of serum albumin’s role in COVID-19, researchers analyzed 373 patients from a Wuhan, China hospital and found that those who died had lower albumin levels and higher levels of blood sugar than survivors, aligning with the researchers’ conclusions. These findings can be found in the journal IUCrJ. DOI:10.1107/S2052252520012944

A team of researchers at Duke University have developed a lab-grown lung model that mimics the air sacs of human lungs. This model has allowed them to observe how SARS-CoV-2 infection attacks the lung cells on a molecular level. Dubbed mini-lungs, these lung organoids are purely human without any helper cells that would interfere with accurate findings. The team plans to next examine a new strain of SARS-CoV-2, called D614G, that has emerged in Italy. A description of this development and early experiments with COVID-19 are published in the journal Cell Stem Cell. DOI:10.1016/j.stem.2020.10.005

Industry News

Emulate announced that it has entered into a Cooperative Research and Development Agreement (CRADA) with the FDA to enable agency-wide studies at FDA to use Organs-on-Chips technology to better understand COVID-19 and evaluate safety of potential vaccines. The CRADA studies will use the Human Emulation System from Emulate—comprised of Organ-Chips, instrumentation and software apps—which is able to recreate the natural physiology of human tissues and organs in several research areas. These research areas include a Lung-Chip, Brain-Chip, Intestine-Chip and Liver-Chip. The Lung-Chip will be used to evaluate COVID-19 vaccines and understand the human immune response against SARS-CoV-2. Press Release

Results of the COVID-19 Host Genetics Initiative (HGI) study were presented at the American Society of Human Genetics (ASHG) 2020 Virtual Meeting. The COVID-19 HGI was formed in March 2020 as a way to bring the international human genetics community together and generate, share, and analyze data related to COVID-19. By June 2020, the HGI included 190 studies from 46 countries and more than 1,100 researchers. The results of the latest meta-analyses are available on the initiative’s website. Press Release

A researcher from Lehigh University has developed a unique approach to predicting COVID-19 outbreaks, combining computational models based on data with human judgements and forecasts. This innovative model has earned support from the Models of Infectious Disease Agent Study (MIDAS) Coordination Center and funding from the National Institutes of Health (NIH). Funding will be utilized to produce this hybrid ensemble and support public health officials on decision-making, as well as making the code and data open source and available to the scientific community. Press Release

A new model using an artificial intelligence-based algorithm predicts acute kidney injury (AKI) requiring dialysis in COVID-19 patients. Using data from more than 3,000 hospitalized COVID-19 patients, researchers at the Icahn School of Medicine at Mount Sinai trained a model based on machine learning to predict AKI that requires dialysis. This model demonstrated high accuracy and features that were important for prediction including blood levels of creatinine and potassium, age, heart rate, and oxygen saturation. This research is being presented online during the American Society of Nephrology (ASN) Kidney Week 2020 Reimagined. Press Release