Novel, Short Form of ACE2, AI Learns ‘Language’ of Viral Mutations, Odd Structure of ORF8: COVID-19 Updates

January 15, 2021

January 15, 2021 I Single-dose nanoparticle vaccine triggers strong immune response in mice, mapping the unique structure of SARS-CoV-2 ORF8 protein, COVID-19 may eventually become as mild as common cold, MDA-5 identified as ‘immune cop’, nanoparticle immunization technology could protect against several strains of coronaviruses, highly specific nanobodies show promising results, and shorter telomeres identified in patients with severe disease. Plus: Human lung bronchioalveolar tissue model successfully demonstrates viral replication along with potential therapy and mitochondria one of the first lines of defense.


Research News

Researchers have developed a new tool for predicting the mutations that allow viruses to escape human immunity and vaccines. By applying natural language processing, the machine learning technique originally developed to train computers to understand human language using a sequence of words, the researchers developed models to predict the mutations that may lead to viral escape using sequences of amino acids. They developed separate language models for influenza A, HIV-1 and SARS-CoV-2 proteins that accurately predicted casual escape mutations and determined structural regions with high escape potential. For SARS-CoV-2, they found the escape potential within the spike protein is significantly enriched in two domains and depleted in another. This research is described in Science. DOI:10.1126/science.abd7331

Biologists at Berkeley Lab’s Advanced Light Source have revealed the odd structure of the SARS-CoV-2 ORF8 protein and have published the structural map in PNAS. Using X-ray crystallography, the team built an atomic model of ORF8 and discovered two unique regions. One region is only present in SARS-CoV-2 and its immediate bat ancestor, and one region is absent from any other coronavirus. Those regions stabilize the protein and create new intermolecular interfaces that are involved in reactions that make SARS-CoV-2 more pathogenic than the strain it evolved from, according to the researchers. They further explain that ORF8’s amino acid sequence is so unlike any other protein that the team had no reference for its overall shape, and it is the 3D shape of a protein that determines its function. DOI:10.1073/pnas.2021785118

A new model developed by Emory and Penn State scientists predicts that SARS-CoV-2 will transition to a mild endemic state. The research, published in Science, drew upon studies of the four common cold coronaviruses and SARS-CoV-1. The researchers determined that immunological indicators suggest that fatality rates and the critical need for mass vaccination may wane in the near future, assuming that immunity to SARS-CoV-2 works similarly to other human coronaviruses. They explain that once the endemic phase is reached and primary exposure is in childhood, COVID-19 may be no more virulent than the common cold. They would, however, predict a different outcome for an emergent coronavirus that causes severe disease in children. Widely available testing and containment will be critical during vaccine roll-out to protect vulnerable populations and continued vaccinations for these vulnerable populations in the endemic phase will still be necessary, according to the researchers. DOI:10.1126/science.abe6522

Scientists at Sanford Burnham Prebys Medical Discovery Institute have identified the ‘immune cop’ that detects SARS-CoV-2 and signals an immune response. The study, published in Cell Reports, surveyed 16 viral RNA binding proteins in human lung epithelial cells and identified MDA-5 as this predominant sensor responsible for activating interferon. Researchers reference past studies that demonstrate interferon responses are higher in patients with mild-to-moderate COVID-19 cases when compared to severe cases, and they suggest that patients who become critically ill are deficient in the interferon signaling pathway. They believe that this research opens opportunities to explore therapies that could enhance the MDA-5 signaling to boost interferon levels early in infection to prevent severe disease. DOI:10.1016/j.celrep.2020.108628

SARS-CoV-2 can infect neurons and damage brain tissue, finds a new study published in the Journal of Experimental Medicine (JEM). Yale School of Medicine researchers analyzed the ability of SARS-CoV-2 to invade human brain organoids and found that the virus was able to infect neurons in these organoids and replicate by boosting the metabolism of infected cells, while neighboring uninfected neurons died as a result of reduced oxygen supply. The Yale team also determined that angiotensin-converting enzyme 2 (ACE2) protein is produced by neurons and that blocking the protein prevents the virus from infecting human brain organoids. Dramatic alterations in the brain’s blood vessels were also observed in mice genetically engineered to produce human ACE2 when infected with SARS-CoV-2. The researchers then confirmed these findings through autopsy of brains from three deceased COVID-19 patients and found localized tissue damage and cell death in all three patients. The team suggests that neurological symptoms associated with COVID-19 may be related to these pathologies and further studies are needed to determine what might predispose some patients to infections of the central nervous system. DOI:10.1084/jem.20202135

A team of researchers from California Institute of Technology has designed nanoparticle immunization technology that could protect against several strains of coronaviruses. The vaccine platform, called a mosaic nanoparticle, was initially developed by collaborators at the University of Oxford. The nanoparticle is shaped like a cage made up of 60 identical proteins, each of which has a small protein tag that functions like a piece of Velcro. The team took fragments of the spike proteins of different coronaviruses and engineered each to have a protein tag that would bind to those on the cage. Displaying eight different coronavirus spike fragments with this particle platform generated a diverse antibody response in mice. The antibodies produced by the mice were able to react to many different strains of coronaviruses, even related strains that were not present on the nanoparticle. The team is still analyzing the mechanism underlying this phenomenon but hopes that this technology can move forward to human clinical trials in the future. This work is described in Science. DOI:10.1126/science.abf6840

New small antibodies, known as nanobodies, show promising effects against COVID-19 infection in a new study published in Science. Researchers from Karolinska Institutet and University of Bonn were able to generate the nanobodies from the immune systems of alpacas and llamas, whose immune systems naturally produce both antibodies and nanobodies. They were vaccinated with the spike protein of SARS-CoV-2, and among the nanobodies generated from the two animals, the researchers selected the best binders. Ultimately, four were identified as showing exceptional ability to block the virus from spreading in human cultured cells. The team used electron cryomicroscopy (cryo-EM) to study in detail how the nanobodies bind to the virus’ spike protein and were able to propose suitable protein links to bind different nanobodies together into combinations relevant for research, as well as provide a possible explanation for the mechanism of how antibodies neutralize SARS-CoV-2. DOI:10.1126/science.abe6230

Patients with severe COVID-19 disease have significantly shorter telomeres, which are known indicators of aging, according to researchers from the Spanish National Cancer Research Center (CNIO). The study, published in Aging, analyzed the telomeres of 89 COVID-19 patients admitted to a Madrid hospital using several techniques. They found, as expected, that the average length of the telomeres decreased as age increased in the patients studied. Interestingly, the telomeres of the most critically ill COVID-19 patients were shorter, unrelated to their age, when compared to those patients with mild disease. The researchers plan to further study this relationship using a mouse model and speculate that telomerase activation could improve some of the pathologies that remain in COVID-19 patients after infection, such as pulmonary fibrosis. DOI:10.18632/aging.202463

A human lung bronchioalveolar tissue model has been developed by Dutch researchers that successfully demonstrates SARS-CoV-2 replication. The team had already created a self-renewing organoid model for the epithelium of the airways conducting gases, and they have now developed a 2D “air interface” system comprised of a basal layer of stem cells in contact with the culture media and top layer exposed to the air—just as it would be in the lungs. Multiple cultures were generated and infected successfully by SARS-CoV-2 targeting primarily alveolar type-II-like cells, known as ATII-L, confirmed by Transmission Electron Microscopy (TEM), surface marker staining and single-cell sequencing. They also discovered that when cultures were treated with the antiviral signaling molecule interferon lambda early in infection, SARS-CoV-2 replication was almost completely blocked, indicating that interferon lambda could be an effective treatment. The team believes that these cultures would also be helpful in the development of therapeutics against ARDS from COVID-19. This research is published in The EMBO Journal. DOI:10.15252/embj.2020105912

Northwestern Medicine investigators have unveiled why COVID-19 pneumonia lasts longer and causes more damage than other pneumonias in a new study published in Nature. The scientists analyzed immune cells from the lungs of COVID-19 pneumonia patients and compared them to cells from patients with pneumonia from other viruses or bacteria. They discovered that, instead of rapidly infecting large regions of the lung, SARS-CoV-2 invades multiple small areas of the lungs. It then hijacks the lungs’ own immune cells and uses them to spread across the lung over a period of several days to weeks, leaving damage behind. The research team also identified macrophages and T cells as critical targets to treat severe SARS-CoV-2 pneumonia and lessen its damage. Their findings suggest that macrophages can be infected with the virus and contribute to spreading the infection though the lung. They plan to test an experimental drug to treat these targets in patients suffering from COVID-19 pneumonia. DOI:10.1038/s41586-020-03148-w

A new, short, form of ACE2 has been identified that may be protective against SARS-CoV-2 in the airways rather than an entry point for the virus. The study, published in Nature Genetics and led by University of Southampton researchers, reports that this novel form of ACE2 protein differs from the longer form of ACE2 that is a key entry point for COVID-19 into nose and lung cells. Previous studies have shown that interferons increase levels of ACE2, which has cast doubt on treatments such as inhaled interferon beta COVID-19 therapy. Researchers of this study determined that these interferons predominantly increase the short ACE2, while levels of the longer form remain unchanged, and believe these findings support the use of interferons in treating COVID-19 patients. DOI:10.1038/s41588-020-00759-x

Researchers analyzed over 50,000 viral sequences from the first wave of the COVID-19 pandemic in the United Kingdom and identified more than 1,000 UK transmission lineages. Using data from the national COVID-19 Genomics UK (COG-UK) consortium in combination with information on epidemiological factors and travel data, the research team determined that the virus lineages introduced before the UK’s national lockdown in March tended to be larger and more geographically dispersed. The highest number of transmission chains were introduced to the UK from Spain (33%), France (29%), and Italy (12%), while China only accounted for 0.4%. According to the researchers, earlier travel and quarantine interventions could have decreased the acceleration and intensity of the UK’s first wave of cases. This study is published in Science. DOI:10.1126/science.abf2946

A single-dose nanoparticle COVID-19 vaccine triggers a robust antibody response in mice, Stanford University researchers report in ACS Central Science. The vaccine consists of multiple copies of the spike protein displayed on ferritin nanoparticles. Scientists explain that viral antigens can be fused to ferritin so that each nanoparticle displays several copies of the protein, which may cause a stronger immune response than a single copy. The team found that after a single immunization, mice produced neutralizing antibody titers that were at least two times higher than those in convalescent plasma from COVID-19 patients and significantly higher than those in mice immunized with the spike protein alone. Although these results must be confirmed in human clinical trials, the researchers suggest that the spike/ferritin nanoparticles could be an effective strategy for single-dose vaccination against COVID-19. DOI:10.1021/acscentsci.0c01405

New research from the University of Southern California (USC) Leonard Davis School of Gerontology suggests that mitochondria are one of the first lines of defense again COVID-19, and the virus affects mitochondrial genes in unique ways. The study, published in Scientific Reports, performed RNA sequencing analyses that compared mitochondrial-COVID interactions to those of other viruses and identified three ways in which COVID-19 “quiets” the body’s cellular protective response that were not seen with other viruses. The researchers believe that these unique differences could offer explanations into why older adults and those with metabolic dysfunction are more susceptible to severe COVID-19 and suggest further studies on mitochondrial biology as a primary intervention target for SARS-CoV-2 and other coronaviruses. DOI:10.1038/s41598-020-79552-z


Industry News

In the first publication from the COVID-19 Host Genome Structural Variant Consortium, the study identifies structural variants (SV) with possible roles in pathogenesis and clinical outcomes using Bionano’s Saphyr System. The new study reports the analysis of the genomes of 37 patients admitted to the ICU at Augusta University with severe COVID-19. Of the SVs revealed by Saphyr, the most compelling finding was the duplication of the STK26 gene. The study found significant upregulation of STK26 in all severely ill patients tested but not in asymptomatic COVID-19 patients, implying the duplication to be a potential novel, prognostic biomarker for the severe immune response seen in critically ill patients with COVID-19. Press Release

New funding provided by UK Research and Innovation (UKRI) will support global COVID-19 genome sequencing to track the spread and evolution of the virus. The grant will enable the CLIMB COVID-19 project, led by the University of Birmingham and Cardiff University, to carry out significant upgrades to its computational equipment. The project has already sequenced more than 150,000 genomes in the United Kingdom, and this new funding will enable global genomic data to be stored and processed while also allowing researchers to extend research to cover other pathogens with pandemic potential. Press Release