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Mouse Models, Machine Learning, Triggering Proteins: COVID-19 Updates



By Bio-IT World Staff

Sept. 4, 2020   A potential new screening approach, improving immune response to vaccines, new mouse models of SARS-CoV-2, exploring ACE2 receptor activity, a protein that may trigger blood clots, the importance of placenta tissue, hopeful signs that a single vaccine can do the job, and a bioengineering technique to boost production of proteins that prompt antibody development. Plus, machine learning to help identify drug combinations that can be repurposed as potential therapies. 

Research Updates: 

A new pathway that targets a common vulnerability in several different pandemic viruses has been identified and can protect cells from infection by Ebola virus as well as coronaviruses like SARS-CoV-2, according to a study that published in Science. Findings were uncovered by an innovative screening approach based on activation of chromosomal segments called transposons to look for new genes that can prevent infection by Ebola virus. The strategy uncovered that the gene MHC class II transactivator induces resistance to the virus in human cell lines by activating the expression of a second gene, CD74. One isoform of CD74, known as p41, disrupts the processing of proteins on the coat of the Ebola virus protein by cellular proteases called cathepsins. This prevents entry of the virus into the cell and subsequent infection. In further research using human cell lines, researchers showed that CD74 p41 also blocked the cathepsin-dependent entry pathway of coronaviruses. The authors say they anticipate application of the transposon screening approach to other models of infection will reveal other mechanisms that have eluded conventional screening strategies. DOI: 10.1126/science.abb3753

Researchers at La Jolla Institute for Immunology led a study, published in Immunity, demonstrating the importance of antigen valency (the number of antibody binding sites on an antigen) in improving the body's immune response to vaccines. With a higher valency, antibodies have more sites to latch onto, yet including a higher antigen valency in a vaccine doesn't mean it works better. Using two-photon microscopy to visualize the effects of valencies on B cell responses, researchers discovered that high-valency antigens can lead the body to make more antibody-producing B cells. In fact, a valency of 60 seems to be enough to boost B cell numbers, and a valency of four might be enough in many cases. Low-valency antigens lead to a smaller, more targeted B cell response. While B cells are rarer, they’re more likely to be sharp shooters, the authors say. They developed a platform that displays different antigens and allows a fair comparison of responses in experiments with mice. Their conclusion was that vaccines need a valency of more than one binding site but that choosing a valency of four over a valency of 60 doesn't have a big effect on B cell responses. DOI: 10.1016/j.immuni.2020.08.001

A review of published preclinical data on sex-specific hormone activity suggests angiotensin-converting enzyme2 (ACE2) is the cellular receptor of the coronavirus responsible for COVID-19 infections and helps bring the virus into the cells of the heart, arteries, kidneys and intestines. It also points to estrogen's role in lowering the level of ACE2 in the heart, which may modulate the severity of COVID-19 in women and explain why symptoms are worse in men. The review, by researchers at Wake Forest School of Medicine, published in Current Hypertension ReportsDOI: 10.1007/s11906-020-01073-x

Researchers at the University of Alberta are preparing to launch clinical trials of a protease inhibitor used to cure a deadly disease caused by a coronavirus in cats that they expect will also be effective as a treatment for humans against COVID-19. Findings were published in Nature Communications after first being posted on the research website BioRxIV. The drug shows enough antiviral action against SARS-CoV-2 to proceed immediately to clinical trials, for which veterinary medicine company Anivive Life Sciences will produce the needed quality and quantity of the drug. Human testing will likely be in Alberta in combination with other promising antivirals such as remdesivir. DOI: 10.1038/s41467-020-18096-2

A new COVID-19 mouse model developed at the University of North Carolina (UNC) at Chapel Hill captures many of the features of human disease and helped advance Moderna’s COVID-19 vaccine candidate to clinical trial. The mouse-adapted SARS-CoV-2 model, described in Nature, has also been used to accelerate the development of other vaccine candidates, including alphavirus replicon platforms developed at UNC. Researchers changed two amino acid positions in the viral genome of standard laboratory mice to generate mild symptoms in both young and old rodents and more severe disease in line with what has been reported in the human population. DOI: 10.1038/s41586-020-2708-8

Army scientists report in JCI Insight that they have developed the first lethal mouse model of SARS-CoV-2 using mice genetically engineered to express the human ACE2 gene. The team used a special type of mice called K18-hACE2, which are specially bred with the human ACE protein instead of the mouse version. This mouse strain, developed at the University of Iowa for the original SARS-CoV in the early 2000s, was revived and recently produced at the Jackson Laboratory. For the latest study, researchers used two groups of 14 (half male/female) K18-hACE2 mice infected with two different doses of SARS-CoV-2 administered by the intranasal route. On day three, four mice per group were euthanized to assess disease severity, while the remaining ten mice per group were monitored up to 28 days. Overall, the K18-hACE2 mice developed acute disease, including weight loss, lung injury, and brain infection, and ultimately succumbed to the disease. DOI: 10.1172/jci.insight.142032

Leveraging the National Drug Discovery Centre and ANSTO's Australian Synchrotron, researchers have identified drug-like compounds that could block the key coronavirus protein PLpro. Initially developed as potential treatments for SARS, the compounds prevented the growth of the SARS-CoV-2 virus in the laboratory. Thousands of currently listed drugs and drug-like compounds were scanned to arrive at the discovery, which published in The EMBO Journal. Other Australian collaborators on the project included scientists from the Walter and Eliza Hall Institute of Medical Research and the Commonwealth Scientific and Industrial Research Organisation, plus the Oncode Institute and Department of Cell and Chemical Biology (Leiden University, The Netherlands). DOI: 10.15252/embj.2020106275

A study of a gateway receptor for SARS-CoV-2 may help explain the wide variety of symptoms and organs involved with COVID-19 infection. The results, which published in Cellular and Molecular Neurobiology, suggest that a multi-organ infection with SARS-CoV-2 may be via the ACE2 receptor, which is found almost everywhere throughout the body. Researchers from Louisiana State University and Alchem Biotech Research (Toronto) analyzed 85 human tissues—lung, digestive, renal-excretory, reproductive, eye, and samples from 21 different regions of the brain—for the presence of ACE2 receptors. Some of the highest ACE2 expression levels were found in the pons and medulla oblongata in the human brainstem, an anatomical region of the brain containing the medullary respiratory centers that may in part explain the susceptibility of many COVID-19 patients to severe respiratory distress. The team further noted that ACE2 receptor activity was easily detected in the eye, suggesting that the visual system may provide an additional entry point for SARS-CoV-2 invasion and that under certain conditions, eyeglasses or face shields may be as important as face masks in reducing SARS-CoV-2 transmission and infection. DOI: 10.1007/s10571-020-00947-7

A single vaccine candidate should be efficacious against currently circulating lineages of SARS-CoV-2, suggest findings of a study by a team of researchers at the Walter Reed Army Institute of Research that published in Proceedings of the National Academy of Sciences. They analyzed 18,514 SARS-CoV-2 sequences sampled since December 2019 and found that neutral evolution, rather than adaptive selection, explains the rare mutations seen across SARS-CoV-2 genomes. Vaccines developed using any randomly selected SARS-CoV-2 sequence should, theoretically, be effective against all circulating viruses. Vaccine developers could consider designing a vaccine insert with the D614G mutation in the virus’s spike protein, as this mutation has become dominant worldwide. DOI: 10.1073/pnas.2008281117

In a study to be published in Cell Reports Medicine, researchers in Germany found that a strong T-cell and antibody response could be detected in patients who had recovered from mild COVID-19 disease and critically ill patients had the same or stronger immunity. The data suggests excessive immune response can cause immunopathogenesis leading to COVID-19-related lung failure, a hypothesis supported by the successful application of immunosuppressive therapies. DOI: 10.1016/j.xcrm.2020.100092

Scientists at Uppsala University and the University Hospital (Sweden) have identified a protein that may trigger blood clots (thrombosis), a common complication in severe COVID-19, as reported in Thrombosis and Haemostasis. A key mechanism of clot formation, they say, may be activation of the complement system—a component of the innate immune system—which can be initiated by proteins such as mannose-binding lectin (MBL). Sixty-five patients receiving intensive care at Uppsala University Hospital had their MBL levels and activity measured and, in all those who developed thrombosis during their hospital stay, MBL activity and levels were found to be elevated. The scientists believe that when the complement system is activated by means of MBL, it contributes to a massive activation of the blood coagulation system as well, and in a way that blood-thinning drugs can't prevent. Findings might eventually lead to testing of MBL activity in COVID-19 patients to identify those who are at high risk of getting thrombosis; MBL could also be a possible target in future development of drugs to prevent the condition. DOI: 10.1055/s-0040-1715835

Researchers from Boston Medical Center's Maxwell Finland Laboratory for Infectious Diseases have identified properties in placenta tissue that may play an important role in preventing the transmission of COVID-19 from a mother to her fetus. Their study, published in Placenta, demonstrates that the COVID-19 virus universally invades the placenta in cases with and without evidence of fetal infection, highlighting the protection that the placenta may offer against COVID-19 infection. Current data indicates a COVID-19 transmission rate of less than 5% in newborns from their mothers. Researchers also found that the placenta contains a unique pattern of cell surface proteins (TMPRSS2 and ACE2) that are important for COVID-19 viral entry. Study results underscore the importance of using placenta tissue in COVID-19 research studies aimed at developing novel ways to diagnose, treat and prevent COVID-19 virus transmission. For this study, samples were collected taken from 15 COVID-19 positive maternal-fetal dyads; five cases had evidence of fetal transmission and the placental tissue of the positive cases was analyzed and compared with ten COVID-19 negative controls. DOI: 10.1016/j.placenta.2020.08.015

A bioengineering technique to boost production of specific proteins could be the basis of an effective vaccine against COVID-19, suggests a study published in Advanced Materials. Scientists at The Ohio State University manipulated a natural cellular process to ramp up levels of two proteins used by the virus to infect other cells, packaged the protein-boosting instructions in nanoparticles and injected them into mice. Within a month, the mice had developed antibodies against the SARS-CoV-2 virus. The technique involves altering specific sequences (untranslated regions, or UTRs) of messenger RNA, whose structure the researchers changed to promote higher-than-usual levels of proteins. The team worked with the two UTRs that bookend the start and finish of protein assembly, functioning as regulators of that process and influencing how the resulting protein interacts with others. Like other SARS-CoV-2 vaccine candidates, they used two antigens used by the novel coronavirus to cause infection, the spike protein on its surface and a receptor binding domain that the virus uses to make its way into host cells. DOI: 10.1002/adma.202004452  

Industry Updates:  

Relation Therapeutics has teamed up with Mila (Quebec AI Institute) to identify COVID-19 therapeutic candidates. Project RE, as it is known, is being supported by a grant from the Bill & Melinda Gates Foundation and will focus on repurposing drug combinations as potential therapies to tackle viral entry and replication. The project will also create a platform to develop therapies that appropriately modulate the immune response through distinct stages of infection. The companies aim to leverage the most powerful machine learning techniques currently being deployed by the world’s largest tech companies and academia to revolutionize computational drug development. The news coincides with five significant new appointments at Relation Therapeutics. Press release

A data scientist at Ben-Gurion University of the Negev sees the end of the coronavirus peak in Israel and believes that New York and California may have reached herd immunity. His findings were presented virtually at the recent International Conference on Artificial Intelligence in Medicine and based on the SIR Model of Infection Dynamics that assigns populations to compartments with labels (susceptible, infectious or recovered). Such models can show the impact of different public health interventions can affect the spread of an epidemic, such as the most efficient technique for issuing a limited number of vaccines in each population. According to the SIR model, herd immunity is defined by a disease reproduction number (average amount of secondary infections an infected person will cause in a completely susceptible population of less than one)—a milestone New York State was close to achieving in late June and California hit in mid-July. While Israel is close to reaching herd immunity, provided restrictions are not relaxed, the outlook for COVID-19 patients admitted to intensive care units in the country is dire. Press release

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