Modeling New Drug Options, Better Look At Immune Response, Impact of Chromosome 12: COVID-19 Updates

February 19, 2021 | Specialized cells in a child’s immune system rapidly target SARS-CoV-2, nasal antiviral blocks transmission in ferrets, machine learning used for drug repurposing, insight into how the virus attacks mucus membrane cells, and a CDC update on anaphylaxis after vaccination. Plus: Fauci on known variants of the virus.

Research Updates 

An international team calculated years of life lost (YLL) across 81 countries due to COVID-19 attributable deaths, and also conducted an analysis based on estimated excess deaths. They found that over 20.5 million years of life have been lost to COVID-19 globally. Three quarters of the YLL result from deaths in ages below 75 and almost a third from deaths below 55. Men have lost 45% more life years than women. They published their findings in Scientific Reports. DOI: 10.1038/s41598-021-83040-3

A team from Boston and Zambia collaborated to gauge the impact of COVID-19 in Africa. They conducted PCR tests on 364 deceased people of all ages at the University Teaching Hospital morgue in Lusaka, Zambia between June and September 2020, enrolled within 48 hours of death and found SARS-CoV-2 infections in 15% of all sampled deaths—most of whom had not been tested before. “Contrary to expectations, deaths with COVID-19 were common in Lusaka,” the authors write. “Cases of COVID -19 were under-reported because testing was rarely done not because COVID -19 was rare,” they contend. Their work is published in The BMJ. DOI: 10.1136/bmj.n334

Specialized cells in a child's immune system rapidly target the new coronavirus (SARS-CoV-2) according to new work published in Nature Communications. Researchers from the Murdoch Children's Research Institute compared 48 infected or exposed children with 70 infected or exposed adults. They found that clinically mild SARS-CoV-2 infection in children is characterized by reduced circulating subsets of monocytes (classical, intermediate, non-classical), dendritic cells, and natural killer cells during the acute phase. In contrast, SARS-CoV-2-infected adults show reduced proportions of non-classical monocytes only. They also observe increased proportions of CD63+ activated neutrophils during the acute phase to SARS-CoV-2 in infected children. DOI: 10.1038/s41467-021-21414-x 

A nasal antiviral created by researchers at Columbia University blocked transmission of SARS-CoV-2 in ferrets, suggesting the nasal spray also may prevent infection in people exposed to the new coronavirus, including recent variants. Daily intranasal administration to ferrets completely prevented SARS-CoV-2 direct-contact transmission during 24-hour co-housing with infected animals, under stringent conditions that resulted in infection of 100% of untreated animals. These lipopeptides in the spray are highly stable and thus may readily translate into safe and effective intranasal prophylaxis to reduce transmission of SARS-CoV-2. The work is published in Science. DOI: 10.1126/science.abf4896 

Guided by a computational docking analysis, a team of researchers from the University of Texas experimentally characterized about 30 FDA/EMA-approved drugs on their inhibition of essential main protease of SARS-CoV-2, the pathogen of COVID-19. From this study, they have published a report in PNAS highlighting that bepridil, an antianginal medication, is potent against SARS-CoV-2. The antiviral analysis of bepridil indicated that it had low micromolar EC50 values in inhibiting SARS-CoV-2 in two highly permissive mammalian cell lines. The authors encourage further preclinical investigations of bepridil in animal models to clear its path for clinical uses in COVID-19 patients. DOI: 10.1073/pnas.2012201118

Researchers at MIT and Harvard look at how antibodies can help us understand immune response to SARS-CoV-2 virus. Existence of antibodies against SARS-CoV-2 doesn’t seem to be enough to determine if a person had long-lasting protection. Instead, antibody effector functions associated with long-lasting protection, like virus neutralization and T cell responses, were only seen if the immune response included high levels of antibodies against a part of the virus called the receptor binding domain. Using a community-based surveillance study, the team sought to define the relationship between titers and functional antibody activity to SARS-CoV-2 over time. In a paper in Nature Communications, they report significant heterogeneity, but limited decay, across antibody titers among 120 identified seroconverters, most of whom had asymptomatic infection. DOI: 10.1038/s41467-021-21336-8 

A German team has studied how SARS-CoV-2 attacks the body’s mucus membrane cells. Using primary epithelial organoids from human colon, they explored how the central antiviral mediator IFN‐γ, which is elevated in COVID‐19, affects epithelial cell differentiation, ACE2 expression, and susceptibility to infection with SARS‐CoV‐2. IFN‐γ‐driven inflammatory responses may induce a vulnerable epithelial state with robust replication of SARS‐CoV‐2, which may have an impact on disease outcome and virus transmission. DOI: 10.15252/emmm.202013191

Using data from the Genetics of Mortality in Critical Care (GenOMICC) consortium, a team from Karolinska Institutet shows that a haplotype at a region on chromosome 12 associated with requiring intensive care when infected with the virus is inherited from Neandertals. This region encodes proteins that activate enzymes that are important during infections with RNA viruses. In contrast to the previously described Neandertal haplotype that increases the risk for severe COVID-19, this Neandertal haplotype is protective against severe disease. The work is published in PNAS. DOI: 10.1073/pnas.2026309118 

Researchers from the European Molecular Biology Laboratory adapted a biophysical method called thermal proteome profiling (TPP) to high biosafety conditions to gain a comprehensive overview of which human proteins are functionally altered during SARS-CoV-2 infection. TPP monitors protein amounts and denaturation temperatures. A shift in denaturation temperature indicates that a particular protein has undergone a functional change upon infection, possibly due to the virus hijacking the protein for use in its own replication. The group published their findings in Molecular Systems Biology and proposes that the work serve as a framework for expanding TPP workflows to globally important human pathogens. DOI: 10.15252/msb.202010188

Anthony Fauci and colleagues have published an editorial in JAMA outlining the known variants of the SARS-CoV-2 virus. To communicate effectively about new SARS-CoV-2 variants, a common nomenclature is needed, the team writes, and they applaud the World Health Organization (WHO)’s work on a systematic nomenclature that does not require a geographic reference. DOI: 10.1001/jama.2021.2088 

CDC researchers published an update on anaphylaxis after vaccination in JAMA Insights. Citing unpublished CDC data, they reported that between December 14, 2020 and January 18, 2021, a total of 9,943,247 doses of the Pfizer-BioNTech vaccine and 7,581,429 doses of the Moderna vaccine were reported administered in the US. CDC identified 66 case reports for anaphylaxis: 47 following Pfizer-BioNTech vaccine for a reporting rate of 4.7 cases/million doses administered, and 19 following Moderna vaccine for a reporting rate of 2.5 cases/million doses administered. DOI: 10.1001/jama.2021.1967

A team from MIT has developed a machine learning-based approach to identify drugs already on the market that could potentially be repurposed to fight Covid-19, particularly in the elderly. They used large-scale transcriptional drug screens combined with RNA-seq data of the lung epithelium with SARS-CoV-2 infection as well as the aging lung. To identify robust druggable protein targets, they propose a principled causal framework that makes use of multiple data modalities. Using the approach, the researchers pinpointed the protein RIPK1 as a promising target for Covid-19 drugs, and identified three approved drugs that act on the expression of RIPK1. They published their approach in Nature Communications. DOI: 10.1038/s41467-021-21056-z

A team from WorldQuant Predictive, an AI predictive products company, and CAS, a division of the American Chemical Society, have collaborated on a unique approach to bioactivity and chemical data curation coupled with random forest analyses has led to a series of target-specific and cross-validated predictive feature fingerprints (PFF) that have high predictability across multiple therapeutic targets and disease stages involved in COVID-19, which include plasma kallikrein, human immunodeficiency virus (HIV)-protease, nonstructural protein (NSP)5, NSP12, Janus kinase (JAK) family, and AT-1. The approach was highly accurate in determining the matched target for the different compound sets and suggests that the models could be used for virtual screening of target-specific compound libraries. The curation-modeling process was successfully applied to a SARS-CoV-2 phenotypic screen and could be used for predictive bioactivity estimation and prioritization for clinical trial selection; virtual screening of drug libraries for the repurposing of drug molecules; and analysis and direction of proprietary data sets. The work is published in ACS Omega. DOI: 10.1021/acsomega.0c05303