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Omicron binds to ACE2 with high affinity, enhancing its transmissibility and infectivity

Jacob Scott

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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), since its emergence, has continuously evolved to evade host hostilities as well as increase transmission by raising new variants of concerns (VOCs). Virus host adaptation is evident by the rise of VOCs (beta, beta, gamma, and delta variants) that impede the neutralization effect of antibodies. Recently (Nov. 24th, 2021), a novel strain of SARS-CoV-2 named Omicron emerged in South Africa and quickly spread worldwide.

Currently, scientists are trying to understand how Omicron is spread, and whether current therapeutics will still be effective against it. Researchers studied the binding strength of Omicron with ACE2 and seven monoclonal antibodies either approved by the FDA or undergoing phase III clinical trials, in a study published on the bioRxiv* preprint server.


Study: Omicron: A heavily mutated SARS-CoV-2 variant exhibits stronger binding to ACE2 and potently escape approved COVID-19 therapeutic antibodies. Image Credit: NIAID

The Omicron Variant

The Omicron variant has many novel mutations in both structural and non-structural proteins. For example, scientists have observed more than 32 mutations in the Spike protein alone, with 15 of these residing in the receptor-binding domain (RBD). Such a large number of mutations have raised concerns over increased transmissibility, immune escape, and vaccine failure.

The non-structural proteins encoded by the ORF1ab contain mutations in the nsp3, nsp4, nsp5, nsp6, nsp12, and nsp14. In addition, Omicron harbors mutations in the other structural proteins, including Envelope (E), Membrane (M), and Nucleocapsid (N). Since N is highly immunogenic, these mutations could help escape the host immune response. About half of the mutations possess the potential to dampen the potency of therapeutic and enhance ACE2 binding. A significant cause for concern is that this variant can infect vaccinated people, as has been demonstrated by vaccinated people in South Africa and Hong Kong being affected.

Phylogeny of the Omicron and annotation of the mutation in Spike protein. The Unrooted phylogenetic tree was constructed from the Nextstrain servers. Wuhan-Hu-1/2019 strains were taken as a reference sequence. B) The full-length Delta and Omicron Spike were built to annotate the relative (not exact) positions of the mutations on the surface map of Spike. C) The amino acids mutated in the RBD of Omicron are shown concerning the ACE2 interface. Residues are colored according to the electrostatic map of the WT strain. Respective Omicron mutations are depicted in the panel below the RBD surface map.

A New Study

By conducting molecular modeling and mutational analyses, scientists sought to understand how the Omicron variant enhanced its transmissibility and whether it can escape the FDA-approved Spike-neutralizing COVID-19 therapeutic antibodies.

The researchers selected seven therapeutic antibodies, including Etesevimab, Bamlanivimab, AZD8895, AZD1061, Imdevimab, Casirivimab, and CT-p59.

Mutations in the Omicron RBD distort the epitopes of therapeutic mAbs. A-D) Crude epitopes of seven selected mAbs are shown on the RBD. Antibodies used as cocktails are labeled with their sponsors. All variable light chains are colored yellow or orange and variable heavy chains are colored red. E) Changes in the binding affinity of the RBDOmic-mAbs relative to RBDWT-mAbs are shown. The Binding energies were calculated through endpoint MM/GBSA). F) Changes in the electrostatic potentials and polar solvation energies are shown to each RBD-mAb complex.

Main Findings

The spike-ACE2 interaction: Researchers observed three deletion sites in the N-terminus domains (NTD) and at least 15 substitutions in the RBD region in the Omicron variant. The Spike also harbors mutations, such as K417, T478, E484, and N501, which have been reported in previous VOCs.

An important observation was that at least 11 (out of the 15) mutated residues could influence ACE2 binding and significantly affect the binding affinity.

The Omicron spike (compared to the prototype SARS-CoV-2) had three deletions, i.e., ?69-70, ?143-145, and ?211, and one highly charged insertion at 214 positions in the Spike, i.e., ins214EPE.

Per-residue changes in the binding affinity of RBD-mAbs were monitored, and the hotspots on CDRs of (A) Bamlanivimab and (B) CT-p59 are labeled. The change in the hydrogen bonds network of the selected hotspots is shown at the right.

In order to monitor the relative binding strength of RBD-ACE2 complexes of both the prototype Wuhan and Omicron strains, scientists used a protein design strategy and calculated binding affinity and stability changes.

Individually substituted residues were seen to have a slight effect on the local stability of the RBD-ACE2 complexes. However, a large increase in the binding affinity by T478K, Q493K, and Q498R led to an overall increase in the binding affinity of the RBDOmic with ACE2.

Researchers studied the change in electrostatic potential of the RBDOmic relative to that of RBDWT. The electrostatic energy of ACE2-RBDOmic was found to be double that of ACE2-RBDWT. The energy distribution suggested that mutations in the RBDOmic directly enhance the binding strength of amino acids in the same network. Overall, the data showed that Omicron binds to ACE2 with greater affinity, partly explaining its increased transmissibility. However, the pathogenicity of the new strain could not be predicted.

Binding of therapeutic antibodies: Scientists constructed structural models of seven mAbs bound to RBDOmic and showed a substantial drop in the total binding energies of Bamlanivimab and CT-p59. Except for AZD1061 (AstraZeneca), all other mAbs showed a significant drop.

Changes in energies were calculated for CT-p59 and Bamlanivimab to gain a better understanding of the mutations involved in weakening the RBDOmic -mAbs interactions.

It was observed that R96 and R50 of the Bamlanivimab, which establish highly stable salt bridges with the E484 of RBDWT, completely lost their binding upon E484A mutation. E102 and R104 in CDRH3 also showed a 50% reduction in binding energies. E484A, Q493K, and Y505H mutations in RBDOmic were responsible for the lowering of the bindings.

Overall, these data raise grave concerns about the efficacy of therapeutic mAbs in Omicron patients.

Concluding Remarks

The Omicron variant has been proven to be more transmissible than the Delta variation, and the threat is now global. Therefore, there is an urgent need to closely monitor the COVID-19 variant and accelerate vaccination, as this could reduce COVID-19 infections dramatically. Additionally, the search for more effective therapeutics must continue.

*Important Notice

bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Journal reference:
Omicron: A heavily mutated SARS-CoV-2 variant exhibits stronger binding to ACE2 and potently escape approved COVID-19 therapeutic antibodies Hyun Goo Woo, Masaud Shah, bioRxiv, 2021.12.04.471200; doi: https://doi.org/10.1101/2021.12.04.471200, https://www.biorxiv.org/content/10.1101/2021.12.04.471200v1

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Unraveling How Strigoractone Hormone Regulates Massive Gene Networks Controlling Plant Growth

Jacob Scott

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As sessile organisms, plants have to continually adapt their growth and architecture to the ever-changing environment. To do so, plants have evolved distinct molecular mechanisms to sense and respond to the environment and integrate the signals from outside with endogenous developmental programs.

New research from Nitzan Shabek’s laboratory at the UC Davis College of Biological Sciences, published in Nature Plants, unravels the underlying mechanism of protein targeting and destruction in a specific plant hormone signaling pathway.

Our lab aims at deciphering sensing mechanisms in plants and understanding how specific enzymes function can be regulated at the molecular levels. We have been studying a new plant hormone signal, strigolactone, that governs numerous processes of growth and development including branching and root architecture.”

Nitzan Shabek, assistant professor of biochemistry and structural biology, Department of Plant Biology

The work stems from a study by Shabek, published in Nature in 2018, unravelling molecular and structural changes in an enzyme, MAX2 (or D3) ubiquitin ligase. MAX2 was found in locked or unlocked forms that can recruit a strigolactone sensor, D14, and target for destruction a DNA transcriptional repressor complex, D53. Ubiquitins are small proteins, found in all eukaryotes, that “tag” other proteins for destruction within a cell.

To find the key to unlock MAX2 and to better understand its molecular dynamics in plants, postdoctoral fellows Lior Tal and Malathy Palayam, with junior specialist Aleczander Young, used an approach that integrated advanced structural biology, biochemistry, and plant genetics.

“We leveraged structure-guided approaches to systemically mutate MAX2 enzyme in Arabidopsis and created a MAX2 stuck in an unlocked form”, said Shabek, “some of these mutations were made by guiding CRISPR/Cas9 genome editing thus providing us a discovery platform to study and analyze the different signaling outputs and illuminate the role of MAX2 dynamics.”


They found that in the unlocked conformation, MAX2 can target the repressor proteins and biochemically decorate them with small ubiquitin proteins, tagging them for destruction. Removing these repressors allows other genes to be expressed – activating a massive gene network that governs shoot branching, root architecture, leaf senescence, and symbiosis with fungi, Shabek said.

Sending these repressors to the proteasome disposal complexes requires the enzyme to relock again. The team also showed that MAX2 not only target the repressors proteins, but once it is locked the strigolactone sensor itself gets destroyed, returning the system to its original state.

Finally, the study uncovered the key to the lock, an organic acid metabolite that can directly trigger the conformational switch.

“Beyond the implication in plants signaling, this is the first work that placed a primary metabolite as a direct new regulator of this type of ubiquitin ligase enzymes and will open new avenues of study in this direction,” Shabek said.

Additional coauthors on the paper are specialist Mily Ron and Professor Anne Britt, Department of Plant Biology. The study was supported by NSF CAREER and EAGER grants to Shabek. X-ray crystallography data was obtained at the Advanced Light Source, Lawrence Berkeley National Laboratory, a U.S. Department of Energy user facility.

Source:
Journal reference:

Tal, L., et al. (2022) A conformational switch in the SCF-D3/MAX2 ubiquitin ligase facilitates strigolactone signalling. Nature Plants. doi.org/10.1038/s41477-022-01145-7.

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UrFU Sociologists Identify Digital Fears Among Young People

Jacob Scott

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Sociologists at the Ural Federal University (UrFU) have identified digital fears among young people. According to experts, these are additional fears that do not replace, but complement and reinforce traditional ones. They emerged against the background of uncertainty, the growth of forces beyond human control. Developed emotional intelligence, creativity, and the ability to collaborate help to overcome them.

In the study, sociologists interviewed 1,050 people aged 18-30. Respondents were asked to assess which digital risks concern them most. The study was launched in 2020 and the results were published in April 2022 in the Changing Societies & Personalities journal.

The first group of fears is influence and control. It touches on the problem of interference with privacy by technical means. This category is the most significant for young people: 55.8% are afraid of total control by means of video-surveillance and monitoring software on their mobile devices. 48.5% of respondents believe they are at risk of wiretapping, tracking content in social networks, and inability to keep correspondence secret.”

Natalia Antonova, Professor, Department of Applied Sociology, UrFU

45.8% of young people fear the manipulative influence of the media and an increase in fake news. At the same time, only 27.8% and 18.1% of respondents are concerned about microchipping and genetic manipulation, respectively. It is likely that these threats seem more controllable, both from the individual (through control of food choices, medical procedures, etc.) and from government programs, the researchers believe.

The second group of concerns is crime and security. Here young people are wary of illegal actions using digital technology.

“One of the main fears of 56% of young people is the security of personal data. This is related both to the growth of personal information in social networks and messengers, and to the growth of hacker attacks and viruses. 42.9% of young citizens are afraid of Internet fraudsters, and 25.8% are afraid of losing important information, including smashing their phones, not saving data, forgetting their passwords, or being without an Internet connection,” explains Sofia Abramova, Associate Professor at the Department of Applied Sociology at UrFU.

The third group of fears is based on changes in the way and pace of life, ways of interaction. Thus, 28.4% of respondents indicate a constant lack of time, the acceleration of communications, and worries about not being able to complete all tasks in time. Respondents are also concerned about the growth of online communications and communications with electronic systems (bots, autoresponders, product systems, etc.).

“As a result, 15.3% of young people raise problems related to increasing social distrust against the background of increasing dependence of human life and health on other people and electronic systems: in public transport, planes, elevators, medical intervention,” explains Sofia Abramova.

Respondents also fear the negative consequences of technological development. For example, 22.2% of young citizens fear the robotization of labor processes and the displacement of humans by robots. 14.6% speak directly about negative emotions in relation to the expansion of artificial intelligence.

The fifth type of fear is social inequality. Young people negatively assess the growth of inequality in access to information resources and technology, the exclusion of citizens from the economy depending on the level of digital competence and education, and age. As a result, they fear that benefits will be distributed more and more unequally, both among the inhabitants of the country and between countries.

“It is noteworthy that young people are simultaneously afraid of total surveillance via phone and afraid of being left without mobile devices. Fears shape the irrational behavior of the digital generation, entailing serious transformations in everyday life,” says Natalia Antonova.

Source:
Journal reference:

Abramova, S.B., et al. (2022) Digital Fears Experienced by Young People in the Age of Technoscience. Changing Societies & Personalities. doi.org/10.15826/csp.2022.6.1.163.

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Study demonstrates increased incidence of SARS-CoV-2 Omicron breakthrough infection in cancer patients

Jacob Scott

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In a recently published article in the journal Cancer Cell, scientists have demonstrated the incidence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in cancer patients residing in Austria and Italy. The study reveals an induction in Omicron breakthrough infections in patients with hematologic and solid cancers.

Study: Enhanced SARS-CoV-2 breakthrough infections in patients with hematologic and solid cancers due to Omicron. Image Credit: Lightspring/Shutterstock

Background

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative pathogen of the coronavirus disease 2019 (COVID-19) pandemic, has been found to cause severe infections in immunocompromised patients, including cancer patients. Moreover, a relatively lower level of neutralizing antibodies in response to COVID-19 vaccines has also been observed in cancer patients, especially those receiving B cell-targeting therapies.

The emergence of SARS-CoV-2 variants with improved immune fitness, such as delta and Omicron variants, has caused a sharp increase in breakthrough infections even in fully vaccinated individuals. However, the vaccines still show high protective efficacy against severe and fatal infections. COVID-19 vaccines have shown acceptable efficacy against severe disease, even in Omicron-infected cancer patients. However, the isolation and quarantine measures associated with SARS-CoV-2 infection may impair the routine administration of anticancer therapy, which can reduce the survival prognosis in cancer patients.

In the current study, the scientists have assessed the incidence of SARS-CoV-2 infection in cancer patients throughout the pandemic.

Study design

The study included 3,959 cancer patients, of whom 77% had solid cancer, and 23% had hematologic cancer. About 69% of the patients did not receive any anticancer treatment at the time of COVID-19 vaccination. Regarding vaccine coverage, about 85% of the patients had received at least one vaccine dose, and 15% remained unvaccinated. The incidence of SARS-CoV-2 infection in these patients was assessed between February 2020 and 2022.

Important observations

SARS-CoV-2 infection was detected in about 24% of the patients during the study period. During the delta-dominated wave, vaccine breakthrough infection was observed in 43% of the patients. In contrast, a significantly higher percentage of breakthrough infection (70%) was observed among the patients during the Omicron-dominated wave. During both delta and Omicron waves, cancer patients receiving systemic anticancer treatment showed a significantly higher percentage of breakthrough infection than those not receiving treatment (83% vs. 56%).

Regarding disease severity irrespective of vaccination status, a higher frequency of COVID-19-related hospitalization was observed during the delta wave compared to that during the Omicron wave. However, a relatively shorter duration of hospital stay was observed in vaccinated patients compared to that in unvaccinated patients. In addition, only 9% of patients with breakthrough infections were admitted to the intensive care unit (ICU). This highlights the protective efficacy of COVID-19 vaccines against severe disease.

Humoral immune response to vaccination

To determine vaccine-induced antibody response against delta and Omicron variants, the scientists measured blood levels of anti-delta and anti-Omicron spike receptor-binding domain (RBD) antibodies in a total of 78 cancer patients. In the analysis, they also included 25 healthcare workers as controls.

In response to vaccination, healthcare workers showed higher levels of total anti-spike antibodies compared to cancer patients. The lowest level of wildtype RBD-specific antibodies was observed in hematologic cancer patients receiving B cell-targeted treatment, followed by hematologic cancer patients not receiving B cell-targeted treatment and patients with solid tumors. A similar trend was observed for delta- and Omicron-specific spike RBD antibodies.

The serum samples collected from hematologic cancer patients without B cell-targeted treatment and solid tumor patients significantly inhibited the interaction between wildtype/delta RBD and angiotensin-converting enzyme 2 (ACE2; host cell receptor for viral entry). However, a significantly lower level of inhibition was observed for patients receiving B cell-targeted treatment. Importantly, a marked reduction in inhibition of Omicron RBD – ACE2 interaction was observed for all patients with solid tumors and hematologic cancer.

Study significance

The study demonstrates an increased incidence of vaccine breakthrough infections but a reduced disease severity among patients with solid tumors and hematologic cancer during the Omicron wave compared to the delta wave.

The study also highlights that COVID-19 vaccine-induced antibody response is lower in cancer patients than in healthy individuals. The reduction in antibody response is highest among hematologic patients receiving B cell-targeted treatment. Overall, a significant impairment in vaccine-induced Omicron neutralization has been observed in cancer patients.

Journal reference:
Mair, M. et al. (2022) “Enhanced SARS-CoV-2 breakthrough infections in patients with hematologic and solid cancers due to Omicron”, Cancer Cell. doi: 10.1016/j.ccell.2022.04.003. https://www.cell.com/cancer-cell/fulltext/S1535-6108(22)00165-9

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