Inflammatory syndrome linked to kids with COVID only occurs in 0.3%

Inflammatory syndrome linked to kids with COVID is rare – only occurring in about 0.3% of children – but black and Latino youngsters are up to THREE TIMES more likely than whites to get it

  • A new study looked at 248 cases of MIS-C in pediatric patients with coronavirus out of more than nine million children
  • MIS-C is a condition in which different body parts become inflamed and is linked to children infected with COVID-19 
  • Researchers determined the incidence rate was 316 persons per 1,000,000 coronavirus infections, or a rate of 0.3%
  • Black children were two times more likely than white children and Hispanic almost three times more likely to be diagnosed with MIS-C
  • Rates were highest among those under age five, and higher among six-10-year-olds, than in older children 

A very small percentage of children develop the inflammatory condition linked to COVID-19, a new study suggests.

Researchers found that just 0.3 percent of youngsters under age 21 were diagnosed with multisystem inflammatory syndrome in children (MIS-C), a disorder in which different body parts become inflamed.

The complication was most common in kids under age five, and black and Hispanic children were up to three times more likely to have the condition than white youngsters.

It’s not clear why minorities are at greater risk of MIS-C, but theories include a greater prevalence of underlying conditions among communities of color and less access to healthcare compared to Caucasian neighborhoods.

The team, from the Centers for Disease Control and Prevention (CDC), says understanding which children are at the highest risk can help doctors keep a close eye on certain patients so they can be treated before they develop MIS-C. 

A new study looked at 248 cases of MIS-C, a condition in which different body parts become inflamed, in pediatric patients with coronavirus out of more than nine million. Pictured: A five- year-old child in a hospital bed at Westchester Medical Center in Valhalla, New York, May 2020

Black children were two times more likely than white children and Hispanic almost three times more likely to be diagnosed with MIS-C, a new study finds

MIS-C was originally thought to be linked with Kawasaki disease, a condition that causes inflammation in the walls of the blood vessels and affects mostly children under five years old.

Cases were first reported in Britain, Italy and Spain in April 2020 and began cropping up in the U.S. in May.

A total of 4,018 cases have been confirmed across the country and at least 36 children have died, according to the CDC.

The majority of children and adolescents develop MIS-C between two and four weeks after being infected with the coronavirus.

Not every child who has developed the condition has tested positive for coronavirus, but 98 percent have – enough for doctors to believe the conditions are linked.

For the study, published in JAMA Network Open, the team looked at data from seven states reporting cases of MIS-C to the CDC.

Between April and June 2020, there were 248 reported cases that occurred in Americans under age 21 out of more than nine million children.

Researchers determined the incidence rate was 316 persons per 1,000,000 coronavirus infections, or a rate of 0.3 percent.

MIS-C rates were highest among those under age five, and higher among six-10-year-olds, than in older children

When broken down by race, about 30.2 percent, or 75 kids, were black and 38.7 percent, 96 kids, were Hispanic.

Comparatively, just 13.7 percent – 34 kids – were white. 

That means black children were two times more likely and Hispanic almost three times more likely to be diagnosed with MIS-C.

Additionally, younger children were much more likely to have the condition than older children.

Those under five years old were the most likely at 33 percent, closely followed by those ages six to 10.

‘These estimates indicated that MIS-C was a rare complication associated with SARS-CoV-2 infection in this cohort overall,’ the authors wrote.

‘Our findings of higher incidence among younger children and among Hispanic or Latino, black, and Asian or Pacific Islander persons emphasize a need for further study of risk factors for MIS-C.’

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Updated Moderna vaccines neutralize South African SARS-CoV-2 variant in mice

Researchers in the United States have conducted a pre-clinical study demonstrating the efficacy of two updated versions of the Moderna mRNA-1273 vaccine against variants of severe acute respiratory syndrome coronavirus 2 – the agent that causes coronavirus disease 2019 (COVID-19).

Study: Variant SARS-CoV-2 mRNA vaccines confer broad neutralization as primary or booster series in mice

The updated vaccine candidates include the monovalent mRNA-1273.351, which is designed to target the B.1.351 variant that emerged in South Africa, and the multivalent mRNA1273.211, which comprises a mixture of the original mRNA-1273 vaccine and mRNA-1273.351.

The vaccines were evaluated in mice as both a primary vaccination series and as a booster dose among animals that had previously been immunized with two doses of mRNA-1273.

The team reports that while the mRNA-1273.351 vaccine elicited high levels of neutralizing antibody titers against B.1.351, the multivalent mRNA-1273.211 was most effective at providing broad cross-variant neutralization.

In addition, a booster dose of mRNA-1273.351 dramatically increased neutralization titers against both wild-type SARS-CoV-2 and the B.1.351 variant.

“Both mRNA-1273.351 and mRNA-1273.211 are currently being evaluated in additional pre-clinical challenge models and in phase 1/2 clinical studies,” says the team from Moderna Inc and the National Institute of Allergy and Infectious Diseases.

Global surveillance for the emergence of further variants of concern (VOCs) is also ongoing, as are efforts to test the ability of mRNA-1273 to neutralize VOCs.

“If additional variants emerge that reduce the neutralization capacity of mRNA-1273 further, additional mRNA vaccine designs may be developed and evaluated,” writes Kai Wu and colleagues.

A pre-print version of the research paper is available on the bioRxiv* server, while the article undergoes peer review.

Model of S protein. mRNA-1273.351 encodes the B.1.351 lineage S variant. Surface representation of the trimeric S protein in the vertical view with the locations of surface-exposed mutated residues highlighted in red spheres and labeled on the grey monomer. The inset shows superimposition of ACE-2 receptor domain and the RBD. S protein structure, 6VSB. ACE2-RBD structure, 6M0J. ACE2, angiotensin converting enzyme 2; NTD, N-terminal domain; RBD, receptor-binding domain.

Variants increasingly pose a threat to vaccination

The emergence of SARS-CoV-2 variants has raised concerns that the virus may have evolved the ability to escape vaccine-induced immunity. Several variants have demonstrated resistance to neutralization by vaccinated sera, particularly the South African B.1.351 lineage that was first identified in December 2020.

The initial stage of the SARS-CoV-2 infection process is mediated by the viral spike protein, which attaches to the host cell receptor via its receptor-binding domain (RBD). This spike RBD is the primary target of the neutralizing antibodies that are generated following infection or vaccination. A neutralization “supersite” has also been identified in the N-terminal domain (NTD) of the spike protein.

Studies have shown that several recently emerged SARS-CoV-2 variants harbor mutations in the RBD and NTD of spike that may confer resistance to vaccine-induced neutralization activity.

“Importantly, mutations in the NTD domain, and specifically the neutralization supersite, are extensive in the B.1.351 lineage virus,” says Wu and colleagues.

Furthermore, “studies have demonstrated reduced neutralization titers against the full B.1.351 variant following mRNA-1273 vaccination,” they add.

What did the researchers do?

Now, Wu and colleagues have evaluated the efficacy of two updated vaccines.

The monovalent mRNA-1273.351 vaccine encodes the spike protein found in the B.1.351 lineage, while the multivalent mRNA-1273.211 comprises a 1:1 mix of mRNA-1273.351 and mRNA-1273.

The original mRNA-1273 vaccine targets the ancestral wild-type virus (Wuhan-Hu-1 variant) that contains a mutation called D614G.

The vaccines were administered in mice as a two-dose primary series and their immunogenicity against D614G and B.1.351 pseudoviruses was evaluated 2 weeks following the first and second immunizations.

The mRNA-1273.351 vaccine was also evaluated as a booster dose in animals that had previously received two doses of mRNA-1273.

What did the study find?

Vaccine mRNA-1273.351 elicited approximately 4-fold higher neutralization titers against B.1.351 than against D614G.

Vaccine mRNA-1273.211, on the other hand, elicited robust neutralization responses against both D614G and B.1.351, with no significant difference observed in neutralization titers.

“Thus, as a primary vaccination series, a multivalent approach appears most effective in broadening immune responses,” says the team.

Next, the researchers tested the ability of mRNA-1273.351 to serve as a booster shot for neutralization against both D614G and B.1.351.

Mice were injected with mRNA-1273 on days 1 and 22 and then evaluated for antibody responses over the course of 7 months before being vaccinated a third time with mRNA-1273.351.

Following this booster injection, neutralization titers against D614G increased 4.5-fold, while titers against B.1.351 increased 15-fold.

The mRNA-1273.351 vaccine is an “effective booster”

“mRNA-1273.351 is an effective third (booster) dose in animals previously vaccinated with a primary vaccination series of mRNA-1273,” says Wu and the team.

“Ongoing studies will evaluate the ability of mRNA-1273, mRNA-1273.351, and mRNA-1273.211 to effectively boost immunity driven by a primary vaccination series of mRNA-1273,” they add.

The team says the mRNA platform approach against SARS-CoV-2 VOCs has now been demonstrated in mice to effectively broaden neutralization across variants and boost antibody levels when applied as a third dose.

“The mRNA platform allows for rapid design of vaccine antigens that incorporate key mutations, allowing for rapid future development of alternative variant-matched vaccines should they be needed,” writes Wu and colleagues.

“Additional VOC designs can be rapidly developed and deployed in the future if needed to address the evolving SARS-CoV-2 virus,” they conclude.

*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:
  • Wu K, et al. Variant SARS-CoV-2 mRNA vaccines confer broad neutralization as primary or booster series in mice. bioRxiv, 2021. doi: https://doi.org/10.1101/2021.04.13.439482, https://www.biorxiv.org/content/10.1101/2021.04.13.439482v1

Posted in: Medical Research News | Disease/Infection News

Tags: ACE2, Allergy, Angiotensin, Antibodies, Antibody, Cell, Coronavirus, Coronavirus Disease COVID-19, Efficacy, Enzyme, Infectious Diseases, Mutation, Protein, Receptor, Research, Respiratory, SARS, SARS-CoV-2, Severe Acute Respiratory, Severe Acute Respiratory Syndrome, Spike Protein, Syndrome, Vaccine, Virus

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Written by

Sally Robertson

Sally first developed an interest in medical communications when she took on the role of Journal Development Editor for BioMed Central (BMC), after having graduated with a degree in biomedical science from Greenwich University.

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Researchers discover a new monoclonal antibody that is effective against SARS-CoV-2 variants

A new monoclonal antibody targets a particular region of the receptor-binding domain (RBD) on the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This region is usually not accessible to immune cells,  which may be why it has broad neutralizing capabilities.

With the coronavirus disease 2019 (COVID-19) pandemic continuing around the globe, new mutants of SARS-CoV-2 are emerging. These new variants are likely more infectious and can better evade our immune response.

The SARS-CoV-2 spike protein, in particular the RBD, is key in binding to host receptors, mainly the angiotensin-converting enzyme 2 (ACE2) in humans. One highly conserved region of the RBD, called antigenic site II, can elicit neutralizing antibodies. However, this region is generally inaccessible because of the RBD conformation, and there is a low fraction of antibodies targeting this site in infected individuals.

Study: Structural basis for broad sarbecovirus neutralization by a human monoclonal antibody. Image Credit: Design_Cells / Shutterstock

In a new study published in the bioRxiv* preprint server, researchers report a new monoclonal antibody that is targeted toward site II and has a broad neutralizing capability.

Testing potency of monoclonal antibody

The authors sorted spike protein-specific memory B cells from a convalescent individual 75 days after symptom onset. They found one monoclonal antibody, called S2X259, which reacted with 29 of 30 spike proteins of sarbecoviruses, including SARS-CoV-2 and its new variants. The antibody also reacted with bat sarbecoviruses, suggesting its broad neutralizing capability.

The antibody also bound strongly to 10 RBDs from different sarbecoviruses. The binding of this antibody was not affected by the different single-point RBD mutations seen in the new variants of SARS-CoV-2, including the United Kingdom, South African, Brazilian, and the B.1.427/B.1.429 variants.

Using pseudotyped virus systems, the team found that the antibody neutralized SARS-CoV-2 and did not lose its potency against the different variants or the N439K or Y453F mutation. The antibody not only neutralized a variety of sarbecoviruses that use the ACE2 receptor but also cross-reacts with sarbecoviruses that do not use ACE2 for infection.

To understand how this antibody has high neutralizing potency, the team imaged the complex formed between the spike protein and the antibody using cryo-electron microscopy. They found that the antibody recognizes a glycan-free site, which requires two RBDs to be in the open conformation. It forms contacts with residues 369-386, 404-411, and 499-508 in the RBD.

The epitope the antibody binds to is conserved in all the circulating SARS-CoV-2 variants. In addition, it does not target the 417 or 484 residues (mutations here are found in B.1.351 and P.1), and this could be why it is potent against the different variants.

The action of this antibody does not affect the neutralization effect of class 1 and class 3 antibodies. The majority of approved antibodies for clinical use belong to these classes. Hence, the new antibody can be used in combination with other antibodies to increase neutralization breadth.

The S2X259 broadly neutralizing sarbecovirus mAb recognizes RBD antigenic site II. a-b, CryoEM structure of the prefusion SARS-CoV-2 S ectodomain trimer with three S2X259 Fab fragments bound to three open RBDs viewed along two orthogonal orientations. c. The S2X259 binding pose involving contacts with multiple RBD regions. Residues corresponding to prevalent RBD mutations are shown as red spheres. d-e, Close-up views showing selected interactions formed between S2X259 and the SARS-CoV-2 RBD. In panels a-e, each SARS-CoV-2 S protomer is coloured distinctly (cyan, pink and gold) whereas the S2X259 light and heavy chain variable domains are coloured magenta and purple, respectively. N-linked glycans are rendered as blue spheres in panels a-c.

Potential use against a broad range of sarbecoviruses

Using computational analysis, the team determined what RBD mutations could escape the antibody from binding. They found only a few RBD mutations disrupt the binding of this antibody. The substitution of the residue at position 504 gave the most significant disruption in binding.

When they replicated a pseudotyped SARS-CoV-2 virus in the presence of the S2X259 antibody, the only mutation they found caused by selective pressure was G504D. This mutation has rarely been seen in human isolates so far.

The selection of a single escape mutation suggests the region targeted by the antibody might not tolerate amino acid substitutions without changing viral fitness. Hence it is conserved across different sarbecoviruses. Thus, there is a high barrier for the emergence of mutations against this antibody, suggesting it could become key in combating the pandemic.

When Syrian hamsters were challenged with SARS-CoV-2, with the antibody administered 48 hours before virus infection, the authors found more than two orders of magnitude decrease in virus in the lungs compared to hamsters that did not receive any treatment. In addition, the antibody also protected hamsters infected with the B.1.351 strain.

The detection of a large variety of sarbecoviruses in bats and other mammals, along with the increased human-animal interactions, makes it likely that more cross-species transmission of viruses can occur. With increasing evidence that antibodies targeting the RBD form a major proportion of neutralizing activity, RBD-based vaccines could elicit high levels of antibodies like S2X259 with high potency. Such strategies can help overcome the current COVID-19 pandemic and help prepare for future sarbecovirus infections.

*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:
  • Tortorici, M. A. et al. (2021) Structural basis for broad sarbecovirus neutralization by a human monoclonal antibody. bioRxiv. https://doi.org/10.1101/2021.04.07.438818, https://www.biorxiv.org/content/10.1101/2021.04.07.438818v1

Posted in: Medical Science News | Medical Research News | Miscellaneous News | Disease/Infection News | Healthcare News

Tags: ACE2, Amino Acid, Angiotensin, Angiotensin-Converting Enzyme 2, Antibodies, Antibody, Coronavirus, Coronavirus Disease COVID-19, Electron, Electron Microscopy, Enzyme, Glycan, Glycans, Immune Response, Lungs, Microscopy, Monoclonal Antibody, Mutation, Pandemic, Protein, Receptor, Respiratory, SARS, SARS-CoV-2, Severe Acute Respiratory, Severe Acute Respiratory Syndrome, Spike Protein, Syndrome, Virus

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Written by

Lakshmi Supriya

Lakshmi Supriya got her BSc in Industrial Chemistry from IIT Kharagpur (India) and a Ph.D. in Polymer Science and Engineering from Virginia Tech (USA).

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Identification of specific anti-SARS-CoV-2 antibodies with cross-neutralization potency

A team of scientists from the USA and Canada recently characterized the cross-neutralizing potency of anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies isolated from coronavirus disease 2019 (COVID-19) patients. The findings reveal that some of the isolated antibodies targeting the spike receptor-binding domain (RBD) and the S2 subunit are capable of cross-neutralizing other members of the human beta-coronavirus family. The study is currently available on the bioRxiv* preprint server.

Study: Isolation and Characterization of Cross-Neutralizing Coronavirus Antibodies from COVID-19+ Subjects. Image Credit: Corona Borealis Studio / Shutterstock

Background

SARS-CoV-2, the causative pathogen of COVID-19, is an enveloped, positive-sense, single-stranded RNA virus of the Coronaviridae family. The viruses belonging to the Coronaviridae family are capable of zoonotic transmission as observed in the current COVID-19 pandemic, as well as in previous outbreaks of SARS-CoV and Middle East respiratory syndrome coronavirus (MERS-CoV).

Given the 54% sequence similarity between different coronavirus strains, many studies have been conducted to investigate the cross-reactive potency of anti-SARS-CoV-2 antibodies. In this context, it has been observed that only a small fraction of antibodies isolated from SARS-CoV-2 infected patients are capable of cross-neutralizing SARS-CoV, MERS-CoV, or other beta (OC43 and HKU1) and alpha (229E and NL63) coronaviruses.

In the current study, the scientists have isolated and characterized a total of 198 monoclonal antibodies targeting SARS-CoV-2 spike protein. Specifically, they have explored the cross-neutralizing potency of these antibodies against different strains of coronaviruses.  

For antibody isolation, serum samples and peripheral blood mononuclear cells have been collected from four COVID-19 positive patients 3 to 7 weeks after the symptom onset.

Important observations

The analysis of serum samples using Enzyme-linked Immunosorbent assay (ELISA) revealed that all enrolled patients developed significant levels of anti-RBD bindings and neutralizing antibodies in response to SARS-CoV-2 infection. The highest virus neutralization potency was observed in samples collected at later timepoints.

By conducting a series of experiments using patient-obtained spike+ and RBD+ B cells (IgG+), the scientists finally isolated 198 anti-SARS-CoV-2 monoclonal antibodies. Moreover, they isolated 59 monoclonal antibodies from healthy individuals as experimental controls. By comparing relative frequencies of each heavy and light chain variable region sequence of patients and healthy controls, they observed that naïve B cell clones preferentially recognized the viral spike protein at the initial stages of infection. In contrast, the anti-spike B cell response predominated 3 – 7 weeks after the symptom onset. Moreover, they noticed that the sequences of heavy and light chain variable regions derived from later-timepoint samples harbored higher amino acid mutations than early-timepoint samples. This indicates that the evolution of B cells occurs continuously during SARS-CoV-2 infection.

Cross-reactive potency of anti-SARS-CoV-2 antibodies

Using various recombinant proteins, including spike S1 and S2 subunits, RBD, and N-terminal domain (NTD), the scientists observed that only a small fraction of isolated monoclonal antibodies recognized and bound the RBD. While exploring the cross-reactivity against SARS-CoV, MERS-CoV, OC43 and HKU1 beta-coronaviruses, and NL63 and 229E alpha-coronaviruses, they noticed that 81 out of 198 monoclonal antibodies bound various subdomains of SARS-CoV spike protein, with RBD being the highly recognized region. In contrast, a significantly lower cross-reactivity was observed against other coronaviruses.

Cross-neutralizing potency of anti-SARS-CoV-2 antibodies

Of 198 monoclonal antibodies, only 14 showed SARS-CoV-2 neutralization potency; of which, one targeted the NTD, one targeted the S2 subunit, and 12 targeted the RBD. Regarding cross-neutralization, only 4 out of 14 antibodies were found to effectively neutralize SARS-CoV. Of all cross-neutralizing antibodies, three were specific to the RBD, and one was specific to the S2 subunit. Importantly, all cross-neutralizing antibodies were found to effectively neutralize the South African variant of SARS-CoV-2 (lineage: B.1.351).  

The mechanistic analysis conducted in the study revealed that the most potent anti-RBD antibodies neutralized SARS-CoV-2 by blocking the angiotensin-converting enzyme 2 (ACE2)-RBD interaction. Moreover, there was an association between the degree of ACE2-RBD binding inhibition and the robustness of neutralization. A similar mechanism was observed for SARS-CoV neutralization.

Interestingly, the analysis revealed that the two most potent anti-SARS-CoV-2 neutralizing antibodies failed to neutralize SARS-CoV. This could be because these two antibodies interacted with the receptor-binding motif in the RBD, which is structurally not similar to that of SARS-CoV RBD.

To explore the infection preventing abilities of neutralizing antibodies, the scientists initially immunized the mice with a panel of neutralizing antibodies with different epitope specificities, followed by experimental infection with SARS-CoV-2. By analyzing the viral RNA in lung samples two days post-infection, they observed that only antibodies with high neutralization efficiency could provide protection against infection.

Study significance

The study reveals that the expansion of B cell populations expressing particular pairs of variable domains is not a prerequisite for generating SARS-CoV-2 and SARS-CoV cross-neutralizing antibodies. The study also identifies one epitope in the spike S2 subunit that is specific to at least four human beta-coronaviruses. Monoclonal antibodies targeting this S2 epitope have cross-neutralization potency.  

*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:
  • Jennewein M. 2021. Isolation and Characterization of Cross-Neutralizing Coronavirus Antibodies from COVID-19+ Subjects. BioRxiv. doi: https://doi.org/10.1101/2021.03.23.436684, https://www.biorxiv.org/content/10.1101/2021.03.23.436684v1

Posted in: Medical Science News | Medical Research News | Disease/Infection News | Healthcare News

Tags: ACE2, Amino Acid, Angiotensin, Angiotensin-Converting Enzyme 2, Antibodies, Antibody, Assay, Blood, Cell, Coronavirus, Coronavirus Disease COVID-19, Enzyme, Evolution, MERS-CoV, Pandemic, Pathogen, Protein, Receptor, Respiratory, RNA, SARS, SARS-CoV-2, Severe Acute Respiratory, Severe Acute Respiratory Syndrome, Spike Protein, Syndrome, Virus

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Written by

Dr. Sanchari Sinha Dutta

Dr. Sanchari Sinha Dutta is a science communicator who believes in spreading the power of science in every corner of the world. She has a Bachelor of Science (B.Sc.) degree and a Master's of Science (M.Sc.) in biology and human physiology. Following her Master's degree, Sanchari went on to study a Ph.D. in human physiology. She has authored more than 10 original research articles, all of which have been published in world renowned international journals.

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Researchers explore nanotechnology’s potential to deliver synergistic therapeutics for COVID-19

From public health to the economy, the coronavirus disease 2019 (COVID-19) pandemic has had a profound impact in nearly all spheres of life. This disease, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pathogen, has claimed over 2.7 million lives so far. Coupled with sickness and mortality issues, the lockdown measures, social distancing and isolation have impacted the mental health of people everywhere.

Anxiety, confusion and fear have taken a toll on the mental health of many people worldwide. To combat this, researchers exploited some naturally occurring antiviral and brain-boosting compounds that may provide new insight.

A team of scientists, from the University of Kashmir, India; Rutgers University, USA; and Prince of Songkla University, Thailand, reviewed the nanoencapsulation approaches of synergistic compounds (Lectins, Caffeine, Cocoa, Flavonoids, Quercetin) and the role of nanotechnology in addressing the COVID-19 pandemic. They discussed the dual action of such compounds for their brain-boosting benefits and antiviral activities. This review was published recently in the International Journal of Biological Macromolecules.

Study: Exploitation of polyphenols and proteins using nanoencapsulation for anti-viral and brain boosting properties – Evoking a synergistic strategy to combat COVID-19 pandemic. Image Credit: NIAID / Flickr

Currently, there are no targeted and safe therapeutic alternatives for COVID-19, exploring the brain-boosting compounds, possibly augmented with antiviral activities, is a prospective research approach. The reviewers here discussed some compounds, derived naturally, like quercitin, caffeine, lectins from banana (Banlec) and cocoa flavonoids. They summarized the natural compounds with their antiviral and brain-boosting properties in this review.

Previously, it has been reported that the COVID-19 situation triggered various mental issues like difficulty in sleep, social media distress and paranoia of acquiring this viral infection; 80% of the participants in the study needed mental healthcare. This state of mind may also result in oxidative stress and loss of immunity, aggravating other symptoms.

Quercitin might prevent the neurons from apoptosis (programmed cell death) and oxidative stress. While caffeine and lectin might provide anti-depressant effects, cocoa flavonoids act as a neuro-protectant.

These suggested compounds are reported to also have antiviral activities. Quercitin has inhibitory action against SARS and MERS, two closely-related pathogens to SARS-CoV-2. Caffeine has antiviral activity against human immunodeficiency virus type I (HIV-1), lectin against influenza virus and the flavonoids can inhibit the fusion of viral membrane with that of the lysosome.

The emerging field of nanotechnology has made a significant impact on the target delivery of nutraceuticals and therapeutics.”

For effective delivery of these compounds to the target sites, nanoencapsulation is a novel tool. It has been established that nanotechnology's application enhances the thermal stability, oral bioavailability and water solubility of the drug. Nanoencapsulation may confer benefits to the drug by modifying the pharmacologically active part of these compounds.

The engineered nanoparticles possess high surface to volume ratio, good absorption properties and many bioactive components including resveratrol, curcumin, polyphenols, genistein, lycopene, anthocyanins and quercetin have been subjected to nanoencapsulation to combat the poor water solubility, low oral bioavailability and low taste profiles.”

Lots of synthesis methods and techniques are available for the nanoencapsulation process. For example, nanotransporters like yeast cells, nanogels, nanofibres and nanosponges are fabricated from polysaccharides and lipids to be employed for nanoencapsulation. Starch nanocomposites and chitosan-coated liposomes, superparamagnetic iron oxide nanoparticles, alginate microparticles and gold nanoparticles are some of the possible nanocarriers. The reviewers recommend the suitable nanoencapsulation approach for each of the compounds discussed here in the review.

The reviewers discussed the issues in drug delivery and how nanotechnological based approaches may help overcome them. For example, they discussed the mechanism of action of an antiviral vaccine named, Nuvec®, which are silica-nanoparticles surface-functionalized with polyethylenimine for carrying nucleic acids. An ideal delivery system for vaccines and medicines, these nanoparticles protect the cargo from nucleic acid enzymes and do not cause any inflammatory response.

Theranostic nanoparticles, classified as inorganic, organic and virus-like self-assembling protein nanoparticles, are excellent tools in the application of nanotechnology to combat COVID-19. Also, the quantum dots (the semiconductor nanomaterials) ranging from 1 to 10 nm with tunable optical wavelength, are novel imaging probes.

The researchers report that owing to their nano size and shape, the quantum dots penetrate the SARS-CoV-2 with sizes ranging from 60 and 140 nm, and the quantum dots also sequester the S protein of SARS-CoV-2 due to their positive surface charge. It can also interact with the negative RNA strand of the virus, creating reactive oxygen species within SARS-CoV-2.

It is established that the nanoparticles can deliver a range of antiviral moieties and target both the adaptive as well as the innate immune system. With nano-dimensions, high surface-to-volume ratio, flexibility and option of administration via alternative routes, the potential of nanotechnology in fighting COVID-19 has not only been realized in the context of developing a nano-vaccine, but by delivering the nano-based antiviral agents, the reviewers explain.

This review has summed up some of the brain-boosting as well as antiviral compounds and highlighted the nano-encapsulating of these synergistic compounds; this may pave a way in strategizing the formulation of therapeutics for combating the adverse conditions of COVID-19.

Journal reference:
  • Nairah Noor, Adil Gani, Asir Gani, Asima Shah, Zanoor ul Ashraf. (2021) Exploitation of polyphenols and proteins using nanoencapsulation for antiviral and brain boosting properties – Evoking a synergistic strategy to combat COVID-19 pandemic, International Journal of Biological Macromolecules. https://doi.org/10.1016/j.ijbiomac.2021.03.028 https://www.sciencedirect.com/science/article/pii/S0141813021005456

Posted in: Medical Research News | Disease/Infection News | Healthcare News

Tags: Antiviral Drug, Anxiety, Apoptosis, Banana, Brain, Caffeine, Cell, Cell Death, Chitosan, Coronavirus, Coronavirus Disease COVID-19, Curcumin, Drug Delivery, Gold Nanoparticles, Healthcare, HIV, HIV-1, Imaging, Immune System, Immunodeficiency, Influenza, Lipids, Liposomes, Lycopene, Macromolecules, Mental Health, Microparticles, Mortality, Nanoparticles, Nanotechnology, Neurons, Nucleic Acid, Oxidative Stress, Oxygen, Pandemic, Paranoia, Pathogen, Programmed Cell Death, Protein, Public Health, Quantum Dots, Quercetin, Research, Respiratory, Resveratrol, RNA, SARS, SARS-CoV-2, Severe Acute Respiratory, Severe Acute Respiratory Syndrome, Sleep, Stress, Syndrome, Therapeutics, Vaccine, Virus, Wavelength, Yeast

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Written by

Dr. Ramya Dwivedi

Ramya has a Ph.D. in Biotechnology from the National Chemical Laboratories (CSIR-NCL), in Pune. Her work consisted of functionalizing nanoparticles with different molecules of biological interest, studying the reaction system and establishing useful applications.

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SARS-CoV-2 can spread through cold-chain transport

In light of growing evidence, researchers say that SARS-CoV-2 virus transmission via contaminated surfaces, and in particular, frozen foods and products that are transported while keeping them at low temperatures, should be taken into account when devising prevention strategies.

Study: Transmission of SARS-CoV-2 via fomite, especially cold chain, should not be ignored. Image Credit: 5m3photos / Shutterstock

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is usually spread by airborne transport. When an infected person sneezes, coughs, talks, or breathes, the virus present in aerosol droplets can be transmitted. Hence, the main strategies to curb its spread have been social distancing and ensuring well-ventilated indoor spaces.

SARS-CoV-2 is stable on various surfaces for different times. The virus's half-life on plastic and stainless steel is about six hours. On the skin, the virus is stable for 96 hours at 22 °C and 14 days at 4 °C. Studies have shown that the virus can be isolated from surfaces such as glass, paper, and banknotes, up to 28 days after infection.

The virus is very stable at low temperatures and can remain on the packaging of cold-chain products, and transportation of these products can lead to viral spreading. Reports from China in the last few months indicate several infections, mainly asymptomatic, caused by imported cold-chain products. The live virus was isolated from the packaging of imported-cold chain products in Qingdao, raising the possibility that trade may be causing virus spread.

Virus can stay alive on surfaces for many days

In a previous study, researchers reported that livestock processing industries contribute significantly to SARS-CoV-2 transmission. For the United States, the authors estimated that for a county with the presence of livestock processing plants, excess COVID-19 cases were 6 to 8% of all the cases in the country, with the vast majority of cases occurring in people not working at the plants.

One reason for the increase in transmission risk in livestock plants is the low indoor temperature. After slaughter, the meat processing area is generally kept between 0 and 12 °C, which allows the virus to remain stable.

Another study reported the stability of SARS-CoV-2 on a variety of surfaces. They found that the presence of a tiny protein in respiratory droplets that can prolong the life of the virus on many different surfaces. Thus, viruses in aerosol droplets from infected persons that settle on surfaces can stay alive, sometimes for more than four days, and transmit the virus when people contact the contaminated surfaces.

Cold-chain virus transport

All these reports provide growing evidence of how SARS-CoV-2 can be transmitted by trade, particularly when the transported goods are maintained at low temperatures.

In a letter published in the Proceedings of the National Academy of Sciences, researchers from Jilin University in China argue that livestock plants and cold-chain industries play a key role in virus transmission and should be taken into account when implementing COVID-19 prevention strategies.

Thus, supervising meatpacking and scattered small-scale meat production could help disease prevention. The authors suggest that the environment in these plants and cold-chain industries should be tested regularly along with frequent disinfection. Imported cold-chain or frozen products should also be sampled and tested to identify any contaminated products and take control measures in time.

Furthermore, any personnel handling such goods should wear personal protective equipment, including masks and gloves. Such personnel should also be screened routinely for the virus. Wiping all frozen packages using disinfectant wipes may also be useful in eliminating the virus.

Journal references:
  • Ji, W. et al. (2021) Transmission of SARS-CoV-2 via fomite, especially cold chain, should not be ignored. PNAS. 118 (11)., ​https://doi.org/10.1073/pnas.2026093118, https://www.pnas.org/content/118/11/e2026093118
  • Taylor, C. A. et al. (2020) Livestock plants and COVID-19 transmission. PNAS 117(50). https://doi.org/10.1073/pnas.2010115117
  • Pastorino, B. et al. (2020) Prolonged Infectivity of SARS-CoV-2 in Fomites. Emerging Infectious Diseases. https://doi.org/10.3201/eid2609.201788

Posted in: Medical Research News | Disease/Infection News

Tags: Cold, Cold chain, Coronavirus, Coronavirus Disease COVID-19, Disinfectant, Disinfection, Meat, Personal Protective Equipment, Protein, Respiratory, SARS, SARS-CoV-2, Severe Acute Respiratory, Severe Acute Respiratory Syndrome, Skin, Syndrome, Virus

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Written by

Lakshmi Supriya

Lakshmi Supriya got her BSc in Industrial Chemistry from IIT Kharagpur (India) and a Ph.D. in Polymer Science and Engineering from Virginia Tech (USA).

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Cannabis compound inhibits SARS-CoV-2 replication in human lung cells

Researchers in the United States have conducted a study showing that a cannabis plant compound inhibited infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in human lung cells.

SARS-CoV-2 is the agent responsible for the coronavirus disease 2019 (COVID-19) pandemic that continues to sweep the globe posing a threat to global public health and the worldwide economy.

Marsha Rosner from the University of Chicago in Illinois and colleagues found that cannabidiol (CBD) and its metabolite 7-OH-CBD potently blocked SARS-CoV-2 replication in lung epithelial cells.

The CBD inhibited viral gene expression and reversed many of the effects the virus has on host gene transcription.

The compound also induced the expression of interferons – cell signaling proteins that are produced by host cells as an early response to viral invasion.

Furthermore, the incidence of SARS-CoV-2 infection was up to an order of magnitude lower in a cohort of patients who had been taking CBD, compared with matched patients who had not been taking CBD.

“This study highlights CBD, and its active metabolite, 7-OH-CBD, as potential preventative agents and therapeutic treatments for SARS-CoV-2 at early stages of infection,” says Rosner and the team.

A pre-print version of the research paper is available on the bioRxiv* server, while the article undergoes peer review.

Study: Cannabidiol Inhibits SARS-CoV-2 Replication and Promotes the Host Innate Immune Response. Image Credit: Stokkete / Shutterstock

Rapid spread of SARS-CoV-2 highlights the need for new treatments

Since the COVID-19 outbreak first began in Wuhan, China, in late December 2019, the rapid spread of SARS-CoV-2 has led to more than 119.5 million infections and caused more than 2.64 million deaths.

Although recently-approved vaccines are now being rolled out in many countries, the virus is still spreading rapidly. Rosner and colleagues say this highlights the need for alternative approaches, particularly among populations with limited access to vaccines.

However, “to date, few therapies have been identified that block SARS-CoV-2 replication and viral production,” write the researchers.

More about SARS-CoV-2 and CBD

The SARS-CoV-2 virus primarily enters host cells through the binding of a surface viral protein called spike to the human host cell receptor angiotensin-converting enzyme 2 (ACE2).

The viral genome is then translated into two large polypeptides that are cleaved by the viral proteases MPro and PLPro to produce the proteins required for viral replication, assembly, and budding.

Rosner and colleagues say that, although limited, some studies have reported that certain cannabinoids have antiviral effects against hepatitis C virus and other viruses.

Furthermore, an oral solution of CBD is already approved by the US food and Drug Administration for the treatment of epilepsy.

High Dose CBD usage in patients is significantly correlated with a reduction in COVID-19 positivity. Associations between reported cannabinoid medication use and COVID-19 test results among adults tested at the University of Chicago Medicine (total n=93,565). P*: p-values of percent positivity of the specified patient population compared to percent positivity of all patients (10% COVID-19 positive among 93,565 patients). Middle right: 85 patients took CBD before their COVID test date. Upper right: 82 of the 85 patients took FDA-approved CBD (Epidiolex®) and were matched to 82 of the 93,167 patients (Matched Controls) with a nearest neighbor propensity score model that scored patients according to their demographics and their recorded diagnoses and medications from the two years before their COVID-19 test. P-values were calculated using Fisher’s exact test two-sided.

What did the current study involve?

To test the effect of CBD on SARS-CoV-2 replication, the researchers pretreated A549 human lung carcinoma cells expressing ACE-2 (A549-ACE2) with 0-10μM CBD for 2 hours before infecting them with SARS-CoV-2.

Analysis of the cells 48 hours later showed that CBD had potently inhibited viral replication in the cells.

Since CBD is often consumed as part of a Cannabis sativa extract, the team investigated whether other cannabinoids could also inhibit SARS-CoV-2 infection, especially those with closely related structures.

Remarkably, the only agent that potently inhibited viral replication was CBD; limited or no antiviral activity was exhibited by the other structurally similar cannabinoids tested.

Furthermore, the CBD metabolite 7-OH-CBD, the active ingredient in the CBD treatment of epilepsy, also effectively inhibited SARS-CoV-2 replication in the A549-ACE2 cells.

CBD effectively eliminated viral RNA expression

When the researchers assessed whether CBD might prevent proteolytic cleavage by Mpro or PLpro, they found CBD had no effect on the activity of either protease.

This led the team to hypothesize that CBD targets host cell processes.

Consistent with this hypothesis, RNA sequencing of infected A549-ACE2 cells treated with CBD for 24 hours revealed significant suppression of SARS-CoV-2-induced changes in gene expression.

The CBD effectively eliminated viral RNA expression, including RNA coding for the spike protein.

Both SARS-CoV-2 and CBD triggered significant changes in cellular gene expression, including the expression of several transcription factors.

Further analysis of host cell RNA showed that the virus-induced changes were almost completely reversed, but rather than the cells returning to a normal cell state, the CBD+virus-infected cells resembled those treated with CBD alone.

What about interferon signaling?

Given that infection with SARS-CoV-2 is known to suppress the interferon signaling pathway, the researchers tested whether CBD could suppress viral infection by introducing this pathway.

Some genes were induced by CBD in both the absence and presence of SARS-CoV-2, including genes that encode interferon receptors and mediators of the interferon signaling pathway.

In addition, CBD effectively reversed the viral induction of cytokines that can trigger a deadly hyperinflammatory response called the “cytokine storm” during the later stages of infection.

“Thus, CBD has the potential not only to act as an antiviral agent at early stages of infection but also to protect the host against an overactive immune system at later stages,” says Rosner and the team.

SARS-CoV-2 incidence was lower in patients who took CBD

Finally, the team assessed the incidence of SARS-CoV-2 infection among 82 patients who had been prescribed CBD prior to SARS-C0V-2 testing and matched patients who had not been prescribed CBD.

Strikingly, the incidence of SARS-CoV-2 was only 1.2% among the patients prescribed CBD, compared with 12.2% among the matched patients who had not been taking CBD.

“The substantial reduction in SARS-CoV-2 infection risk of approximately an order of magnitude in patients who took FDA-approved CBD highlights the potential efficacy of this drug in combating SARS-CoV2 infection,” says Rosner and colleagues.

“We advocate carefully designed placebo-controlled clinical trials with known concentrations and highly-characterized formulations in order to define CBD’s role in preventing and treating early SARS-CoV-2 infection,” they conclude.  

*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:
  • Rosner M, et al. Cannabidiol Inhibits SARS-CoV-2 Replication and Promotes the Host Innate Immune Response. bioRxiv, 2021. doi: https://doi.org/10.1101/2021.03.10.432967, https://www.biorxiv.org/content/10.1101/2021.03.10.432967v1

Posted in: Medical Research News | Disease/Infection News

Tags: ACE2, Angiotensin, Angiotensin-Converting Enzyme 2, Cannabidiol, Cannabinoid, Cannabis, Carcinoma, Cell, Cell Signaling, Compound, Coronavirus, Coronavirus Disease COVID-19, Cytokine, Cytokines, Efficacy, Enzyme, Epilepsy, Gene, Gene Expression, Genes, Genome, Hepatitis C, Immune Response, Immune System, Medicine, Metabolite, Pandemic, Placebo, Protein, Public Health, Receptor, Research, Respiratory, RNA, RNA Sequencing, SARS, SARS-CoV-2, Severe Acute Respiratory, Severe Acute Respiratory Syndrome, Signaling Pathway, Spike Protein, Syndrome, Transcription, Transcription Factors, Virus

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Written by

Sally Robertson

Sally first developed an interest in medical communications when she took on the role of Journal Development Editor for BioMed Central (BMC), after having graduated with a degree in biomedical science from Greenwich University.

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Push is on for states to ban organ transplant discrimination

Griffin Dalrymple is an energetic 7-year-old who loves going to school in Eureka, Montana. But two years ago, the boy described by his mother, Jayci, as a "ball of fire" was suddenly knocked back by severe bacterial pneumonia that hospitalized him for two weeks.

As her son lay in the intensive care unit with a tube in his tiny lungs, Jayci began imagining worst-case scenarios. She worried that if Griffin ended up needing a lung transplant, he might be refused because he has Down syndrome.

"It was terrifying knowing that they could deny him certain lifesaving services," she said.

Denying organ transplants to people with intellectual and neurodevelopmental disabilities like Down syndrome or autism is common in the United States, even though it is illegal under the Americans with Disabilities Act.

According to one widely cited 2008 study, 44% of organ transplant centers said they would not add a child with some level of neurodevelopmental disability to the organ transplant list. Eighty-five percent might consider the disability as a factor in deciding whether to list the person.

After Griffin recovered, Jayci brought Montana lawmakers' attention to the issue. Largely as a result of her campaigning, the state is considering a bill that would ban physicians from denying an organ transplant based solely on a patient's disability. Last month, the bill — nicknamed "Griffin's Law" — passed the Montana Senate 50-0.

Although Montana has no transplant centers of its own, advocates hope this bill and others like it will draw attention to the issue and pressure physicians to examine why they are making certain decisions. Andrés Gallegos, chairman of the National Council on Disability, said he hopes such legislation will inspire "a change of heart so people understand that they are discriminating."

If the bill passes the state House and is signed by the governor, Montana would become the 17th state to ban such discrimination. Seven other states and the federal government have similar bills pending, although some experts doubt such laws will be enforceable enough to eliminate discrimination.

With more than 100,000 people on the waiting list for organs nationwide, and average wait times extending three to five years for some organs, physicians have to frequently make heart-rending decisions about which patients are likely to benefit most.

According to a 2019 report from the NCD, many physicians and organ transplant centers worry that patients with intellectual or neurodevelopmental disabilities are more likely to have co-occurring conditions that would make a transplant dangerous, or that these patients' quality of life is unlikely to improve with a transplant. Others believe that these patients may not be able to comply with post-transplant requirements, such as taking immunosuppressive drugs.

But the report, which scoured research papers and medical reports, found that none of these concerns is universally true. Rather, disabled patients can benefit as much as any other patient, according to the NCD, an independent federal agency.

"If a determination is made to not include a person on the list only because that individual has a disability, that's blatant discrimination," said Gallegos.

Many intellectually disabled patients and their families see this firsthand. When Joe Eitl was born in 1983 with a congenital heart defect, his mother, Peg, was told that Joe would never be a candidate for a new heart because of his Down syndrome. So, when his heart failed in 2019, eight hospitals refused to even consider a transplant for Joe, who lives with his mother in Philadelphia.

Peg Eitl conceded that Joe's case was difficult, given he'd had prior reconstructive heart surgery that would complicate a transplant. She pleaded with transplant centers for more than a year and even considered suing them. Last October, Vanderbilt University agreed to perform the procedure. Joe came home Feb. 10 and is recovering.

"I think my greatest frustration was the value placed on someone with special needs," Peg Eitl said. "It pains me that they’re discounted as being less than and not as worthy."

Bioethicist David Magnus of Stanford University, who authored the 2008 study on the extent of transplant discrimination, said people like Peg Eitl shouldn't have to prove that Joe would benefit from a transplant. Because people with disabilities are a protected class in the United States, he said, "the burden is on people who want to discriminate."

But that doesn't appear to be the case in practice. In September, Magnus published a follow-up survey of more than 300 transplant programs. Of these, 71% said they would automatically disqualify an adult with an IQ under 35, which is considered severe intellectual disability, while 12% would disqualify a child at that level. Only about 20% of the institutions had formal guidelines regarding child patients.

Magnus suspects these numbers are low given that some physicians may be unwilling to admit to discrimination. He has not yet studied whether new state laws have affected physicians' likelihood to discriminate against disabled patients.

But Magnus doubts that laws like Montana's bill will be enforceable. Part of determining any patient's eligibility for a transplant, he said, is whether they or a caretaker can comply with post-transplant requirements such as remembering to take immunosuppressant drugs. If a person with a disability can't meet these criteria, that person might not be a good candidate.

"All of these are terribly difficult judgments," Magnus said.

Transplant surgeons need to maximize the limited supply of organs and ensure they survive in the patients who receive them. If they don't, "it's taking an organ from someone who could have benefited from it," said Dr. Marwan Abouljoud, president of the American Society of Transplant Surgeons.

Abouljoud said institutions have differing standards for weighing the importance of an intellectual disability in a transplant decision. Ideally, he said, the committee that determines whether to list someone for a transplant will include social workers and behavioral psychologists, as well as program leadership, who can find ways to help the person comply.

On Feb. 12, the transplant surgeons' society adopted a new statement supporting nondiscrimination and encouraging transplant centers to find ways to support these patients. "We will be urging states to adopt local policies on this," Abouljoud said.

Sam Crane, legal director at the Autistic Self Advocacy Network, which has written model legislation adopted by several states, said that some bills — including Montana's — address the concern about post-transplant care. They ban transplant centers from basing their decision solely on a person's ability to carry out post-transplant requirements and require an investigation into sources of support to help the patient comply.

But Crane said physicians could still come up with a pretext to avoid adding a disabled person to the transplant list if they believe a person without a disability would benefit more from receiving an organ.

"It's very difficult to prove discrimination in that sort of situation," she said.

Although a similar nondiscrimination bill has been introduced in the U.S. House of Representatives, Crane said advocates prefer to focus on state laws. Organizations like the autism group have taken the position that the ADA and other federal laws already prohibit this kind of discrimination, making federal legislation unnecessary. Gallegos added that states can also enact stricter requirements than the federal government and fit them to their specific medical systems.

Under state laws, patients can appeal to local courts for an emergency injunction or restraining order. These hearings can be conducted quickly, allowing a judge to decide whether to compel an institution to add a person to the transplant list.

That speed is what Jayci Dalrymple hopes Griffin's Law will achieve. "When you're needing to stop discrimination, you’re racing the clock," she said.

This article was reprinted from khn.org with permission from the Henry J. Kaiser Family Foundation. Kaiser Health News, an editorially independent news service, is a program of the Kaiser Family Foundation, a nonpartisan health care policy research organization unaffiliated with Kaiser Permanente.

Posted in: Healthcare News

Tags: Autism, Congenital Heart Defect, Disability, Down Syndrome, Drugs, Healthcare, Heart, Heart Defect, Heart Surgery, Intensive Care, Kidney, Lung Transplant, Lungs, Organ Donation, Pneumonia, Public Health, Research, Surgery, Syndrome, Transplant

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Novel host-viral-microbiome interactions during COVID-19 may determine outcome

The current pandemic of coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been spreading rapidly for over a year. Though primarily a respiratory illness, its manifestations are often protean and may be life-threatening.

A new preprint on the medRxiv* server discusses how the underlying disease mechanisms are regulated such that the local or mucosal immune response is distinct from the systemic response.

Study: Distinct systemic and mucosal immune responses to SARS-CoV-2. Image Credit: Andrii Vodolazhskyi / Shutterstock

Viral suppression of innate but not adaptive immunity

The initial infection of epithelial cells in the upper respiratory tract, via the angiotensin-converting enzyme 2 (ACE2), triggers early innate defenses that prevent replicative infection and progressive disease.

These include immune and non-immune components, such as mucus and certain chemicals produced during the course of metabolism, as well as cell signaling proteins (cytokines) and interferons that are either produced during the normal cell cycle or in response to infection.

It has been established that the virus suppresses the activation of the innate immune system, beginning with the dendritic cells that present antigens to the immune effector and antibody-producing cells. It also reduces the intensity of type I and II interferon antiviral responses. The result is the hyperactivation of inflammatory macrophages.

Adaptive immune responses play a later role. These include antibodies such as the secretory immunoglobulin (Ig) A that guards the mucosal barriers and has been detected in COVID-19 patients, within blood, saliva and nasopharyngeal samples.

Lymphocyte counts in the peripheral blood are low in COVID-19 patients, but both B and T cells show efficient and specific antiviral memory responses. This includes high numbers of plasma cells which secrete specific neutralizing antibodies to the viral spike protein.

The specific T cell responses in the blood are associated with disease severity, which is therefore not the result of defective adaptive immunity, at least in the initial stages.

Cytokine storm in severe COVID-19

The cytokine storm characterized by systemic hyperinflammation, in proportion to viral ribonucleic acid (RNA) loads in the tissues, is a notable feature of severe and critical COVID-19.

The current study sought to identify the regulatory factors in local and systemic immunity to SARS-CoV-2 infection associated with the clinical phenotype.

The researchers found that nasal and systemic immunity were very different from each other in the same individual. The chief differences involve local cytokines in the nose and the nasal microbiome.

Strong local and systemic antibody responses

Following infection, the researchers found spike-specific IgG and IgA antibodies in plasma, with the titers and probability being proportional to disease severity. Plasma neutralizing activity was also proportional to disease severity, and to the frequency of anti-spike IgA and IgG.

Total IgM, IgG and IgA levels, and IgG subclasses, were similar in patients and healthy controls.

Anti-spike IgA, and IgG, responses, were higher in nasopharyngeal secretions as well, in proportion to the severity of the disease. Notably, critical patients showed an increase in total IgA in nasal secretions.

These findings show that they are mounted against the viral spike protein in acute COVID-19.

independent regulation of mucosal and systemic immunity

Making use of paired nasopharyngeal-plasma specimens, the researchers found that almost 90% of patients seroconverted, with both IgG and IgA anti-spike antibodies.

However, much fewer showed antibodies to the spike in their nasopharyngeal secretions. Those who did show such “nasoconversion,” however, developed anti-spike IgG and IgA.

Among the group of controls and infected individuals, both plasma and nasopharynx showed spike antibodies in about 30%. About 37% showed seroconversion but not nasoconversion. The latter occurred alone in 5%, and 30% of people showed neither.

All controls were in the last category, of course. However, two moderate COVID-19 patients were also seronegative and nasonegative at this point in time.

Two critically ill patients were seronegative but strongly nasopositive. The other patients were equally split between being both seropositive and nasopositive, or seropositive without nasoconversion.

About 12% failed to seroconvert altogether.

Strangely, there was no obvious relationship between the systemic and local spike antibodies in the same individual. Plasma levels of anti-spike IgA and IgG antibody levels vs antibody titers in the nasopharynx were not correlated, neither was IgA correlated with IgG responses.

This result suggests independent regulation of mucosal and systemic immune responses to SARS-CoV-2.”

Cytokines mediate inflammation and local immunity

The study also showed that ten cytokines in plasma were significantly different in critical COVID-19 patients compared to other patients, but in the nasopharynx, 13 cytokines were differentially regulated. Only two were common between the two groups.

Some of the nasal cytokines were higher in sicker patients. Thus, even cytokines appear to be differentially regulated in SARS-CoV-2 infection depending on the compartment of infection. The secretion of interferons was not associated with antiviral antibodies.

The higher levels of certain cytokines, but not interferons, in association with anti-spike antibodies in the nasopharyngeal secretions suggest that the former are involved in inflammation, and thus in the generation of local antibodies.

Viral load and immune response

The investigators found that the viral load is higher in both the local and the systemic compartments in COVID-19 patients, but they appeared to be independent of each other.

Plasma viral loads predicted the systemic inflammatory response and higher levels of specific regulatory cytokines, but a lower interferon response. This supports earlier findings of virus-induced hyper-inflammation. They also predicted high plasma anti-spike IgA and IgG, showing that they drive spike-specific antibody responses.

Nasopharyngeal viral loads showed inverse associations with inflammatory cytokines.

Microbiome regulation of immune responses

The researchers also found that SARS-CoV-2 infection is associated with disturbances of the nasopharyngeal microbiome, and that patients with critical COVID-19 patients show dysbiosis.

Moreover, following infection with this virus, the levels of certain cytokines fell, such as IL-33, IFNγ, IFNα/β and IFNλ3. These are associated with higher counts of ‘good’ bacteria that may increase resistance to SARS-CoV-2 and increased diversity overall.

Viral load, spike antibodies, neutralizing capacity and inflammatory cytokines were found to be associated with microbial community composition and growth. Thus, bacterial communities in the nose are closely associated with local and systemic inflammatory signaling and antibody responses during COVID-19.

Critical COVID-19 patients showed, in this study, a cluster of cytokines and growth factors at high levels in their blood which do not appear to be related to antiviral mechanisms. Instead, they are possibly linked to the regulation of the nasal microbiome, such that increases in these cytokines drive down cornerstone genera like Corynebacterium and Dolosigranulum.

Conversely, the inflammatory cytokine IL-6 is associated with higher levels of the pathobiontic Staphylococcus genus.

What are the implications?

The researchers suggest that protective immunity in SARS-CoV-2 infection hinges on several important regulatory points. One is the nasal microbiome, which is disrupted in this infection and results in a decrease in some cytokines that are important in controlling the virus.

The second is the local cytokine profile in the nasal mucosa, which determines the production of local antibodies in the nasopharynx. And thirdly, some bacterial genera increase in association with higher levels of inflammation, both mucosal and systemic. These appear to be the result of specific cytokine release patterns and are associated with poor outcomes.

This indicates the need to understand, through future studies, how the nasal microbiome is involved in the local and systemic reactions to the infection. Some researchers have shown a possible link between microbiota in the nose and the baseline production of type I and type III interferons.

Such individual differences in the amount of interferon secreted by the nasal bacteria could explain, in part, why different individuals respond so differently to the virus.

The range of mucosal immune responses (or the absence thereof) may also determine novel therapeutic modalities to enhance individual protection against the virus by increasing specific IgA production. Especially important may be the cytokine CCL2 and type I interferon.

The presence of SARS-CoV-2 infection could cause epithelial barrier breakdown and perturbations of nasal flora. These changes may, in turn, allow nasal pathobionts to enter the body, triggering systemic inflammation. A similar cycle has been reported to occur in the gut.

As a result, these patients may have a higher risk of severe COVID-19 disease. “Our study identifies novel host-viral-microbiome interactions during infection with SARS-CoV-2 which may help new strategies for identifying at risk individuals.”

*Important Notice

medRxiv 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:
  • Smith, N. et al. (2021). Distinct systemic and mucosal immune responses to SARS-CoV-2. medRxiv preprint. doi: https://doi.org/10.1101/2021.03.01.21251633, https://www.medrxiv.org/content/10.1101/2021.03.01.21251633v1

Posted in: Medical Science News | Medical Research News | Miscellaneous News | Disease/Infection News | Healthcare News

Tags: ACE2, Angiotensin, Angiotensin-Converting Enzyme 2, Antibodies, Antibody, Bacteria, Blood, Cell, Cell Cycle, Cell Signaling, Coronavirus, Coronavirus Disease COVID-19, Cytokine, Cytokines, Dysbiosis, Enzyme, Frequency, Immune Response, Immune System, Immunoglobulin, Inflammation, Lymphocyte, Metabolism, Microbiome, Pandemic, Phenotype, Protein, Respiratory, Respiratory Illness, Ribonucleic Acid, RNA, SARS, SARS-CoV-2, Severe Acute Respiratory, Severe Acute Respiratory Syndrome, Spike Protein, Syndrome, Virus

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Written by

Dr. Liji Thomas

Dr. Liji Thomas is an OB-GYN, who graduated from the Government Medical College, University of Calicut, Kerala, in 2001. Liji practiced as a full-time consultant in obstetrics/gynecology in a private hospital for a few years following her graduation. She has counseled hundreds of patients facing issues from pregnancy-related problems and infertility, and has been in charge of over 2,000 deliveries, striving always to achieve a normal delivery rather than operative.

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Comparative analysis of SARS-CoV-2 antivirals leads to new potential treatment for COVID-19

A rapid spread of the virus that caused symptoms similar to severe pneumonia was first reported in Wuhan, China, in December 2019. Scientists found that this novel virus belonged to the family Coronaviridae and was later named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Worldwide, researchers are developing various vaccines, medicines, facemasks, and many other means to contain the SARS-CoV-2 infection.

Among various antiviral drugs, remdesivir has been approved for the treatment of coronavirus disease 2019 (COVID-19), caused by SARS-CoV-2 infection. Remdesivir is a nucleoside analog that inhibits the SARS-CoV-2 RNA-dependent RNA-polymerase (RdRp). It is a virus polymerase inhibitor that involves the termination of both the viral transcript and newly synthesized viral genomes. However, there are some limitations that have escalated the need to develop other potential antiviral drugs that have minimal side effects and maximum efficacy.

Study: A comparative analysis of SARS-CoV-2 antivirals characterizes 3CLpro inhibitor PF-00835231 as a potential new treatment for COVID-19. Image Credit: Ekaterina Bondaretc / Shutterstock

Researchers have discovered an alternate target site of SARS-CoV-2: the 3CLpro (Mpro), main protease. This protease plays a key role in the life cycle of the virus. After the virus enters into the host cell, the positive-stranded RNA genome of the virus gets rapidly translated into two polyproteins. These polyproteins are processed into functional protein by PL2 pro and 3CLpro viral protease. Two of the main functions of 3CLpro are governing proper assembly and folding of polymerase subunits required to develop into a properly functional polymerase complex. Thereby, inhibition of 3CLpro would effectively stop the viral life cycle. Further, the unique substrate preference of 3CLpro also makes it an effective target site.

To date, PF -07304814 is the only 3CLpro inhibitor that has reached the clinical trials. It is a ketone-based covalent cysteine protease inhibitor administered as a phosphate prodrug, thereby converting to its active form, PF-90 00835231. In 2003, PF-00835231 was developed in response to the previous coronavirus epidemic as an inhibitor for the 3CLpro. However, due to the rapid decline in the infection rate, it was not brought to clinical trials, and further study about its efficacy was stopped.

Scientists believe that PF-00835231 would be effective against the novel SARS-CoV-2. This is because of a 96% similarity at the amino acid level and 100% similarity within the catalytic pocket of the 3CLpro present in both SARS-CoV and SARS-CoV-2. A recent study demonstrated the effectiveness of PF-00835231 at high micromolar levels.

In a forthcoming paper in the Journal of Virology, scientists compared the in vitro efficacy and cytotoxicity profiles of PF-00835231 and remdesivir in two human model systems for SARS-CoV-2 infection; namely, A549+ACE2 cells and polarized human airway epithelial cultures. After the initial characterization of A549+ACE2 cells to study SARS-CoV-2, an in vitro study was carried out to evaluate the efficacy and cytotoxicity of PF-00835231, GC-376 (protease inhibitor at the preclinical stage), and remdesivir in A549+ACE2 cells.

The team also conducted time-of-drug-addition assays in A549+ACE2 cells to define and compare the action time of the antiviral drugs within the SARS-CoV-2 life cycle. The role of efflux transporter Multi-Drug Resistance Protein 1 (MDR1) on the antiviral efficacy of PF-00835231 was also studied. The main focus of the study was to provide in vitro evidence of the potential PF-00835231 as an effective antiviral drug for SARS-CoV-2 and also highlight its negative effects based on prior studies.

This research has shown that both PF-00835231 and remdesivir are similarly potent in studying a model of polarized human airway epithelial cultures (HAEC). However, in A549+ACE2 cell assay, PF-00835231 revealed better activity than the preclinical GC-376 and similar or marginally effect as remdesivir.

The optimal time to start antiviral drug treatment is the first week after the onset of symptoms, i.e. when the virus replication is actively ongoing. In the case of patients who are severely affected by COVID-19, the active replication of SARS-CoV-2 can be prolonged. This study revealed that intravenous treatment of PF-00835231 would remain effective for severely infected patients. Intravenous remdesivir treatment was also found to be effective against SARS-CoV-2.

Cell composition of polarized human airway epithelial cultures (HAEC), and cytotoxicity of PF-00835231 and remdesivir. a. Schematic representation of a transwell containing a polarized HAEC in air-liquid interface. Dark blue, cycling basal cells; light blue, basal cells; red, suprabasal cells; purple, secretory cells; yellow, microfold cells; green, ciliated cells; grey, mucus. To test for cytotoxicity, drugs were added to the media in the basolateral chamber. b. Clustered UMAP of single cells determined by single-cell RNA sequencing from n=3 uninfected HAEC. Clusters were determined by markers from the literature(37, 38) and by differentially expressed marker genes for each cluster determined by Wilcox test. c., d. Representative cross-sections of uninfected HAEC, 72 h post treatment with 10 µM PF-00835231 or 10 µM remdesivir. H&E (c.) or PAS-Alcian blue staining (d.). e. Trans-epithelial resistance (TEER) in drug1205 treated, uninfected HAEC over time as a measure of epithelial integrity. Means ? SEM from n=3 independent experiments. f. CellTiter-glo assay on undifferentiated, basal-like Bci-NS1.1 precursor cells. Means ? SEM from n=3 independent experiments.

The current research has also demonstrated a significant synergistic effect between PF-00835231 and remdesivir in inhibiting SARS-CoV-2. Researchers believe that the use of multiple antiviral drugs with different modes of action or target sites would efficiently circumvent cross-resistance caused by mutations. Hence, the development of antiviral treatments using multiple antiviral drugs would significantly improve antiviral therapy in COVID -19.

To summarize, the team's research reveals the significance of the novel antiviral drug, PF–00835231, against SARS-CoV-2 with the help of 3D in vitro models of human airway epithelium. This would help to decrease the mortality rate of COVID-19 and also pave the way to explore new treatment methods for other harmful viruses.

Journal reference:
  • Maren de Vries, Adil S. Mohamed, Rachel A. Prescott, Ana M. Valero Jimenez, Ludovic Desvignes, Rebecca O'Connor, Claire Steppan, Joseph C. Devlin, Ellie Ivanova, Alberto Herrera, Austin Schinlever, Paige Loose, Kelly Ruggles, Sergei B. Koralov, Annaliesa S. Anderson, Joseph Binder, Meike Dittmann. A comparative analysis of SARS-CoV-2 antivirals characterizes 3CLpro inhibitor PF-00835231 as a potential new treatment for COVID-19, Journal of Virology Feb 2021, JVI.01819-20; DOI: 10.1128/JVI.01819-20 https://jvi.asm.org/content/early/2021/02/19/JVI.01819-20

Posted in: Medical Science News | Medical Research News | Disease/Infection News | Healthcare News | Pharmaceutical News

Tags: ACE2, Amino Acid, Antiviral Drug, Assay, Cell, Coronavirus, Coronavirus Disease COVID-19, Cysteine, Cytotoxicity, Drug Repurposing, Drugs, Efficacy, Genome, in vitro, Mortality, Nucleoside, Pneumonia, Polymerase, Preclinical, Protein, Remdesivir, Research, Respiratory, RNA, SARS, SARS-CoV-2, Severe Acute Respiratory, Severe Acute Respiratory Syndrome, Syndrome, Virology, Virus

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Dr. Priyom Bose

Priyom holds a Ph.D. in Plant Biology and Biotechnology from the University of Madras, India. She is an active researcher and an experienced science writer. Priyom has also co-authored several original research articles that have been published in reputed peer-reviewed journals. She is also an avid reader and an amateur photographer.

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